Methamphetamine alters the circadian oscillator and its couplings on multiple scales in knockout mice.

Disruptions to circadian rhythms in mammals are associated with alterations in their physiological and mental states. Circadian rhythms are currently analyzed in the time domain using approaches such as actograms, thus failing to appreciate their time-localized characteristics, time-varying nature and multiscale dynamics. In this study, we apply time-resolved analysis to investigate behavioral rhythms in knockout (KO) mice and their changes following methamphetamine administration, focusing on circadian (around 24 h), low-frequency ultradian (around 7 h), high-frequency ultradian (around 30 min), and circabidian (around 48 h) oscillations. In the absence of methamphetamine, KO mice in constant darkness exhibited a dominant, ∼7 h oscillation. We demonstrate that methamphetamine exposure restores the circadian rhythm, although the frequency of the methamphetamine sensitive circadian oscillator varied considerably compared to the highly regular wild-type circadian rhythm. Additionally, methamphetamine increased multiscale activity and induced a circabidian oscillation in the KO mice. The information transfer between oscillatory modes, with frequencies around circadian, low-frequency ultradian and high-frequency ultradian activity, due to their mutual couplings, was also investigated. For 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 genes and following methamphetamine administration may have profound implications for health and disease.