0278 HYPOCRETIN AS A MEDIATOR OF POST-TRAUMATIC BRAIN INJURY SLEEP DISTURBANCE

Abstract

Introduction: Disorders of sleep and wakefulness occur in the majority of individuals who have experienced traumatic brain injury (TBI), with increased sleep need and excessive daytime sleepiness often reported. Behavioral and pharmacological therapies have limited efficacy, in part, because the etiology of post-TBI sleep disturbances is not well understood. The hypocretinergic system is essential for the maintenance of wakefulness and is perturbed in human TBI patients and in animal models of TBI. However, previous studies examining the role of hypocretin in responses to TBI have all been correlational. We hypothesized that post-TBI sleep disturbances in hypocretin-null (KO) mice would be less severe than in wild type mice subjected to TBI. Methods: Adult male C57BL/6 and hypocretin KO mice were implanted with EEG recording electrodes and baseline recordings were obtained. After baseline recordings, animals were subjected to a controlled cortical impact (CCI) or sham surgery. EEG recordings were obtained from the same animals at 3, 7, 15, and 30 days post-surgery. Since hypocretin plays an important role in regulating neuroinflammation, especially microglial response, brains were examined with immunohistochemistry for microglial activation. Results: Similar to previous studies, wild type mice exhibited a decrease in wakefulness during the dark period at chronic time points in response to TBI. Hypocretin KO mice exhibited less time in wakefulness and shorter bouts of wakefulness during the dark period compared to wild type mice. At chronic time points, post-TBI sleep-wake disturbance was attenuated in hypocretin KO mice compared to wild type mice. Conclusion: Hypocretin is a mediator of post-TBI changes in sleepwake behavior. Thus, hypocretin may be a therapeutic target for treatment of chronic sleep-wake disturbances that occur after TBI.