Sleep Deprivation Engages the Orexin/Hypocretin System to Regulate Food Reward Seeking.

Background: Inadequate sleep is a prevalent health issue in modern society, with unintended consequences in dysregulation of the reward system. For example, acute sleep deprivation (SD) in humans increases craving for and intake of calorie-dense foods, which lead to further health concerns. The circuit and molecular mechanisms underlying sleep-regulation of reward, however, remain poorly understood. The hypothalamic orexin (also called hypocretin) system is phylogenetically conserved to dually regulate sleep/arousal and reward. Here, we tested the hypothesis that acute SD engages the orexin system to modulate food reward-seeking.

Methods: We used sucrose self-administration model in male and female mice to test how acute SD by gentle handling regulates sucrose reward seeking. We then administered specific orexin receptor antagonists systemically (Ox1R antagonist SB-334867 10 mg/kg or Ox2R antagonist seltorexant 10 mg/kg) or in selective brain regions (up to 100 μM) to assess their respective roles.

Results: We found that under normal sleep conditions the orexin system is minimally involved in sucrose reward seeking. By contrast, SD increased sucrose self-administration in both male and female mice, and preferentially engaged orexin receptor 2 (Ox2R) signaling in females to mediate this effect. Moreover, in nucleus accumbens (NAc) or paraventricular nucleus of hypothalamus (PVN), key reward regulatory regions enriched in Ox2Rs, blocking Ox2R signaling in each individually did not counteract the SD effects in females. Finally, c-Fos analysis showed highly correlative activity levels between diverse cortical and subcortical regions during sucrose self-administration in females, revealing differential network engagement following SD, which was partially restored by systemic Ox2R antagonism following SD in females.

Conclusion: These results highlight Ox2R signaling in counteracting the acute SD effects on food reward seeking in females.