Propofol Promotes Anesthesia Through the Activation of Centrally-Projecting Edinger-Westphal Nucleus Urocortin 1-Positive Neurons.

Propofol Promotes Anesthesia Through the Activation of Centrally-Projecting Edinger–Westphal Nucleus Urocortin 1-Positive Neurons - PMC Skip to main content An official website of the United States government Here's how you know Here's how you know Search Log in Primary site navigation Search Log in Search PMC Full-Text Archive Search in PMC Journal List User Guide As a library, NLM provides access to scientific literature. Inclusion in an NLM database does not imply endorsement of, or agreement with, the contents by NLM or the National Institutes of Health. Learn more: PMC Disclaimer | PMC Copyright Notice letter Neurosci Bull . 2025 Apr 24;41(6):1109–1114. doi: 10.1007/s12264-025-01401-8 Propofol Promotes Anesthesia Through the Activation of Centrally-Projecting Edinger–Westphal Nucleus Urocortin 1-Positive Neurons Jing Huang 1, # , Yiwen Hu 1, # , Sheng Jing 1 , Fuhai Bai 1 , Zonghong Long 1 , Zhuoxi Wu 1 , Liang Fang 1 , Lei Cao 1 , Youliang Deng 1 , Xiaohang Bao 1, ✉ , Hong Li 1, ✉ Author information Article notes Copyright and License information 1 Department of Anesthesiology, Second Affiliated Hospital, Army Medical University, Chongqing, 400037 China ✉ Corresponding author. # Contributed equally. Received 2024 Oct 9; Accepted 2025 Feb 21; Collection date 2025 Jun. © Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences 2025 PMC Copyright notice PMCID: PMC12158893  PMID: 40272724 Dear Editor, General anesthetics play a pivotal role in inducing a safe and reversible loss of consciousness in patients, the importance of which cannot be overstated [ 1 ]. Among the intravenous anesthetics, propofol stands out for its rapid onset and swift systemic clearance, effectively eliminating the prolonged sedation associated with earlier agents [ 2 ]. Extensive research has shown that propofol exerts its anesthetic effects primarily by acting on γ-aminobutyric acid A receptors (GABA A Rs), thereby disrupting connections between cortical regions and leading to the inhibition of the cortex, thalamus, and reticular formation [ 1 , 2 ]. The emerging perspective posits that propofol may exert its anesthetic effects by inhibiting wake-promoting neural circuits and/or by activating sleep-promoting neural circuits [ 3 ]. Although the inhibitory effects of propofol on the brain have been extensively investigated, its activating effects are currently poorly documented. Some studies have provided preliminary evidence of the activating effects of propofol, such as that it can activate the sleep-promoting neurons in the supraoptic nucleus (SON), mediating the onset and maintenance of anesthesia [ 4 ]. The norepinephrine-negative neurons in the classical sleep center in the ventrolateral preoptic nucleus (VLPO) can be activated by propofol to facilitate anesthesia [ 5 ]. In addition, the glutamatergic neurons in the lateral habenula (LHb) are also considered to be activated by propofol and mediate the induction of anesthesia through the activation of downstream GABAergic and peptidergic circuits [ 6 ]. However, it is not yet fully clear which neurons are activated by propofol, and whether these propofol-activated neurons are involved in the induction of anesthesia. In this study, we utilized whole-brain c-fos immunofluorescence to delineate the neural substrates activated during propofol anesthesia. The Edinger–Westphal (EW) nucleus, located in the midbrain, which is activated following propofol anesthesia, has drawn our attention. The EW nucleus is divided into the preganglionic EW (EWpg) and the centrally-projecting EW (EWcp). Previous studies have identified the EWpg as a component of the oculomotor nuclear complex, which governs the ciliary reflex [ 7 , 8 ]. It is worth noting that the EWcp plays a multifaceted role, being closely associated with addiction, attention, maternal preparatory nesting, stress responses, and energy homeostasis [ 7 – 15 ]. However, activation of the EWcp during propofol anesthesia has not been reported, and its exact role in propofol-induced anesthesia remains unclear. The EWcp harbors a variety of neuronal types, including Urocortin 1 positive (Ucn1 + ), glutamatergic, and dopaminergic neurons [ 8 , 16 ]. A previous study by our group has shown that Ucn1 + /cocaine- and amphetamine-regulated