Regulation of REM and NREM Sleep by Preoptic Glutamatergic Neurons.

The preoptic area of the hypothalamus, long thought to only promote sleep, contains glutamatergic neurons (MLPO_VGLUT2) that actually drive wakefulness and suppress REM sleep. Using fiber photometry in mice, these neurons were highly active during REM sleep, wakefulness, and brief arousals, but minimally active during non-REM sleep. Chemogenetic stimulation of MLPO_VGLUT2 inhibited REM sleep onset, independent of non-REM fragmentation caused by hypothermia, and blocked the REM sleep rebound normally seen after total sleep deprivation. Chemogenetic inhibition increased REM sleep time only during the light phase. Mapping showed these neurons project to brain regions that promote wakefulness and inhibit REM sleep. The authors conclude that MLPO_VGLUT2 powerfully suppress REM sleep, and their overactivation disrupts REM recovery.

Study at a glance

Abstract

The preoptic area of the hypothalamus is key for the control of sleep onset and sleep homeostasis. Although traditionally considered exclusively somnogenic, recent studies identified a group of preoptic glutamatergic neurons that promote wakefulness. Specifically, our previous investigations demonstrated that chemogenetic stimulation of glutamatergic neurons within the medial-lateral preoptic area (MLPO_VGLUT2) promotes wakefulness, fragments non-rapid eye movement sleep (NREMs), and suppresses REM sleep (REMs). This evidence is further supported by recent work showing that preoptic glutamatergic neurons are activated during microarousals that fragment sleep in response to stress, and optogenetic stimulation of these neurons promotes microarousals and wakefulness. Thus, while the wake-promoting function of MLPO_VGLUT2 is clear, their role in sleep homeostasis has not been assessed. We tested the hypothesis that MLPO_VGLUT2 are wake-active, and their activation will increase wakefulness and disrupt sleep homeostasis via projections to arousal-promoting systems. Using fiber photometry, we found that MLPO_VGLUT2 were highly active during REMs, wakefulness and brief arousals, and remained minimally active during NREMs. Chemogenetic stimulation of MLPO_VGLUT2 inhibited REMs onset - independent of NREMs fragmentation produced by simultaneous hypothermia - and suppressed the REMs homeostatic response after total sleep deprivation. Chemogenetic inhibition of MLPO_VGLUT2 increased REMs time (during the light phase only) but did not influence REMs and NREMs homeostasis. Anterograde projection mapping revealed that MLPO_VGLUT2 innervate central regions that promote wakefulness and inhibit REMs. We conclude that MLPO_VGLUT2 powerfully suppress REMs and that exogenous -and possibly pathologic- activation of these neurons disrupts REMs recovery, presumably by directly or indirectly activating REMs-inhibitory mechanisms.