GABA neurons in the ventral tegmental area regulate non-rapid eye movement sleep in mice

Sleep/wakefulness cycle is regulated by coordinated interactions between sleep- and wakefulness-regulating neural circuitry. However, the detailed mechanism is far from understood. Here, we found that glutamic acid decarboxylase 67-positive GABAergic neurons in the ventral tegmental area (VTA Gad67+ ) are a key regulator of non-rapid eye movement (NREM) sleep in mice. VTA Gad67+ project to multiple brain areas implicated in sleep/wakefulness regulation such as the lateral hypothalamus (LH). Chemogenetic activation of VTA Gad67+ promoted NREM sleep with higher delta power whereas optogenetic inhibition of these induced prompt arousal from NREM sleep, even under highly somnolescent conditions, but not from REM sleep. VTA Gad67+ showed the highest activity in NREM sleep and the lowest activity in REM sleep. Moreover, VTA Gad67+ directly innervated and inhibited wake-promoting orexin/hypocretin neurons by releasing GABA. As such, optogenetic activation of VTA Gad67+ terminals in the LH promoted NREM sleep. Taken together, we revealed that VTA Gad67+ play an important role in the regulation of NREM sleep.