Barnes, Samuel J K and Alanazi, Mansour and Yamazaki, Shin and Stefanovska, Aneta (2025) Methamphetamine alters the circadian oscillator and its couplings on multiple scales in <i>Per1/2/3</i> knockout mice. PNAS Nexus. ISSN 2752-6542
Full text not available from this repository.Abstract
Disruptions to circadian rhythms in mammals are associated with alterations in their physiological and mental states. Circadian rhythms are currently analysed in the time domain using approaches such as actograms, thus failing to appreciate their time-localised characteristics, time-varying nature and multiscale dynamics. In this study, we apply time-resolved analysis to investigate behavioural rhythms in Per1/2/3 knockout (KO) mice and their changes following methamphetamine administration, focusing on circadian (around 24 hours), low-frequency ultradian (around 7 hours), high-frequency ultradian (around 30 minutes) and circabidian (around 48 hours) oscillations. In the absence of methamphetamine, Per1/2/3 KO mice in constant darkness exhibited a dominant, approximately 7 hour oscillation. We demonstrate that methamphetamine exposure restores the circadian rhythm, although the frequency of the methamphetamine sensitive circadian oscillator (MASCO) varied considerably compared to the highly regular wild-type circadian rhythm. Additionally, methamphetamine increased multiscale activity and induced a circabidian oscillation in the Per1/2/3 KO mice. The information transfer between oscillatory modes, with frequencies around circadian, lowfrequency ultradian and high-frequency ultradian activity, due to their mutual couplings, was also investigated. For Per1/2/3 KO mice in constant darkness, the most prevalent coupling was between low and high-frequency ultradian activity. Following methamphetamine administration, the coupling between the circadian and high-frequency ultradian activity became dominant. In each case, the direction of information transfer was between the corresponding phases from the slower to faster oscillations. The time-varying nature of the circadian rhythm exhibited in the absence of Per1/2/3 genes and following methamphetamine administration may have profound implications for health and disease.