Hypocretin (orexin) is critical in sustaining theta/gamma-rich waking behaviors that drive sleep need.

Abstract

<i>Hcrt</i> gene inactivation in mice leads to behavioral state instability, abnormal transitions to paradoxical sleep, and cataplexy, hallmarks of narcolepsy. Sleep homeostasis is, however, considered unimpaired in patients and narcoleptic mice. We find that whereas <i>Hcrt</i>^<i>ko/ko</i> mice respond to 6-h sleep deprivation (SD) with a slow-wave sleep (SWS) EEG δ (1.0 to 4.0 Hz) power rebound like <i>WT</i> littermates, spontaneous waking fails to induce a δ power reflecting prior waking duration. This correlates with impaired θ (6.0 to 9.5 Hz) and fast-γ (55 to 80 Hz) activity in prior waking. We algorithmically identify a theta-dominated wakefulness (TDW) substate underlying motivated behaviors and typically preceding cataplexy in <i>Hcrt</i>^<i>ko/ko</i> mice. <i>Hcrt</i>^<i>ko/ko</i> mice fully implement TDW when waking is enforced, but spontaneous TDW episode duration is greatly reduced. A reformulation of the classic sleep homeostasis model, where homeostatic pressure rises exclusively in TDW rather than all waking, predicts δ power dynamics both in <i>Hcrt</i>^<i>ko/ko</i> and <i>WT</i> mouse baseline and recovery SWS. The low homeostatic impact of <i>Hcrt</i>^<i>ko/ko</i> mouse spontaneous waking correlates with decreased cortical expression of neuronal activity-related genes (notably <i>Bdnf</i>, <i>Egr1</i>/<i>Zif268</i>, and <i>Per2</i>). Thus, spontaneous TDW stability relies on Hcrt to sustain θ/fast-γ network activity and associated plasticity, whereas other arousal circuits sustain TDW during SD. We propose that TDW identifies a discrete global brain activity mode that is regulated by context-dependent neuromodulators and acts as a major driver of sleep homeostasis. Hcrt loss in <i>Hcrt</i>^<i>ko/ko</i> mice causes impaired TDW maintenance in baseline wake and blunted δ power in SWS, reproducing, respectively, narcolepsy excessive daytime sleepiness and poor sleep quality.