1 Department of Anesthesiology and Pain Medicine, University of Washington , Seattle, Washington.
2 Graduate Program in Neurobiology and Behavior, University of Washington , Seattle, Washington.
J Neurotrauma. 2019 Mar 1;36(5):802-814. doi: 10.1089/neu.2018.5810. Epub 2018 Oct 3.
Traumatic brain injury (TBI) is a major cause of disability worldwide. Post-TBI sleep and wake disturbances are extremely common and difficult for patients to manage. Sleep and wake disturbances contribute to poor functional and emotional outcomes from TBI, yet effective therapies remain elusive. A more comprehensive understanding of mechanisms underlying post-TBI sleep and wake disturbance will facilitate development of effective pharmacotherapies. Previous research in human patients and animal models indicates that altered hypocretinergic function may be a major contributor to sleep-wake disturbance after TBI. In this study, we further elucidate the role of hypocretin by determining the impact of TBI on sleep-wake behavior of hypocretin knockout (HCRT KO) mice. Adult male C57BL/6J and HCRT KO mice were implanted with electroencephalography recording electrodes, and pre-injury baseline recordings were obtained. Mice were then subjected to either moderate TBI or sham surgery. Additional recordings were obtained and sleep-wake behavior determined at 3, 7, 15, and 30 days after TBI or sham procedures. At baseline, HCRT KO mice had a significantly different sleep-wake phenotype than control C57BL/6J mice. Post-TBI sleep-wake behavior was altered in a genotype-dependent manner: sleep of HCRT KO mice was not altered by TBI, whereas C57BL/6J mice had more non-rapid eye movement sleep, less wakefulness, and more short wake bouts and fewer long wake bouts. Numbers of hypocretin-positive cells were reduced in C57BL/6J mice by TBI. Collectively, these data indicate that the hypocretinergic system is involved in the alterations in sleep-wake behavior that develop after TBI in this model, and suggest potential therapeutic interventions.
创伤性脑损伤（TBI）是全球范围内导致残疾的主要原因。TBI 后睡眠和觉醒障碍极为常见，患者难以应对。睡眠和觉醒障碍会导致 TBI 的功能和情绪结果不佳，但有效的治疗方法仍然难以捉摸。对 TBI 后睡眠和觉醒障碍的潜在机制有更全面的了解，将有助于开发有效的药物治疗方法。先前在人类患者和动物模型中的研究表明，下丘脑泌素能功能的改变可能是 TBI 后睡眠-觉醒障碍的主要原因。在这项研究中，我们通过确定 TBI 对下丘脑泌素敲除（HCRT KO）小鼠睡眠-觉醒行为的影响，进一步阐明了下丘脑泌素的作用。成年雄性 C57BL/6J 和 HCRT KO 小鼠被植入脑电图记录电极，并获得损伤前的基线记录。然后，将小鼠进行中度 TBI 或假手术。在 TBI 或假手术程序后 3、7、15 和 30 天获得额外的记录并确定睡眠-觉醒行为。在基线时，HCRT KO 小鼠的睡眠-觉醒表型与对照 C57BL/6J 小鼠明显不同。TBI 后睡眠-觉醒行为呈基因型依赖性改变：HCRT KO 小鼠的睡眠不受 TBI 影响，而 C57BL/6J 小鼠的非快速眼动睡眠增加，觉醒减少，短觉醒发作增加，长觉醒发作减少。TBI 使 C57BL/6J 小鼠中的下丘脑泌素阳性细胞数量减少。总的来说，这些数据表明，在该模型中，下丘脑泌素能系统参与了 TBI 后睡眠-觉醒行为的改变，并提示潜在的治疗干预措施。