transcript-positive (CART + ) neurons in the EWcp are involved in the induction of sleep and sevoflurane general anesthesia [ 17 ]. However, the neural mechanisms underlying inhalation and intravenous anesthetics are not entirely congruent, and it remains unclear whether this population of neurons participates in propofol-mediated anesthesia. Firstly, to determine which neural substrates are activated by propofol, we administered propofol intraperitoneally (i.p.) to C57/BL6J mice (180 mg/kg) and applied immunofluorescent staining for c-fos labeling after 2 h of propofol anesthesia (Fig. 1 A). We found a significant increase in c-fos expression within the VLPO, the oval nucleus of the bed nuclei of the stria terminalis, paraventricular hypothalamic nucleus, SON, central amygdala, LHb, and ventrolateral periaqueductal gray (Fig. 1 B, C), along with a notable decrease in c-fos expression in the tuberomammillary nucleus (Fig .1 B, C), in alignment with the findings reported in previous studies [ 6 , 18 ]. Encouragingly, we found that the EWcp also exhibited a significant increase in c-fos expression following 2 h of propofol anesthesia (Fig. 1 B, C). Subsequently, we applied statistical analyses across the anterior, middle, and posterior sections of the EWcp (Bregma − 2.96 mm, − 3.64 mm, and − 4.04 mm, respectively), revealing a pronounced upregulation of c-fos expression in all sections after propofol anesthesia (Fig. S1 ). Notably, the middle section displayed a slightly higher expression, with the anterior and posterior sections showing slightly lower levels, which may be correlated with the neuronal density distribution in the EWcp (Fig. S1 ). These results suggest that EWcp neurons may be activated by propofol during anesthesia, although undoubtedly, more direct evidence is required to confirm this hypothesis. Fig 1. Open in a new tab Propofol induces neuronal activation in the EWcp region. A Schematic of the propofol-induced general anesthesia process; left, the control group; right, the propofol anesthesia group. B C-fos expression across various brain regions during propofol-induced general anesthesia; white dashed lines, target brain region. BF, basal forebrain; VLPO, ventrolateral preoptic nucleus, scale bars, 200 μm; ovBNST, oval nucleus of the bed nuclei of the stria terminalis, scale bars, 100 μm; SON, supraoptic nucleus; PVH, paraventricular hypothalamic nucleus, scale bars 200 μm; PVT, paraventricular thalamus; LHb, lateral habenula, scale bars, 100 μm; CeA, central amygdalar nucleus, scale bar, 100 μm; TMN: tuberomammillary nucleus, scale bar, 100 μm; EWcp, centrally projecting Edinger–Westphal nucleus, scale bar 100 μm; DR, dorsal raphe; vlPAG, ventrolateral periaqueductal gray, scale bars, 200 μm. C Counts of c-fos-positive cells across brain regions ( n = 6 mice, Student’s t test, BF: t 10 = −0.901, P = 0.389; VLPO: t 10 = −2.401, * P = 0.0372; ovBNST: t 10 = −4.748, *** P < 0.001; PVH: t 10 = −5.260, *** P < 0.001; SON: t 10 = −6.694, *** P < 0.001; CeA: t 10 = −5.217, *** P < 0.001; PVT: t 10 = −1.265, P = 0.235; LHb: t 10 = −18.562, *** P < 0.001; TMN: t 10 = 2.253, * P = 0.0479; EWcp: t 10 = −8.765, *** P < 0.001; DR: t 10 = −0.679, P = 0.512; vlPAG: t 10 = −2.316, * P = 0.0430). D Representative image of a recording site in the EWcp region; scale bar, 0.1 mm; red arrow, glass electrode tip. E Patch-clamp recording sites, depicting responsive (blue) and non-responsive (gray) cells. F Distribution of propofol-responsive and unresponsive neurons in the EWcp. G , H Whole-cell patch-clamp recordings of EWcp neurons treated with varying concentrations of propofol, highlighting the dose-dependence of propofol-induced inward currents (10 μmol/L: n = 8 cells from 4 mice, 100 μmol/L: n = 10 cells from 4 mice, 1000 μmol/L: n = 12 cells from 5 mice; one-way ANOVA, F = 61.5, *** P < 0.001, 1 mmol/L vs 10 μmol/L: t = 10.541, *** P < 0.001; 1 mmol/L vs 100 μmol/L: t = 7.613, *** P < 0.001; 100 μmol/L vs 10 μmol/L: t = 3.272, ** P = 0.003). I , J Bath’s application of propofol increases the firing rate of EWcp neurons (paired t -test, t 7 = −2.584, * P = 0.0362). To further test whether EWcp neurons can be activated by propofol, we conducted in vitro patch-clamp experiments on EWcp neurons perfused with varying concentrations of propofol (Fig. 1 D). We found that the majority of EWcp neurons were activated by