Effect of Aging and a Dual Orexin Receptor Antagonist on Sleep Architecture and Non-REM Oscillations Including an REM Behavior Disorder Phenotype in the PS19 Mouse Model of Tauopathy.

Abstract

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.