Subthalamic CaMKIIα-expressing neurons facilitate recovery from propofol anesthesia via the STN–ventral pallidum pathway

Propofol is extensively used in clinical anesthesia, yet its mechanisms of action remain incompletely understood. CaMKIIα-expressing neurons in the subthalamic nucleus (STN) have been associated with arousal-related pain perception and impulse regulation, but their role in propofol anesthesia remains unclear. In this study, c-Fos immunohistochemistry, live calcium-signal recording by fiber photometry, electroencephalography (EEG), and electromyography (EMG) were employed to assess the activity of STN CaMKIIα-expressing neurons during propofol anesthesia. It was observed that the activity of STN CaMKIIα-expressing neurons was markedly reduced under propofol anesthesia. Both optogenetic and chemogenetic activation of this population promoted cortical arousal and shortened recovery time without affecting anesthetic induction. Through anterograde and retrograde tracing approaches, a direct projection from the STN to the ventral pallidum (VP) was identified. Optogenetic stimulation of STN CaMKIIα-expressing axon terminals within the VP modified EEG spectral power during maintenance and emergence and enhanced emergence from propofol anesthesia. Collectively, these findings indicate that STN CaMKIIα-expressing neurons play an important role in promoting behavioral emergence from propofol anesthesia, at least partially through the STN-VP circuit. This study provides circuit-level evidence that improves mechanistic insight into emergence from general anesthesia and identifies the STN-VP pathway as a potential target for modulating anesthetic recovery.