propofol (91.9%), while a small portion showed no response to propofol perfusion (9.1%) (Fig. 1 E, F). Using a voltage clamp, perfusion with 10 μmol/L, 100 μmol/L, and 1 mM propofol resulted in a dose-dependent increase in excitatory inward currents (Fig. 1 G, H). In the current clamp, perfusion with 100 μmol/L propofol led to a significant increase in spontaneous firing of EWcp neurons (Fig. 1 I, J). Subsequently, to verify the brain region-specific activation of EWcp neurons by propofol, we conducted in vitro patch-clamp experiments on the para-EWcp, the region adjacent to the EWcp (Fig. S2A). We found that 3/4 of the neurons in the para-EWcp were inhibited by propofol, while the remaining 1/4 showed no response to propofol perfusion (Fig. S2B, C). Under voltage-clamp, perfusion with 100 μmol/L propofol resulted in inhibitory outward currents or no response in para-EWcp neurons (Fig. S2D, E). In the current clamp, perfusion with 100 μmol/L propofol led to a significant reduction in the spontaneous firing of para-EWcp neurons (Fig. S2F, G). These results indicated that EWcp neurons are activated in a propofol dose-dependent manner with regional specificity. To investigate how propofol-activated EWcp neurons contribute to the propofol anesthetic process, we utilized the fos-TRAP method to specifically label the propofol-activated EWcp neurons and subjected them to chemogenetic inhibition. Initially, we injected AAV2/9-hSyn-DIO-hM4D(Gi)-mCherry into the EWcp of Fos 2A−iCreERT2 mice. One week after the viral injection, a consecutive five-day treatment of tamoxifen was administered via i.p. injection. Subsequently, the mice were exposed to propofol anesthesia for 2 h to label the propofol-activated EWcp neurons with hM4D-mCherry (Fig. 2 A, B). To validate the efficacy of the fos-TRAP method, 4 weeks after the viral injection, mice were administered either clozapine N-oxide (CNO) or saline via i.p. injection. Half an hour later, the mice were subjected to propofol anesthesia for an additional 2 h, followed by perfusion and sectioning for fos immunofluorescent staining. We found that the number of c-fos-positive cells in the EWcp of the CNO group was markedly lower than in the control group (~ 90%), showing that the fos-TRAP method can effectively inhibit propofol-activated EWcp neurons (Fig. 2 C). Following the chemogenetic inhibition of propofol-activated EWcp neurons, we found a significant reduction in both the total duration of propofol anesthesia and the time spent in deep anesthesia, as well as a marked decrease in the duration of loss of the righting reflex (Fig. 2 D, E). These findings suggest that propofol-activated EWcp neurons are involved in the propofol anesthesia process. Fig. 2. Open in a new tab Propofol-activated Ucn1 + EWcp neurons participate in propofol anesthesia. A Schematic of TRAP technology for the specific chemogenetic inhibition of propofol-activated neurons. B Chemogenetic inhibition of virus injection. Left, schematic and right, a representative image of the injection site. Scale bars, 200 μm and 100 μm (insert). C Representative immunofluorescence images (left) and statistical analysis (right) of TRAP-captured propofol-activated neurons (red) and c-fos + neurons (green) induced by re-exposure to propofol ( n = 6 sections from 3 mice, t 10 = 15.627, *** P < 0.001, Student’s t -test). D Representative EEG/EMG recordings of chemogenetic inhibition of propofol-activated neurons in propofol-induced anesthesia. Blue boxes, total anesthesia times; green dashed lines, duration of deep anesthesia. E Left, total anesthesia time with propofol exposure after intraperitoneal injection of saline or CNO ( n = 11, Wilcoxon signed rank test, Z = −2.138, * P = 0.032). Middle, duration of deep anesthesia with propofol exposure after intraperitoneal injection of saline or CNO ( n = 11, paired t-test, t 10 = 2.299, * P = 0.0443). Right, duration of loss of righting reflex with propofol exposure after intraperitoneal injection of saline or CNO ( n = 11, paired t-test, t 10 = 2.642, * P = 0.0247). F Representative images of two-color in situ hybridization between c-fos (red) and Slc17a6 (green) at the anterior (upper, Bregma − 2.96 mm), middle (middle, Bregma − 3.64 mm), and caudal (lower, Bregma − 4.04 mm) layers of the EWcp. Scale bars, 100 μm. G Representative images of two-color in situ hybridization between c-fos (red) and