Control of REM sleep and wakefulness by lateral periaqueductal gray glutamatergic neurons

Rapid eye movement (REM) sleep is thought to be a cortical state closer to wakefulness than non-REM sleep, yet a few brain regions regulate both states. This study identifies the glutamatergic neurons in the lateral periaqueductal gray (LPAG) that are specifically activated during wakefulness and REM sleep, as demonstrated by fiber photometry and optic tetrode recordings. Chemogenetic inhibition of LPAG vesicular glutamate transporter 2 (Vglut2) neurons reduced REM sleep and wakefulness while boosting non-REM sleep; their activation induced wakefulness, with high theta power and immobility. Chemogenetic suppression of the LPAG-sublaterodorsal tegmental nucleus projection curtailed REM sleep, and its optogenetic activation triggered REM sleep, proving that this pathway drives REM sleep. Meanwhile, LPAG^Vglut2 neurons promoted wakefulness through outputs to the locus coeruleus and ventral gigantocellular reticular nucleus, as supported by optogenetic manipulations. Overall, the results show that LPAG^Vglut2 circuits govern both REM sleep and wakefulness, uncovering a crucial region involved in the regulation of both REM sleep and wakefulness.