Orexin Neurons to Sublaterodorsal Tegmental Nucleus Pathway Prevents Sleep Onset REM Sleep-Like Behavior by Relieving the REM Sleep Pressure.

Proper timing of vigilance states serves fundamental brain functions. Although disturbance of sleep onset rapid eye movement (SOREM) sleep is frequently reported after orexin deficiency, their causal relationship still remains elusive. Here, we further study a specific subgroup of orexin neurons with convergent projection to the REM sleep promoting sublaterodorsal tegmental nucleus (OXSLD neurons). Intriguingly, although OXSLD and other projection-labeled orexin neurons exhibit similar activity dynamics during REM sleep, only the activation level of OXSLD neurons exhibits a significant positive correlation with the post-inter-REM sleep interval duration, revealing an essential role for the orexin-sublaterodorsal tegmental nucleus (SLD) neural pathway in relieving REM sleep pressure. Monosynaptic tracing reveals that multiple inputs may help shape this REM sleep-related dynamics of OXSLD neurons. Genetic ablation further shows that the homeostatic architecture of sleep/wakefulness cycles, especially avoidance of SOREM sleep-like transition, is dependent on this activity. A positive correlation between the SOREM sleep occurrence probability and depression states of narcoleptic patients further demonstrates the possible significance of the orexin-SLD pathway on REM sleep homeostasis.

Publisher Correction: Orexin signaling modulates synchronized excitation in the sublaterodorsal tegmental nucleus to stabilize REM sleep.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Orexin signaling modulates synchronized excitation in the sublaterodorsal tegmental nucleus to stabilize REM sleep.

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.

Orexin enhances firing activities in the gigantocellular reticular nucleus through the activation of non-selective cationic conductance.

Orexin/hypocretin has been implicated in central motor control. The gigantocellular reticular nucleus (Gi), a key element of the brainstem motor inhibitory system, also receives orexinergic innervations. However, the modulations of orexin on the neuronal activities and the underlying cellular mechanisms in Gi neurons remain unknown. Here, through whole-cell patch-clamp recordings, we first observed that orexin increased the firing frequency in Gi neurons. Interestingly, a postsynaptic depolarization elicited by orexin was observed in the presence of tetrodotoxin, without altering the input resistance of Gi neurons at around -60 mV. Moreover, through comparing the current-frequency curves constructed by identical current injections from equal membrane potentials, we found that orexin also increased the repetitive firing ability of Gi neurons. This action appeared to be caused by the shortening of inter-spike intervals, without altering the waveform of individual action potentials. We finally revealed that activation of the non-selective cationic conductance contributed to the orexin-elicited excitation in Gi neurons. Together, these results suggest that orexin may facilitate Gi-mediated motor functions through enhancing the neuronal activities of Gi neurons.