Ventrolateral periaqueductal gray GABAergic neurons promote arousal of sevoflurane anesthesia through cortico-midbrain circuit

The mechanism of general anesthesia remains elusive. The ventrolateral periaqueductal gray (vlPAG) in the midbrain regulates sleep and awake states. However, the role of vlPAG and its circuits in anesthesia is unclear. We utilized opto/chemogenetics, righting reflex, and electroencephalographic recording to assess consciousness changes. We employed fiber photometry to measure the activity of neurons and neurotransmitters. As a result, photometry recording showed that the activity of GABA neurons in vlPAG decreased during sevoflurane anesthesia and was reactivated after anesthesia. Activating GABAergic neurons in vlPAG promoted arousal during anesthesia, while inhibiting them delayed this process. Furthermore, medial prefrontal cortex (mPFC) to vlPAG pyramidal neurons projections and vlPAG to ventral tegmental area (VTA) GABAergic projections played a prominent role in the anesthesia-awake transition. GABA neurotransmitter activity of VTA synchronized with mPFC-vlPAG pyramidal neuron projections. Therefore, the cortico-midbrain circuits centered on vlPAG GABAergic neurons exert an arousal-promoting effect during sevoflurane anesthesia.