Authors: Tong L et al.
Anesthesiology. December 2025. DOI: 10.1097/ALN.0000000000005903
Summary
This experimental study examined the role of glutamatergic neurons in the dorsomedial periaqueductal gray (dmPAG) in regulating arousal and emergence across multiple general anesthetic agents. Although general anesthetics act through diverse molecular targets, they may converge on shared neural circuits controlling consciousness. The periaqueductal gray is known to participate in instinctive behaviors and sleep–wake regulation, but its contribution to anesthetic-induced unconsciousness and recovery has remained unclear.
Using male and female mice, the investigators evaluated neural activity during anesthesia induced by sevoflurane, propofol, ketamine, and dexmedetomidine. Calcium imaging revealed that dmPAG glutamatergic neuron activity was consistently suppressed during anesthesia and increased during wakefulness across all agents. This pattern suggests a shared arousal-related role for these neurons independent of anesthetic class.
Causal manipulation confirmed this relationship. Optogenetic activation of dmPAG glutamatergic neurons significantly delayed anesthetic induction while markedly accelerating emergence from sevoflurane anesthesia. During maintained anesthesia, neuronal activation produced electroencephalographic changes characteristic of wakefulness, including a profound reduction in burst-suppression ratio. Chemogenetic activation produced similar effects across all anesthetics tested, whereas chemogenetic inhibition enhanced anesthetic depth, shortened induction time, and delayed recovery.
These findings identify dmPAG glutamatergic neurons as a central arousal-promoting circuit that opposes anesthetic-induced unconsciousness and facilitates recovery. The results support the concept of a shared neural substrate underlying loss and return of consciousness across multiple anesthetic agents and provide mechanistic insight into the neurobiology of emergence from anesthesia.
Key Points
Glutamatergic neurons in the dorsomedial PAG are suppressed during anesthesia and activated during wakefulness across inhalational and intravenous agents.
Activation of dmPAG glutamatergic neurons delays induction and accelerates emergence from anesthesia.
Neuronal activation reduces EEG burst suppression and induces wake-like cortical activity during anesthesia.
Inhibition of dmPAG glutamatergic neurons potentiates anesthetic effects across multiple agents.
The dmPAG represents a common arousal circuit involved in both anesthetic-induced unconsciousness and recovery.
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