Authors: Tong L et al.
Journal: Anesthesiology, December 15, 2025. DOI: 10.1097/ALN.0000000000005903
Summary
This preclinical study investigated the role of glutamatergic neurons in the dorsomedial periaqueductal gray (dmPAG) as a shared neural substrate regulating arousal and emergence across multiple general anesthetics. Although general anesthetics differ in molecular targets, the authors hypothesized that convergent brainstem circuitry may govern transitions between unconsciousness and wakefulness.
Using mice of both sexes, the investigators examined neuronal activity in dmPAG glutamatergic neurons during exposure to sevoflurane, propofol, ketamine, and dexmedetomidine. Calcium imaging demonstrated that dmPAG glutamatergic neuron activity was consistently suppressed during anesthesia and increased during wakefulness, irrespective of anesthetic class. This finding suggests a common arousal-related signaling pathway.
Causal manipulation of dmPAG glutamatergic neurons confirmed their functional relevance. Optogenetic activation prolonged induction time and markedly accelerated emergence from sevoflurane anesthesia, while simultaneously shifting EEG patterns toward wakefulness even during anesthetic maintenance. Burst suppression was dramatically reduced with neuronal activation. Chemogenetic activation produced similar effects, whereas chemogenetic inhibition deepened anesthetic effects and delayed recovery across all tested anesthetics.
Collectively, the data indicate that dmPAG glutamatergic neurons play a central role in both loss and recovery of consciousness under general anesthesia. These neurons appear to function as a hub within the arousal network, providing mechanistic insight into how structurally distinct anesthetics converge on shared neural circuits.
Key Points
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DmPAG glutamatergic neuronal activity is suppressed during anesthesia and increases during arousal.
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This pattern is consistent across volatile, intravenous, dissociative, and α₂-agonist anesthetics.
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Activation of dmPAG glutamatergic neurons delays induction and accelerates emergence.
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Neuronal activation shifts EEG signatures toward wakefulness and reduces burst suppression.
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Inhibition of dmPAG glutamatergic neurons potentiates anesthetic depth and delays recovery.
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The dmPAG may represent a common neural substrate regulating anesthetic-induced unconsciousness.
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