Novel murine closed-loop auditory stimulation paradigm elicits macrostructural sleep benefits in neurodegeneration

Boosting slow-wave activity (SWA) by modulating slow waves through closed-loop auditory stimulation (CLAS) might provide a powerful non-pharmacological tool to investigate the link between sleep and neurodegeneration. Here, we established mouse CLAS (mCLAS)-mediated SWA enhancement and explored its effects on sleep deficits in neurodegeneration, by targeting the up-phase of slow waves in mouse models of Alzheimer's disease (AD, Tg2576) and Parkinson's disease (PD, M83). We found that tracking a 2 Hz component of slow waves leads to highest precision of non-rapid eye movement (NREM) sleep detection in mice, and that its combination with a 30° up-phase target produces a significant 15-30% SWA increase from baseline in wild-type (WT_AD) and transgenic (TG_AD) mice versus a mock stimulation group. Conversely, combining 2 Hz with a 40° phase target yields a significant increase ranging 30-35% in WT_PD and TG_PD mice. Interestingly, these phase-target-triggered SWA increases are not genotype dependent but strain specific. Sleep alterations that may contribute to disease progression and burden were described in AD and PD lines. Notably, pathological sleep traits were rescued by mCLAS, which elicited a 14% decrease of pathologically heightened NREM sleep fragmentation in TG_AD mice, accompanied by a steep decrease in microarousal events during both light and dark periods. Overall, our results indicate that model-tailored phase targeting is key to modulate SWA through mCLAS, prompting the acute alleviation of key neurodegeneration-associated sleep phenotypes and potentiating sleep regulation and consolidation. Further experiments assessing the long-term effect of mCLAS in neurodegeneration may majorly impact the establishment of sleep-based therapies.