Neural circuitry mediating hypercapnia-induced microarousal and impaired sleep depth.

Sleep disruption in obstructive sleep apnea syndrome is characterized by frequent microarousals and reduced sleep depth, yet the underlying mechanisms remain unclear. Here, we show that intermittent hypercapnic air (HA) induces time-locked microarousals, fragments sleep, reduces non-rapid eye movement (NREM) sleep depth, and diminishes rapid eye movement (REM) sleep. HA exposure activates glutamatergic neurons in the nucleus tract solitary (NTSVglut2), and their optogenetic or chemogenetic activation is sufficient to trigger arousal and impair sleep. Projection-specific activation reveals that NTSVglut2 projections to the paraventricular nucleus (PVN), parabrachial nucleus (PB), paraventricular thalamus, and locus coeruleus (LC) promote arousal, whereas projections to the PB and LC additionally reduce NREM sleep depth. Inhibition of NTSVglut2 projection to the PVN significantly postpones HA-induced arousal. NTSVglut2 terminals monosynaptically activate corticotropin-releasing hormone neurons in the PVN (PVNCRH), and inhibition of PVNCRH neurons or knockdown of Slc17a6 (encoding Vglut2), but not Crh, delays hypercapnia-induced arousal. These findings identify neural circuits underlying hypercapnia-induced microarousal and reduced sleep depth.