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

Abstract

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 (VTAGad67+) are a key regulator of non-rapid eye movement (NREM) sleep in mice. VTAGad67+ project to multiple brain areas implicated in sleep/wakefulness regulation such as the lateral hypothalamus (LH). Chemogenetic activation of VTAGad67+ 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. VTAGad67+ showed the highest activity in NREM sleep and the lowest activity in REM sleep. Moreover, VTAGad67+ directly innervated and inhibited wake-promoting orexin/hypocretin neurons by releasing GABA. As such, optogenetic activation of VTAGad67+ terminals in the LH promoted NREM sleep. Taken together, we revealed that VTAGad67+ play an important role in the regulation of NREM sleep.

Sleep deprivation triggers somatostatin neurons in prefrontal cortex to initiate nesting and sleep via the preoptic and lateral hypothalamus

“…Following sleep deprivation, the PFC to LH projection could induce NREM sleep by inhibiting arousal-promoting GABA and orexin neurons in the LH 66,67 ; this would be a similar mechanism to how VTA GABA neurons induce NREM sleep by sending their GABAergic projections to the LH 23,68,69 . Sustained local stimulation of this projection could disinhibit REM sleep-promoting MCH/GABA cells 70 .…”

Dissociating orexin-dependent and -independent functions of orexin neurons using novel Orexin-Flp knock-in mice

“…Besides, OF mice can also be useful for analyzing long-range neuronal connections. By using the Orexin-Flp; Gad67-Cre bigenic mice, we recently found that GABAergic neurons in the ventral tegmental area inhibited orexin neuronal activity by making monosynaptic inhibitory projections and regulate NERM sleep in mice (Chowdhury et al, 2019).…”

Migraine and Sleep—An Unexplained Association?

“…The second important NREM controlling system is the parafacial zone (PZ) consisting of GABAergic neurons, which are necessary for the induction of deep NREM, expressed as slow-wave sleep [65]. The ventrolateral tegmental nucleus (VTA), which was first discovered to be a part of the arousal system because of its dopaminergic neurons, has been proven to play a role in promotion of NREM sleep because its GABAergic neurons inhibit both dopaminergic neurons and also the lateral hypothalamus region [66,67] Other GABAergic neurons located in the ventrolateral periaqueductal grey region (vlPAG) stabilize NREM sleep, reducing REM sleep episodes at the same time [68]. Neurons expressing the adenosine receptor A2a located in the nucleus accumbens and in rostral striatum also promote NREM sleep by inhibition of pallidum [69].…”