The impact of tau pathology on sleep microarchitecture features, including slow oscillations, spindles, and their coupling, has been understudied, despite the proposed importance of these electrophysiological features toward learning and memory. Dual orexin receptor antagonists (DORAs) are known to promote sleep, but whether and how they affect sleep microarchitecture in the setting of tauopathy is unknown. In the PS19 mouse model of tauopathy MAPT (microtubule-associated protein tau) P301S (both male and female), young PS19 mice 2–3 months old show a sleep electrophysiology signature with markedly reduced spindle duration and power and elevated slow oscillation (SO) density compared with littermate controls, although there is no significant tau hyperphosphorylation, tangle formation, or neurodegeneration at this age. With aging, there is evidence for sleep disruption in PS19 mice, characterized by reduced REM duration, increased non-REM and REM fragmentation, and more frequent brief arousals at the macrolevel and reduced spindle density, SO density, and spindle-SO coupling at the microlevel. In ~33% of aged PS19 mice, we unexpectedly observed abnormal goal-directed behaviors in REM, including mastication, paw grasp, and forelimb/hindlimb extension, seemingly consistent with REM behavior disorder (RBD). Oral administration of DORA-12 in aged PS19 mice increased non-REM and REM duration, albeit with shorter bout lengths, and increased spindle density, spindle duration, and SO density without change to spindle–SO coupling, power in either the SO or spindle bands, or the arousal index. We observed a significant effect of DORA-12 on objective measures of RBD, thereby encouraging future exploration of DORA effects on sleep-mediated cognition and RBD treatment.

SIGNIFICANCE STATEMENT The specific effect of tauopathy on sleep macroarchitecture and microarchitecture throughout aging remains unknown. Our key findings include the following: (1) the identification of a sleep EEG signature constituting an early biomarker of impending tauopathy; (2) sleep physiology deteriorates with aging that are also markers of off-line cognitive processing; (3) the novel observation that dream enactment behaviors reminiscent of RBD occur, likely the first such observation in a tauopathy model; and (4) a dual orexin receptor antagonist is capable of restoring several of the sleep macroarchitecture and microarchitecture abnormalities.

尽管有人提出这些电生理特征对学习和记忆的重要性，但 tau 蛋白病理学对睡眠微结构特征（包括慢振荡、纺锤体及其耦合）的影响尚未得到充分研究。众所周知，双重食欲素受体拮抗剂 (DORA) 可以促进睡眠，但它们是否以及如何影响 tau 蛋白病背景下的睡眠微结构尚不清楚。在 tau 蛋白病 MAPT（微管相关蛋白 tau）P301S（雄性和雌性）的 PS19 小鼠模型中，2-3 个月大的年轻 PS19 小鼠表现出睡眠电生理学特征，纺锤体持续时间和功率显着减少，慢振荡 (SO) 升高与同窝对照相比，尽管该年龄没有显着的 tau 蛋白过度磷酸化、缠结形成或神经变性，但密度仍然较高。随着衰老，有证据表明 PS19 小鼠的睡眠受到干扰，其特征是 REM 持续时间缩短、非 REM 和 REM 碎片增加、宏观层面上更频繁的短暂觉醒以及纺锤体密度、SO 密度和纺锤体-SO 耦合的降低。微观层面。在约 33% 的老年 PS19 小鼠中，我们意外地观察到 REM 中异常的目标导向行为，包括咀嚼、抓爪和前肢/后肢伸展，这似乎与 REM 行为障碍 (RBD) 一致。老年 PS19 小鼠口服 DORA-12 增加了非快速眼动和快速眼动持续时间，尽管发作时间较短，并且增加了纺锤体密度、纺锤体持续时间和 SO 密度，而没有改变纺锤体-SO 耦合、SO 或纺锤体的功率条带，或唤醒指数。我们观察到 DORA-12 对 RBD 客观测量有显着影响，从而鼓励未来探索 DORA 对睡眠介导的认知和 RBD 治疗的影响。

意义陈述tau 蛋白病对整个衰老过程中睡眠宏观结构和微观结构的具体影响仍不清楚。我们的主要发现包括以下内容：(1) 睡眠脑电图特征的识别构成了即将发生的 tau 蛋白病的早期生物标志物； (2) 睡眠生理学随着年龄的增长而恶化，这也是离线认知处理的标志； (3) 出现令人想起 RBD 的梦境表现行为的新观察，这可能是 tau 蛋白病模型中的首次此类观察； (4)双重食欲素受体拮抗剂能够恢复多种睡眠宏观结构和微结构异常。