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

The endogenous arousal pathway, centered around the midbrain dopaminergic (DA) system, plays a crucial role in regulating consciousness transitions. However, the role of substantia nigra pars compacta (SNc) DA neurons, particularly their projections to the dorsal striatum (DS), in propofol-induced unconsciousness and wakefulness is not yet clear. This study combines fiber optic recording, optogenetics, and chemogenetics to manipulate SNc DA cell bodies or their terminals towards DS in C57BL/6 J mice. The results showed that SNc DA manipulation had no effect on the induction period; however, during the awakening period, activation can accelerate the recovery of the righting reflex (RORR) and induce awakening related EEG features, while inhibition delays RORR and enhances slow wave activity. Importantly, this awakening effect is state dependent: it occurs when SNc DA neurons are activated during anesthesia maintenance and recovery phases but not during induction phase activation. In addition, the effect of SNc DA manipulation is time-dependent, that is, it regulates the awakening period without affecting the induction period. Pathway specific manipulation indicates that photoactivation of DS terminals can promote wakefulness, while inhibition prolongs RORR without affecting the induction period. Therefore, it is believed that SNc DA neurons mainly exert time-dependent and pathway specific effects on propofol awakening through the substantia nigra striatum, and participate in the process of propofol anesthesia awakening.