It was yet to be reported that how the real-time manipulation of dDpMe GABA neurons would affect REM, NREM, and wake state transitions. However, direct evidence proving dDpMe GABA neurons as the essential elements in REM sleep regulation and REM-related disorders was still not sufficient. In humans, lesions of pons containing the dDpMe caused cataplexy and visual hallucinations due to excessive REM sleep 24, 25. Recent research reported a cluster of neurons expressing Atoh1 derived from the hindbrain that inhibited REM sleep by the dDpMe 18. Furthermore, dDpMe GABAergic (dDpMe GABA) neurons were found to be activated by REM-sleep deprivation 23. found the vlPAG/DpMe GABAergic neurons projecting to the SLD, the key REM sleep center 22. Consistently, chemical lesion of the area ventrolateral part to the vlPAG, the dorsal part of the deep mesencephalic nucleus (dDpMe, also called lateral pontine tegmentum) increased excessive REM sleep in mice 20. reported that electrical destruction of the dorsal norepinephrine bundle (including vlPAG/DpMe) in the mesencephalon induced an increase in REM sleep 21. However, the vital mechanisms of REM-sleep cessation are still controversial, and the neural mechanism underlying the maintenance of the REM sleep necessary for living and termination of endless REM sleep or REM-like pathological sleep remains largely uncertain. Since the 1970s, non-monoamine-based inhibitory neurons in the ventrolateral periaqueductal gray matter/the deep mesencephalic nucleus (vlPAG/DpMe) have been reported as key parts of REM sleep inhibition 18, 19, 20. Previous studies reveal that the monoaminergic neurons in the brainstem cease firing specifically during REM sleep, including serotonergic neurons from the raphe nuclei and noradrenergic neurons from the locus coeruleus (LC) 16, 17. Although previous studies have described several brain regions that contribute to the promotion of REM sleep, such as the sublaterodorsal nucleus (SLD), ventral medulla, lateral hypothalamus (LH), etc 12, 13, 14, 15, the core mechanisms controlling the termination of REM sleep and REM/NREM alternations have been paid less attention to. Dysregulation of REM sleep leads to numerous sleep disorders, including narcolepsy 10, 11. REM sleep is associated with brain development 6, 7 and memory 8, 9. Of the rapid-eye-movements produced by bursting of oculomotor muscles, REM sleep is also characterized by desynchronized cortical electroencephalogram (EEG), high-amplitude theta waves, and muscle atonia 5. REM sleep was first described in 1953 by Kleitman and Aserinsky as regularly occurring “active sleep” in human infants, which is distinct from the quiescent sleep periods known as NREM sleep 4. For continuous sleep in healthy human, rapid eye movement (REM) sleep follows non-REM (NREM) sleep several times during a typical night of sleep, while reductions in NREM sleep, disinhibition of REM sleep, and insomnia usually accompanied by non-consolidated sleep 3. The periodic rhythm and continuity are essential for sleep physiology 1, 2. Our results demonstrated that dDpMe GABAergic neurons controlled REM sleep termination along with REM/NREM transitions and represented a novel potential target to treat narcolepsy. In addition, dDpMe GABAergic neurons efficiently suppressed cataplexy in a rodent model. In-depth studies of neural circuits revealed that sublaterodorsal nucleus glutamatergic neurons were essential for REM sleep termination by dDpMe GABAergic neurons. Physiologically, dDpMe GABAergic neurons causally suppressed REM sleep and promoted NREM sleep through the sublaterodorsal nucleus and lateral hypothalamus. Next, we investigated the roles of dDpMe GABAergic neuronal circuits in brain state regulation using optogenetics, RNA interference technology, and celltype-specific lesion. Using fiber photometry and optic tetrode recording, we characterized the dorsal part of the deep mesencephalic nucleus (dDpMe) GABAergic neurons as REM relatively inactive and two different firing patterns under spontaneous sleep–wake cycles. Here, we reveal a key brainstem region of GABAergic neurons in the control of both physiological REM sleep and cataplexy. However, the neuronal mechanisms controlling REM sleep termination and keeping sleep continuation remain largely unknown. Physiological rapid eye movement (REM) sleep termination is vital for initiating non-REM (NREM) sleep or arousal, whereas the suppression of excessive REM sleep is promising in treating narcolepsy.
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