Prelimbic cortical pyramidal neurons to ventral tegmental area projections promotes arousal from sevoflurane anesthesia

Aims: General anesthesia has been used in surgical procedures for approximately 180 years, yet the precise mechanism of anesthetic drugs remains elusive. There is significant anatomical connectivity between the ventral tegmental area (VTA) and the prelimbic cortex (PrL). Projections from VTA dopaminergic neurons (VTA^DA ) to the PrL play a role in the transition from sevoflurane anesthesia to arousal. It is still uncertain whether the prelimbic cortex pyramidal neuron (PrL^Pyr ) and its projections to VTA (PrL^Pyr -VTA) are involved in anesthesia-arousal regulation.

Methods: We employed chemogenetics and optogenetics to selectively manipulate neuronal activity in the PrL^Pyr -VTA pathway. Electroencephalography spectra and burst-suppression ratios (BSR) were used to assess the depth of anesthesia. Furthermore, the loss or recovery of the righting reflex was monitored to indicate the induction or emergence time of general anesthesia. To elucidate the receptor mechanisms in the PrL^Pyr -VTA projection's impact on anesthesia and arousal, we microinjected NMDA receptor antagonists (MK-801) or AMPA receptor antagonists (NBQX) into the VTA.

Results: Our findings show that chemogenetic or optogenetic activation of PrL^Pyr neurons prolonged anesthesia induction and promoted emergence. Additionally, chemogenetic activation of the PrL^Pyr -VTA neural pathway delayed anesthesia induction and promoted anesthesia emergence. Likewise, optogenetic activation of the PrL^Pyr -VTA projections extended the induction time and facilitated emergence from sevoflurane anesthesia. Moreover, antagonizing NMDA receptors in the VTA attenuates the delayed anesthesia induction and promotes emergence caused by activating the PrL^Pyr -VTA projections.

Conclusion: This study demonstrates that PrL^Pyr neurons and their projections to the VTA are involved in facilitating emergence from sevoflurane anesthesia, with the PrL^Pyr -VTA pathway exerting its effects through the activation of NMDA receptors within the VTA.

general anesthesia; prelimbic cortex; pyramidal neuron; sevoflurane; ventral tegmental area.