Sleep-Mediated Regulation of Natural Reward Seeking –Roles of Nucleus Accumbens and Orexin/Hypocretin Signaling

Abstract

Inadequate sleep is a prevalent health issue in modern society, with unintended consequences in dysregulation of the reward system. Acute sleep deprivation (SD) in humans increases cravings for and intake of calorie-dense foods, which leads to further health concerns. However, animal model studies to follow up on the neural mechanisms of SD-mediated regulation of reward have been limited.

Mice typically exhibit increased natural reward seeking following acute SD, mirroring human findings. Therefore, my dissertation aims to use a mouse self-administration (SA) model to examine sleep-mediated regulation of reward seeking, focusing on the nucleus accumbens (NAc) and orexin system. The NAc is a reward-processing hub that integrates external and internal signals to regulate reward-seeking behaviors. However, it is not known how NAc activities in mice during reward seeking may be altered by acute SD. Thus, in Chapter 2, we utilized in vivo fiber photometry to monitor NAc calcium (Ca²⁺) dynamics during self-initiated sucrose SA and examined its changes following acute SD. We found that NAc Ca²⁺ dynamics during sucrose SA are associated with behavioral outcomes and evolve across different training stages. Furthermore, SD increases sucrose SA while also dampening NAc Ca²⁺ responses and reducing the sensitivity to reward updates.

The orexin system regulates sleep and reward seeking through widespread brain circuitry. While orexin signaling in the brain promotes reward seeking and acute SD increases orexin activity, the extent to which SD influences the orexin system in natural reward seeking remains unclear. In Chapter 3, we examined whether orexin signaling is required for acute SD to regulate sucrose SA. We found that the orexin system plays a minimal role in sucrose SA under normal sleep conditions. By contrast, SD preferentially engages orexin receptor 2 (OX₂R) signaling in females to increase sucrose SA; OX₂R signaling within NAc is not required for the SD effect. Finally, SD disrupts coordinated activities across cortical, subcortical, and midbrain regions during reward seeking, which is partly ameliorated by systemic OX₂R antagonism in females. Together, results from the two studies demonstrate the impact of SD on NAc activities and the complexity of the orexin system in sleep-regulation of reward.