Ucn1 (green) at the anterior (upper, Bregma − 2.96 mm), middle (middle, Bregma − 3.64 mm), and caudal (bottom, Bregma − 4.04 mm) layers of the EWcp. Scale bars, 100 μm. Insert images represent the enlarged EWcp area, Scale bar: 50 μm. H Neuronal overlay statistics of the EWcp. Note that c-fos -labeled propofol-activated neurons are not overlaid with Slc17a6 -positive neurons. n = 3 mice. I Neuronal overlay statistics of the EWcp. Note that c-fos -labeled propofol-activated neurons are overwhelmingly overlaid with Ucn1 + neurons. n = 3 mice. J Propofol-activated EWcp neurons are Ucn1 + neurons. Left panel, cell membrane current after propofol administration; dashed line, recorded cell. Right panel, immunofluorescence image of electrophysiologically recorded cells co-labeled with Ucn1 (arrows indicate fluorescent dye-positive). K The proportion of Ucn1 + neurons among propofol-activated EWcp neurons. Orange, Ucn1 + neurons; gray, Ucn1 − neurons. L EWcp neurons unresponsive to propofol are Ucn1 − neurons. Left panel, membrane current after propofol administration; dashed line, recorded cell. Right panel, immunofluorescence image of the electrophysiologically recorded cells without co-labeling with Ucn1 (arrows indicate fluorescent dye-positive). M The proportion of Ucn1 − neurons among EWcp neurons unresponsive to propofol; gray, Ucn1 − neurons. The EWcp is composed of a diverse array of neuronal types, including glutamatergic, Ucn1 + , CART + , and cholecystokinin neurons [ 8 ]. To delineate the identity of propofol-activated EWcp neurons, we applied two-color fluorescence in situ hybridization experiments following 2 h of propofol anesthesia, aiming to co-label c-fos and various neuronal markers. Previous research has indicated that glutamatergic neurons in the PIII region (which includes the EWcp) promote sleep [ 19 ]. Therefore, we utilized the fluorescent probe Slc17a6 , which targets glutamate neurons, for co-labeling with c-fos after 2 h of propofol exposure. Our findings revealed that propofol-activated neurons seldom exhibited co-labeling with the glutamatergic marker Slc17a6 (Fig. 2 F, H). This suggests that the propofol-activated neurons are not the same group of glutamatergic sleep-promoting neurons in the PIII region. Subsequently, we determined whether the propofol-activated neurons corresponded to those sleep-promoting Ucn1 + /CART + neurons previously reported to be activated by sevoflurane anesthesia [ 17 ]. Encouragingly, we found that propofol-activated c-fos + neurons were highly co-labeled with Ucn1 across the anterior (Bregma − 2.96 mm), middle (Bregma − 3.64 mm), and caudal (Bregma − 4.04 mm) sections (Fig. 2 G, I). Finally, we further tested whether the propofol-activated neurons in the EWcp were Ucn1 + neurons by combining patch-clamp with fluorescent dye injection, based on previously established methods [ 20 ]. We found that 87.5% of the neurons activated by propofol in the EWcp were Ucn1 + neurons (Fig. 2 J, K), whereas all the neurons unresponsive to propofol in the EWcp were Ucn1 − neurons (Fig. 2 L, M). Together, these data suggest that the propofol-activated neurons are not glutamatergic but instead a distinct group of Ucn1 + peptidergic neurons. In the present study, we elucidated that Ucn1 + neurons in the EWcp can be specifically activated by propofol, and inhibiting propofol-activated EWcp neurons attenuates the anesthetic action of propofol. These findings offer a novel target for understanding the neural mechanisms underlying propofol anesthesia. Over the past few decades, it has been widely believed that nearly all general anesthetics, including propofol, exert their effects by inducing a broad inhibitory action on cortical regions and subcortical arousal nuclei [ 1 ]. Recent studies have begun to focus on the activating effects of general anesthetics that contribute to anesthesia, such as the activation of the SON, LHb, and VLPO [ 4 , 6 , 21 ]. These studies primarily focus on reporting the hypothalamic and thalamic nuclei activated by propofol. This study is the first to propose that EWcp Ucn1 + peptidergic neurons in the midbrain are involved in propofol anesthesia. The EWcp includes various types of neurons such as glutamatergic, peptidergic, and cholinergic neurons [ 8 ]. Behavioral evidence suggests that Ucn1 + EWcp neurons are associated with addiction, attention, maternal preparatory