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.

Interactions between sleep disruption, motor learning, and p70 S6 kinase 1 signaling.

Offline gains in motor performance after initial motor learning likely depend on sleep, but the molecular mechanisms by which this occurs are understudied. Regulation of mRNA translation via p70 S6 kinase 1 (S6K1) signaling represents one potential mechanism, as protein synthesis is thought to be increased during sleep compared to wake and is necessary for several forms of long-term memory. Using phosphorylation of ribosomal protein S6 (RpS6) as a readout of S6K1 activity, we demonstrate that a period of 10 h of acute sleep disruption impairs both S6K1 signaling and offline gains in motor performance on the rotarod in adult wild type C57/Bl6 mice. Rotarod motor learning results in increased abundance of RpS6 in the striatum, and inhibition of S6K1 either indirectly with rapamycin or directly with PF-4708671 diminished the offline improvement in motor performance without affecting the initial acquisition of rotarod motor learning when sleep is normal. In sum, S6K1 activity is required for sleep-dependent offline gains in motor performance and is inhibited following acute sleep disruption, while motor learning increases the abundance of striatal RpS6. Thus, S6K1 signaling represents a plausible mechanism mediating the beneficial effects of sleep on motor performance.

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.

Necessity of Sleep for Motor Gist Learning in Mice.

With respect to behavior, the term memory "consolidation" has canonically been used to describe increased fidelity during testing to a learned behavior shaped during training. While the sleeping brain appears to certainly aid in consolidation by this definition for a variety of memories, including motor memories, growing evidence suggests that sleep allows for much more flexible use of the information encountered during prior wakefulness. Sleep has been shown to augment the extraction of gist or patterns from wake experience in human subjects, but this has been difficult to recapitulate in animal models owing to the semantic requirements in many such tasks. Here we establish a model of motor gist learning in mice in which two bouts of exclusive forward running on the rotarod significantly augments the first experience of exclusive backward running. This augmentation does not occur if sleep is disrupted following the forward running template behavior or if a period of natural wakefulness follows one of the two bouts of exclusive forward running. This suggests that sleep is required for the extraction of the motor gist of forward running to apply to backward running.

Role of normal sleep and sleep apnea in human memory processing.

A fundamental problem in the field of obstructive sleep apnea (OSA) and memory is that it has historically minimized the basic neurobiology of sleep's role in memory. Memory formation has been classically divided into phases of encoding, processing/consolidation, and retrieval. An abundance of evidence suggests that sleep plays a critical role specifically in the processing/consolidation phase, but may do so differentially for memories that were encoded using particular brain circuits. In this review, we discuss some of the more established evidence for sleep's function in the processing of declarative, spatial navigational, emotional, and motor/procedural memories and more emerging evidence highlighting sleep's importance in higher order functions such as probabilistic learning, transitive inference, and category/gist learning. Furthermore, we discuss sleep's capacity for memory augmentation through targeted/cued memory reactivation. OSA - by virtue of its associated sleep fragmentation, intermittent hypoxia, and potential brain structural effects - is well positioned to specifically impact the processing/consolidation phase, but testing this possibility requires experimental paradigms in which memory encoding and retrieval are separated by a period of sleep with and without the presence of OSA. We argue that such paradigms should focus on the specific types of memory tasks for which sleep has been shown to have a significant effect. We discuss the small number of studies in which this has been done, in which OSA nearly uniformly negatively impacts offline memory processing. When periods of offline processing are minimal or absent and do not contain sleep, as is the case in the broad literature on OSA and memory, the effects of OSA on memory are far less consistent.