0049 Sleep and Electroencephalogram Effects from a Dual Orexin Receptor Antagonist in Mice with Traumatic Brain Injury

Abstract Introduction Traumatic brain injuries (TBI) can cause persistent sleep dysregulation regardless of injury severity including hypersomnia, hyposmia, sleepiness, sleep fragmentation, and altered electroencephalogram (EEG) power spectra. Most TBIs are mild in severity, occur in the frontal cortex, and sleep dysregulation can change over time. Orexin targets two receptors that stimulate monoamine release in the brain to promote wakefulness. Our goal was to determine if a dual orexin receptor antagonist (DORA) could improve sleep dysregulation in mice with TBI. Methods Two-month-old male and female C57BL/6J mice were randomly assigned to treatment groups. Mice underwent polysomnography surgery. After recovery, mice were administered vehicle by gavage then underwent baseline sleep recordings for 24 h followed by a multiple sleep latency test (MSLT). Mice received a craniectomy and mild/moderate TBI via controlled cortical impact or only a craniectomy serving as a control. A DORA or vehicle were given by gavage, and sleep and MSLT were recorded 24 h, 2 wks, 1 m, and 2 m post-TBI. Sleep state amounts and episode durations and frequencies, sleep latency, and EEG power spectra (0-40 Hz) were determined with significance set at p 0.05. Results In mice given the DORA or vehicle, non-rapid-eye movement (NREM) sleep was significantly increased 24 h after TBI compared to controls. Conversely, NREM sleep was significantly reduced 2 m post-TBI in both vehicle and DORA groups. DORA and/or TBI groups had significantly reduced waking episodes 24 h post-injury but increased waking episodes 2 m post-TBI compared to controls indicating sleep fragmentation. Largely, significantly increased sleep latency time in the MSLT was found throughout all times post-injury in the DORA and TBI groups compared to the controls, which suggests increased sleepiness. Relative to controls, TBI significantly increased EEG delta power (0.5-4 Hz) 24 h post-TBI and significantly reduced EEG delta power 2 m post-TBI, although other frequency bands were not affected. Conclusion These data suggest that a DORA induces sleepiness but has minimal effects on impaired sleep amounts, sleep fragmentation, sleepiness, and EEG power spectra 2 m after mild/moderate TBI. Support (if any) Merit Review Award (I01BX005379)(MRZ) and SPiRE Award (I21RX003722)(GBK) Department of Veterans Affairs