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Feedforward Inhibition Mediated by Preoptic Area Parvalbumin Neurons Contributes to Orexin-Induced Active Arousal from Anesthesia

Year: 2026

Type: article

Abstract: The orexinergic system can actively promote arousal from general anesthesia, but the downstream circuit mechanisms that mediate this effect remain poorly defined. Orexin neurons densely innervate the sleep-promoting preoptic area (POA) of the hypothalamus, yet whether and how the POA contributes to orexin-induced arousal from general anesthesia is unknown. Using fiber photometry, optogenetics, neuropharmacology, and in vitro and in vivo electrophysiology in mice, we examined the orexin-to-POA circuit during isoflurane anesthesia and arousal process. We found that orexinergic inputs to the POA are suppressed by isoflurane anesthesia and recover before behavioral arousal. Enhancing POA orexinergic afferents markedly accelerated both behavioral and electrocorticographic arousal. This effect was mediated specifically by orexin type-1 receptors because local blockade of these receptors within the POA attenuated the arousal response. In situ hybridization and in vitro electrophysiology further implicated POA GABAergic neurons in this process. In vivo recordings revealed heterogeneous firing responses among POA GABAergic neurons, with excitation of a subset of parvalbumin-positive neurons preceding suppression of other GABAergic neurons, consistent with a feedforward inhibitory process contributing to orexin-induced arousal. These findings define a specific circuit mechanism for the transition from anesthesia to consciousness and suggest that parvalbumin neuron-associated feedforward inhibition within the POA mediates orexin-induced active arousal.

Source: Research

DOI: 10.34133/research.1474