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Introduction
Approximately ten million patients receive general anesthesia for surgery in China every year. While intravenous anesthetics cause unconsciousness, the mechanism and neural basis of unconsciousness are poorly understood (1). At the molecular level, there are dozens of molecules known to be general anesthetic targets, including a number of ion channels (2), gap-junction channels (3), and G protein-coupled receptors (4). It's remarkable that there is no single molecular target shared by all general anesthetics (1). Therefore, effects of general anesthetics must be comprehended in the context of network connectivity.
There are similarities between general anesthesia and natural sleep. Imaging studies have shown some parallels between the anesthetized brain and the brain during deep non-rapid-eye-movement (NREM) sleep (5,6). Electroencephalogram (EEG) studies have suggested that loss of consciousness caused by general anesthetics resembles the rapid transition from normal wakefulness to sleep (7). Sleep-related EEG waves that resembled gamma, delta and spindle waves have been observed during general anesthesia (8). These findings led an increasingly popular theory that anesthetics may induce unconsciousness by acting on endogenous sleep-arousal neural circuitry. But it remains unclear to what extent sleep-arousal pathway, such as the ventrolateral preoptic nucleus (VLPO)-locus coeruleus (LC) are involved in generating the hypnotic state.
Commonly used general anesthetic propofol exerts sedative effects by targeting GABAA receptors. And GABA is the primary inhibitory neurotransmitter released by sleep-promoting neurons in the VLPO, which plays a critical role in inducing and maintaining sleep (9). The VLPO sends GABAergic inhibitory projections to several wake-promoting nuclei throughout the neuroaxis (10), including the LC, tuberomammillary nucleus (TMN) and orexinergic neurons in the lateral hypothalamus (11). Previous research has demonstrated that propofol and various barbiturates activate sleep-promoting VLPO neurons through different receptors (12–14). Moreover, the inhalational anesthetic isoflurane directly depolarizes VLPO neurons (15). Nevertheless, lesion of VLPO neurons could be expected to produce resistance to anesthesia because of the accrual of sleep debt (16). Thus, it remains controversial whether VLPO activation contributes to anesthetic-induced unconsciousness.
In the present study, we hypothesized that propofol may act on VLPO neurons to stimulate the release of GABA, thereby inhibiting wakefulness-promoting neurons in the LC. To validate the hypothesis, we examined the LoRR (loss of righting reflex) and RoRR (recovery of righting reflex) time following GABAA...