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Designer receptors exclusively activated by designer drugs (DREADDs) are chemogenetic tools for remote control of targeted cell populations using chemical actuators that bind to modified receptors. Despite the popularity of DREADDs in neuroscience and sleep research, potential effects of the DREADD actuator clozapine-N-oxide (CNO) on sleep have never been systematically tested. Here, we show that intraperitoneal injections of commonly used CNO doses (1, 5, and 10 mg/kg) alter sleep in wild-type male laboratory mice. Using electroencephalography (EEG) and electromyography (EMG) to analyse sleep, we found a dose-dependent suppression of rapid eye movement (REM) sleep, changes in EEG spectral power during non-REM (NREM) sleep, and altered sleep architecture in a pattern previously reported for clozapine. Effects of CNO on sleep could arise from back-metabolism to clozapine or binding to endogenous neurotransmitter receptors. Interestingly, we found that the novel DREADD actuator, compound 21 (C21, 3 mg/kg), similarly modulates sleep despite a lack of back-metabolism to clozapine. Our results demonstrate that both CNO and C21 can modulate sleep of mice not expressing DREADD receptors. This implies that back-metabolism to clozapine is not the sole mechanism underlying side effects of chemogenetic actuators. Therefore, any chemogenetic experiment should include a DREADD-free control group injected with the same CNO, C21, or newly developed actuator. We suggest that electrophysiological sleep assessment could serve as a sensitive tool to test the biological inertness of novel chemogenetic actuators.

Sleep-wake history, wake behaviors, lighting conditions, and circadian time influence sleep, but neither their relative contribution nor the underlying mechanisms are fully understood. The dynamics of electroencephalogram (EEG) slow-wave activity (SWA) during sleep can be described using the two-process model, whereby the parameters of homeostatic Process S are estimated using empirical EEG SWA (0.5-4 Hz) in nonrapid eye movement sleep (NREMS), and the 24 hr distribution of vigilance states. We hypothesized that the influence of extrinsic factors on sleep homeostasis, such as the time of day or wake behavior, would manifest in systematic deviations between empirical SWA and model predictions. To test this hypothesis, we performed parameter estimation and tested model predictions using NREMS SWA derived from continuous EEG recordings from the frontal and occipital cortex in mice. The animals showed prolonged wake periods, followed by consolidated sleep, both during the dark and light phases, and wakefulness primarily consisted of voluntary wheel running, learning a new motor skill or novel object exploration. Simulated SWA matched empirical levels well across conditions, and neither waking experience nor time of day had a significant influence on the fit between data and simulation. However, we consistently observed that Process S declined during sleep significantly faster in the frontal than in the occipital area of the neocortex. The striking resilience of the model to specific wake behaviors, lighting conditions, and time of day suggests that intrinsic factors underpinning the dynamics of Process S are robust to extrinsic influences, despite their major role in shaping the overall amount and distribution of vigilance states across 24 hr. ispartof: SLEEP vol:41 issue:7 ispartof: location:United States status: published

Introduction: Our previous survey and diary studies have shown that the adolescents attending school on rotating morning and afternoon school schedules obtain recommended amount of sleep and schedule their sleep at preferred time in 9 out of 14 days of such schedule. In this study, we wanted to compare several objective and subjective indices of sleep and sleepiness over two consecutive weeks with different school start times (SST). We also wanted to examine the relative contribution of different sleep and sleepiness measures in predicting depressiveness on weekends following each school schedule. Methods: A total of 21 secondary school students (11 females, 16 y) participated in the study. They were keeping sleep-wake diaries, wearing wrist actigraphs, and giving sleepiness ratings at predesignated times with actigraph-score option for two consecutive weeks with alternating morning and afternoon SST, and the respective week-ends. On Fridays of each school week they came to laboratory where MSLT measurements were conducted four times at two-h intervals. Results: During both school weeks students went to bed at similar times, reported similar sleep quality and had similar sleep efficiency. However, on week with afternoon SST they slept on average 81 min longer (p< 0.001) due to significantly later wake-up times. On week with morning SST, social jetlag was on average 2.03 h in contrast to 1.23 h on week with afternoon SST (p< 0.01). Differences in self-reported sleepiness during school weeks and in physiological sleepiness at the end of school weeks with different SST were not found. Regression model for morning schedule explained 53.2% of variance of depressive symptoms (p< 0.05), with average sleep duration and subjective daytime sleepiness being significant individual predictors. Physiological sleepiness at the end of school week did not predict depressiveness on the respective weekend. The regression model for afternoon school schedule was overall not significant. Conclusion: In adolescents on weekly rotating school schedules, morning SST results both in shorter sleep duration and greater sleep irregularity between school days and weekends than the afternoon SST. Our results indicate that sleep loss on school days and subjectively reported sleepiness have a significant impact on depressive symptoms reported on weekend following morning SST. Disclosure: No

Objective: The results of our pre-COVID studies on sleep quality (SQ) in older adults showed that SQ was impaired in 71% of residents of nursing homes (NH) and in 50% of community dwelling older adults of comparable age. During the COVID-19 pandemic older adults, and especially NH residents, have been at higher risk of SARS-CoV-2 infection, impairments in SQ and impairments in mental health due to physical distancing restrictions. The aim of the present study was to examine SQ in NH residents during the COVID-19 pandemic and to compare it with the results of NH residents collected five years earlier. Method: The results of 202 residents of several NH in Zagreb (79% females, 69-97) collected in 2021 were analysed and compared to results of other 161 participants (80% females, 63-100 years) collected in 2016. Participants were ambulatory, without diagnosis of dementia, and the data was collected in NHs as part of larger studies. Participants answered the questionnaires with either a trained interviewer assistance (in 2016) or themselves with researchers’ control and assistance (in 2021). SQ was assessed by Pittsburgh Sleep Quality Index (PSQI). In both studies participants self- rated their subjective health in comparison to their peers, and answered different loneliness scales with two comparable items. Results: Total PSQI score was greater than 5 in 48% of NH residents in 2021, which was lower percentage than in 2016. Multivariate ANOVAs showed that participants in 2021 rated their health significantly poorer in comparison to their peers than participants in 2016(p < 0.001), and they reported more impairments in daytime functioning (p < 0.05). However, their SQ was generally less impaired (M[PSQI2021] = 6.77 vs. M[PSQI2016] = 8.26, p < 0.001), their sleep duration longer (p < 0.001) and sleep efficiency better than in participants in 2016 (p < 0.001). Conclusion: The accelerated turnover due to COVID- 19 pandemic may have changed the characteristics of residents of long-term care setting who may perceive themselves as having poorer health but reporting generally better SQ. In analysing SQ in NH residents during the COVID-19 pandemic it is especially important to consider wider socio- cultural context. Disclosure: No