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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\u2014independent of NREMs fragmentation produced by simultaneous hypothermia\u2014and 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 innervates central regions that promote wakefulness and inhibit REMs. We conclude that MLPO_VGLUT2 powerfully suppresses REMs and that exogenous\u2014and possibly pathologic\u2014activation of these neurons disrupts REMs recovery, presumably by directly or indirectly activating REMs-inhibitory mechanisms.<\/jats:p>","DOI":"10.1093\/sleep\/zsaf141","type":"journal-article","created":{"date-parts":[[2025,5,26]],"date-time":"2025-05-26T08:07:46Z","timestamp":1748246866000},"source":"Crossref","is-referenced-by-count":6,"title":["Regulation of REM and NREM sleep by preoptic glutamatergic neurons"],"prefix":"10.1093","volume":"48","author":[{"given":"Alejandra","family":"Mondino","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, University of Michigan Medical School , Ann Arbor, MI,","place":["USA"]},{"name":"Departamento de Fisiolog\u00eda, Facultad de Medicina, Universidad de la Rep\u00fablica , 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