Abstract
The relationship between orexin/hypocretin and rapid eye movement (REM) sleep remains elusive. Here, we find that a proportion of orexin neurons project to the sublaterodorsal tegmental nucleus (SLD) and exhibit REM sleep-related activation. In SLD, orexin directly excites orexin receptor-positive neurons (occupying ~3/4 of total-population) and increases gap junction conductance among neurons. Their interaction spreads the orexin-elicited partial-excitation to activate SLD network globally. Besides, the activated SLD network exhibits increased probability of synchronized firings. This synchronized excitation promotes the correspondence between SLD and its downstream target to enhance SLD output. Using optogenetics and fiber-photometry, we consequently find that orexin-enhanced SLD output prolongs REM sleep episodes through consolidating brain state activation/muscle tone inhibition. After chemogenetic silencing of SLD orexin signaling, a ~17% reduction of REM sleep amounts and disruptions of REM sleep muscle atonia are observed. These findings reveal a stabilization role of orexin in REM sleep.
Highlights
The relationship between orexin/hypocretin and rapid eye movement (REM) sleep remains elusive
Both of them were sporadically distributed across the lateral hypothalamus (LH) (Supplementary Fig. 1a–d), indicating that the injected region (Supplementary Fig. 2a) of the sublaterodorsal tegmental nucleus (SLD) was innervated by orexin neurons
In the SLD, the orexin receptors (OXRs) were abundantly expressed in vesicular glutamate transporter-1 (VGLUT1)-positive glutamatergic neurons (Fig. 1f), and few OXRs/glutamate decarboxylase-67 (GAD-67)-positive GABAergic somas were detected (Fig. 1g)
Summary
The relationship between orexin/hypocretin and rapid eye movement (REM) sleep remains elusive. Using optogenetics and fiber-photometry, we find that orexin-enhanced SLD output prolongs REM sleep episodes through consolidating brain state activation/muscle tone inhibition. During REM sleep, the firing activities of the SLD glutamatergic neurons are carriers of output information for brain state activation, such as fast electroencephalogram (EEG) activities in the corticohippocampal region, and muscle atonia[11,19,20]. While loss of orexin signaling has been reported to correlate with impaired brain states reflected by abnormal fast-EEG activities and muscle tone regulation in either wakefulness or REM sleep[9,10,30], the specific influences of orexin on the neuronal membrane and network dynamics in the SLD, and their contributions to the functional brain state during REM sleep have not been investigated. An essential role for SLD orexin signaling in REM sleep stabilization is presented
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