The destruction of ultradian and circadian rhythms

Alanazi, Mansour and Stefanovska, Aneta (2024) The destruction of ultradian and circadian rhythms. PhD thesis, Lancaster University.

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Abstract

One of the most generally recognised rhythms observed across various living creatures is the circadian rhythm, a recurrent biological activity lasting around 24 hours. It is said to have evolved in reaction to the regular environmental alternation of light and darkness. Pacemaker cells, which are thought to be critical in generating the circadian rhythm, have been identified in suprachiasmatic nucleus (SCN) in 1972. However, there is ongoing discussion about whether the circadian rhythm is a truly basic rhythm generated in the SCN, or whether alternative mechanism are involved in its modulation. Arousing stimuli, such as scheduled feeding, running wheel access, or methamphetamine (MA) administration, represent non-canonical circadian processes. Here, we investigate the circadian rhythm in genetically modified mice with the Per1/2/3 genes knocked out, resulting in a disturbance of this rhythm, as Per1/2/3 genes are essential components of the mammalian canonical circadian mechanism. Additionally the effect of MA, a potent central nervous system stimulant, was evaluated on Per1/2/3 genes knock out mice. As a reference, a group of wild-type mice was also recorded. In each case wheel running activity was recorded every minute for a period of 4 to 9 weeks. The investigation aimed to deduce whether rhythms remained when the clock genes were disabled and how MA affects them. Nonlinear time-series analysis methods, specifically developed for analysis of oscillatory processes with time-varying frequencies, where used to analyse the recorded time series. We show that MA restores the circadian rhythm and increases the total power. Moreover, the rhythm gets more irregular with MA administration compared to the wild-type case. Additionally, MA introduces a new circabidian rhythm at around 40 hours. In addition to the power analysis, couplings between rhythms on different timescales were considered. Firstly, harmonic analysis was performed to deduce which of the observed oscillations result from independent modes. This analysis revealed that, in all Per1/2/3 knock out mice not exposed to MA, there is a harmonic relationship between the 7 and 3.5 hour cycles. Following this, to elucidate the coupling between the remaining independent modes, bispectral analysis and dynamic Bayesian inference were applied. The Per1/2/3 knocked out mice exposed to MA exhibited coupling between ∼24 hours and ∼1 hour oscillations, while in the Per1/2/3 knocked out mice not exposed to MA a coupling between ∼8 hours and ∼1 hour oscillations was observed. This study revealed the relationship between oscillators in the absence of a canonical circadian clock as well as the effect of MA. Power and coupling analyses provide a useful approach for understanding the functional significance of behavioural rhythms. Such investigations are vital, as disruptions in circadian rhythms are implicated in various diseases, including cancer, obesity, and mood disorders. Based on the obtained results a phenomenological model was developed. It elucidates the dynamic characteristics of circadian rhythms in Per1/2/3 knockout mice, particularly focusing on the alterations induced by methamphetamine exposure. The model captures the time-varying nature of oscillations and their interactions, providing insights into the underlying mechanisms of circadian regulation and potential implications for behavioural health.