Rapid, noninvasive, and unsupervised detection of sleep/wake using piezoelectric monitoring for pharmacological studies in narcoleptic mice

Background: Assessment of sleep/wake by electroencephalography (EEG) and electromyography (EMG) is invasive, resource intensive, and not amenable to rapid screening at scale for drug discovery. In the preclinical development of therapeutics for narcolepsy, efficacy tests are hindered by the lack of a non-EEG/EMG based translational test of symptom severity. The current methods study offers proof-of-principle that PiezoSleep (noninvasive, unsupervised piezoelectric monitoring of gross body movement, together with respiration patterns during behavioral quiescence), can be used to determine sleep/wake as applicable to the development of wake-promoting therapeutics. First, the translational wake-maintenance score (the ratio of time during the first half of the dark period spent in long wake bouts to short sleep bouts) was introduced as a means by which to rank narcoleptic and wild type mice by sleepiness severity. The wake-maintenance score was used in the PiezoSleep narcolepsy screen to identify the most highly symptomatic mice for resource-intensive EEG/EMG studies for further analysis of specific arousal states. Second, PiezoSleep was demonstrated for use in high-throughput screening of wake-promoting compounds using modafinil in narcoleptic and wild type mice. Results: The PiezoSleep narcolepsy screen revealed a 15-fold difference in wake-maintenance scores between wild type mice and the most severely affected narcoleptic mice. Follow-up EEG/EMG study indicated 82% of the narcoleptic mice with the lowest wake-maintenance scores met or exceeded the cataplexy-occurrence threshold (≥ 3 bouts) for inclusion in therapeutic efficacy studies. In the PiezoSleep dose-response study, the ED50 for wake-promotion by modafinil was approximately 50 mg/kg in both genotypes. Using unsupervised piezoelectric monitoring, the efficacy of wake-promoting compounds can be determined in a 5-arm study with 60 mice in less than one week--a fraction of the time compared to EEG/EMG studies. Conclusions: PiezoSleep offers rapid, scalable assessment of sleep/wake for high-throughput screening in drug discovery.