nesting, stress responses, and energy homeostasis [ 7 – 15 ], but the physiological processes involved in their activation are not yet fully understood. This study elucidates that propofol-activated EWcp Ucn1 + neurons participate in propofol anesthesia, aligning with our previous findings that these neurons do not colocalize with PIII glutamatergic neurons and are distinct from the PIII glutamatergic sleep-promoting neurons [ 17 , 19 ]. Interestingly, this group of anesthetic-activated EWcp Ucn1 + neurons has been demonstrated to also have sleep-promoting effects, indicating that they possess dual characteristics, promoting both anesthesia and sleep. In terms of neuronal distribution, Ucn1 + neurons are concentrated in the EWcp area, while glutamatergic neurons are more widely distributed (including the EWpg and the entire PIII area) and are less dense in the EWcp and cannot be activated by anesthetics. Therefore, we believe that PIII glutamatergic neurons are monofunctional sleep-promoting neurons and do not promote anesthesia. Furthermore, the activation of EWcp Ucn1 + neurons can lead to a decrease in body temperature, which is also a significant manifestation during general anesthesia [ 22 ]. EWcp Ucn1 + neurons have also been reported to be activated by general anesthetics such as dexmedetomidine and midazolam [ 17 ], suggesting that this group of neurons may represent a common target for the actions of various general anesthetics. Currently, it is believed that propofol’s classical target is the GABA A receptor [ 1 , 2 ], with evidence suggesting that propofol can mediate the disinhibition of VLPO neurons by modulating GABAergic transmission to induce general anesthesia [ 5 ]. Interestingly, EWcp Ucn1 + neurons are innervated by a significant number of GABAergic terminals [ 23 ], but whether propofol induces disinhibition (activation) of EWcp neurons through modulation of GABAergic transmission requires further direct evidence. The specific receptor and ion channel mechanisms by which propofol activates EWcp neurons also need to be further elucidated. Our results also indicate that not all EWcp Ucn1 + neurons can be activated by propofol (Fig. 2 G, I, J–M). Previous research suggests that EWcp neurons have different firing characteristics [ 24 ], indicating that there are different functional subpopulations in the EWcp that require further clarification. In addition, a recent study has suggested that EWpg neurons are involved in the suppression of pupillary unrest by general anesthesia and propofol sedation [ 25 ]. From our results, it can be concluded that although c-fos + neurons activated by propofol are predominantly expressed in the EWcp, there is also scattered expression in the EWpg (Fig. 1 B). This suggests that neurons activated by propofol anesthesia may also play an important role in the EWpg, and this requires more supporting evidence. In summary, our research has elucidated that propofol specifically activates Ucn1 + neurons in the EWcp, and inhibition of propofol-activated EWcp neurons significantly attenuates the anesthetic effect of propofol. While the specific receptor and molecular mechanisms of how propofol activates EWcp neurons require further investigation, these findings offer a novel target for understanding the neural mechanisms underlying propofol anesthesia. Supplementary Information Below is the link to the electronic supplementary material. Supplementary file1 (PDF 531 KB) (530.7KB, pdf) Acknowledgments Thanks are due to Zhian Hu, Chao He, and Kuikui Fan for assistance with the experiments and valuable discussion, and Rongrong Li for critical comments on the manuscript. This work was supported by grants from the National Natural Science Foundation of China (82101273) and the Second Affiliated Hospital of the Army Medical University Incubation Program for Young Doctoral Talents (2023YQB007). Conflict of interest The authors claim that there are no conflicts of interest. Footnotes Jing Huang and Yiwen Hu have contributed equally to this work. Contributor Information Xiaohang Bao, Email: anestmmu@163.com. Hong Li, Email: lh78553@tmmu.edu.cn. References 1. Franks NP. General anaesthesia: from molecular targets to neuronal pathways of sleep and arousal. Nat Rev Neurosci 2008, 9: 370–386. [ DOI ] [ PubMed ] [ Google Scholar ] 2. Walsh CT. 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