Effect of aging and a dual orexin receptor antagonist on sleep architecture and NREM oscillations including a REM Behavior Disorder phenotype in the PS19 mouse model of tauopathy.

The impact of tau pathology on sleep microarchitecture features, including slow oscillations, spindles, and their coupling has been understudied, in spite of 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 P301S, both male and female), young 2-3 month PS19 mice show a sleep electrophysiology signature with markedly reduced spindle duration and power and elevated slow oscillation (SO) density compared to littermate controls, even though 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 macro-level, and reduced spindle density, SO density, and spindle-SO coupling at the micro-level. In ∼33% of aged PS19 mice, we unexpectedly observed abnormal goal-directed behaviors in REM, including mastication, paw grasp, and fore limb/hind limb 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 macro- and microarchitecture throughout aging remains unknown. Our key findings include: 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 offline cognitive processing, 3) the novel observation that dream enactment behaviors reminiscent of REM behavior disorder (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 macro- and microarchitecture abnormalities.