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Aims General anesthesia has been widely applied in surgical or nonsurgical medical procedures, but the mechanism behind remains elusive. Because of shared neural circuits of sleep and anesthesia, whether serotonergic system, which is highly implicated in modulation of sleep and wakefulness, regulates general anesthesia as well is worth investigating. Methods Immunostaining and fiber photometry were used to assess the neuronal activities. Electroencephalography spectra and burst‐suppression ratio (BSR) were used to measure anesthetic depth and loss or recovery of righting reflex to indicate the induction or emergence time of general anesthesia. Regulation of serotonergic system was achieved through optogenetic, chemogenetic, or pharmacological methods. Results We found that both Fos expression and calcium activity were significantly decreased during general anesthesia. Activation of 5‐HT neurons in the dorsal raphe nucleus (DRN) decreased the depth of anesthesia and facilitated the emergence from anesthesia, and inhibition deepened the anesthesia and prolonged the emergence time. Furthermore, agonism or antagonism of 5‐HT 1A or 2C receptors mimicked the effect of manipulating DRN serotonergic neurons. Conclusion Our results demonstrate that 5‐HT neurons in the DRN play a regulative role of general anesthesia, and activation of serotonergic neurons could facilitate emergence from general anesthesia partly through 5‐HT 1A and 2C receptors., General anesthesia decreases the activities of serotonergic neurons in the dorsal raphe. Activation of DRN 5‐HT neurons reduced the depth of anesthesia and accelerated the emergence from general anesthesia, partially through the 5‐HT 1A and 2C receptors.

Background The neuropeptide orexin promotes arousal from general anaesthesia, however the neuronal circuits that mediate this effect have not been defined. We investigated whether orexinergic neurones modulate the basal forebrain (BF) and locus coeruleus (LC) in emergence from anaesthesia. Methods Hcrtcre rats were generated using a CRISPR/Cas9-based approach. Viruses encoding optogenetic probes were injected into the perifornical lateral hypothalamic (PeFLH) area, optogenetic fibres were embedded in the PeFLH, BF, or LC, and changes in anaesthesia state under 1.4 vol% or 0.8 vol% isoflurane were determined. Results In the PeFLH, 98.8% (0.4%) of orexin-A-positive cells expressed tdTomato, and 91.9% (2.2%) of tdTomato cells were orexin-A-positive. Under 1.4 vol% isoflurane anaesthesia, compared with control groups, burst suppression ratio was less, and emergence time was shorter in groups with optogenetic activation of orexinergic cell bodies in the PeFLH (923 [162] vs 493 [68] s, P=0.0003) or orexinergic terminals in the BF (937 (122) vs 674 (108) s, P=0.0049) or LC (913 [128] vs 742 [76] s, P=0.022). Optical stimulation of orexinergic terminals in the BF and LC also improved the movement scores of rats under 0.8 vol% isoflurane anaesthesia. Conclusions Activation of orexinergic terminals in the FB or LC mediates facilitation of emergence from anaesthesia by orexinergic neurones during isoflurane anaesthesia.

Background Previous clinical studies have shown that emergence from isoflurane anaesthesia takes longer in elderly patients compared with middle-aged patients. The current study investigated whether delayed emergence from anaesthesia in older age is associated with the age-related decrease in orexin receptors by using a rat model. Methods Adult and aged Sprague–Dawley rats were used to assess the time to emergence after 30 min isoflurane anaesthesia (1.4 vol%), and differences in the orexinergic systems, including the number of orexinergic neurones, plasma orexin concentrations, and expression of orexin-1 (OX1R) and orexin-2 receptors, compared using immunofluorescence, radioimmunoassay, western blot, and real-time polymerase chain reaction. The effects of OX1R expression on emergence time were determined by virus-mediated overexpression of OX1R using intra-cerebroventricular injection. Results The median (range) emergence time of aged rats was longer than that in adult rats [1082 (1010–1130) compared with 848 (829–938) s; P=0.0009]. Plasma orexin concentrations were higher in the aged group than the adult group [34 (33–37) and 25 (22–31) pg ml−1, respectively; P=0.04], but the number of orexinergic neurones was similar in both groups. Protein expression of OX1R was lower in the aged group compared with the adult group [0.47 (0.35–0.58) compared with 0.97 (0.86–1.32), respectively; P=0.002]. Overexpression of OX1R significantly shortened the emergence time in aged rats from [1120 (1040–1190) s] to [769 (576–928) s; P=0.03]. Conclusions Age-related decrease in OX1R expression is associated with delayed emergence from isoflurane anaesthesia in aged rats.

Caloric restriction (CR) has been shown to have several health benefits and provides protection against type 2 diabetes, neurodegenerative and cerebral vascular diseases. It reduces the brain infarct size and promotes neurological functional recovery after cerebral ischemia. Sirtuin 1 (SIRT1) plays an important role in the biological effects induced by CR. This study investigated the role of SIRT1 in ischemic tolerance in the brain induced by CR. Sprague drawly rats were divided into two groups based on food intake. Ad libitum (AL) group was fed with normal diet while the CR group received 60% calories compared to AL. All animals were subjected to a middle cerebral artery occlusion for 90 min. Results showed the neurological function score of CR group was higher and the brain infarct volume was markedly reduced in CR group compared to AL group at 24 h after reperfusion (p

Preconditioning with volatile anesthetics can create an ischemia tolerance against cerebral ischemia-reperfusion injury. We investigated whether ubiquitin conjugase 9 (Ubc9), the E2 conjugase for SUMOylation, is associated with neuroprotection induced by isoflurane preconditioning (IsoPC). In vitro, Ubc9 protein expression was evaluated at 4 and 24 h after reoxygenation. The role of Ubc9 in the neuroprotective effect was assessed in the presence or absence of Ubc9 small interfering RNA (siRNA). In vivo, rats were preconditionally exposed for 1 h to 2 % isoflurane for five consecutive days followed by middle cerebral artery occlusion. Neurobehavioral scores and infarction volume were determined at different times after reperfusion. The role of Ubc9 in ischemic tolerance was evaluated by intracerebroventricular microinjection with the Ubc9 siRNA. We showed that isoflurane preconditioning improved the cell viability of the SH-SY5Y cells that were challenged by oxygen-glucose deprivation. It also reduced brain infarct volumes and improved neurologic outcomes in the focal cerebral ischemic rat. The expression of Ubc9 was upregulated by isoflurane preconditioning. Knockdown of Ubc9 significantly attenuated the isoflurane preconditioning-induced neuroprotective effects. Isoflurane preconditioning-induced neuroprotection against ischemic injuries is mediated by Ubc9. These results suggest a novel mechanism for isoflurane preconditioning-induced tolerance to cerebral ischemia.