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.

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.

Dynamics of sleep spindles and coupling to slow oscillations following motor learning in adult mice.

Sleep spindles have been implicated in motor learning in human subjects, but their occurrence, timing in relation to cortical slow oscillations, and relationship to offline gains in motor learning have not been examined in animal models. In this study, we recorded EEG over bilateral primary motor cortex in conjunction with EMG for 24 h following a period of either baseline handling or following rotarod motor learning to monitor sleep. We measured several biophysical properties of sleep spindles and their temporal coupling with cortical slow oscillations (SO, <1 Hz) and cortical delta waves (1-4 Hz). Following motor learning, we found an increase in spindles during an early period of NREM sleep (1-4 h) without changes to biophysical properties such as spindle power, peak frequency and coherence. In this same period of early NREM sleep, both SO and delta power increased after motor learning. Notably, a vast majority of spindles were associated with minimal SO power, but in the subset that were associated with significant SO power (>1 z-score above the population mean), spindle-associated SO power was greater in spindles following motor learning compared to baseline sleep. Also, we did not observe a group-level preferred phase in spindle-SO or spindle-delta coupling. While SO power alone was not predictive of motor performance in early NREM sleep, both spindle density and the difference in the magnitude of the mean resultant vector length of the phase angle for SO-associated spindles, a measure of its coupling precision, were positively correlated with offline change in motor performance. These findings support a role for sleep spindles and their coupling to slow oscillations in motor learning and establish a model in which spindle timing and the brain circuits that support offline plasticity can be mechanistically explored.