The nigrostriatal dopaminergic pathway mediates state-dependent emergence from propofol anesthesia in mice

Background Endogenous arousal pathways critically control transitions between states of consciousness, and the midbrain dopaminergic (DA) system is a central node in this network. However, the specific role of substantia nigra pars compacta (SNc) dopaminergic (DA) neurons and their projection pathways in propofol-induced unconsciousness and emergence remains elusive. Methods In C57BL/6J mice, we combined fiber photometry, optogenetics, and chemogenetics to bidirectionally manipulate SNc DA somata and their terminals in the dorsal striatum (DS). We continuously recorded cortical EEG dynamics and behavioral endpoints - loss of righting reflex (LORR) and return of righting reflex (RORR) - throughout anesthetic induction, maintenance, and emergence. Results Manipulating SNc DA neurons did not alter anesthetic induction: LORR latency remained unchanged after either activation or inhibition. By contrast, during emergence, activation of SNc DA neurons significantly shortened RORR and produced an electrophysiological signature of arousal, with increased gamma power and decreased delta/theta power. Inhibition of SNc DA neurons produced the opposite effect, prolonging RORR and augmenting slow-wave activity. Pathway-specific manipulations showed that the nigrostriatal SNc ^DA -DS projection mediates these effects: optogenetic or chemogenetic activation of SNc DA terminals in the DS accelerated emergence, whereas terminal inhibition delayed RORR. None of these pathway-specific interventions affected induction. Conclusion SNc DA neurons exert a time-dependent, pathway-specific influence on recovery from propofol anesthesia, acting primarily via the nigrostriatal SNc→DS projection. These data identify the SNc ^DA -DS circuit as a critical neuroanatomical substrate for emergence from general anesthesia.