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

Significance As in narcolepsy patients, overall time spent awake and asleep is normal in mice lacking the wake-enhancing neuromodulator hypocretin/orexin. We discovered, however, that these mice, in baseline conditions, are impaired in maintaining theta-dominated wakefulness (TDW), a waking substate characteristic of goal-driven, explorative behaviors and associated with heightened θ/fast-γ activity. We demonstrate that TDW instability causes profound blunting of EEG δ activity in subsequent slow-wave sleep, a measure gauging homeostatic sleep need. In contrast, manually enforced waking induced unimpaired TDW expression and normal δ activity in recovery sleep. This suggests that TDW, not overall waking, drives sleep need, a hypothesis we verified by modeling the homeostatic process. We propose that Hcrt is critical for spontaneous waking but that enforced waking relies on other neuromodulators, such as norepinephrine.