The destruction of ultradian and circadian rhythms
Creators: name: Alanazi, Mansour
Publisher: name: Lancaster University
Year: 2024
Subjects: non-linear dynamics
circadian rhythm
time-series analysis
coupled oscillators
bispectral analysis
methamphetamine
geneticaly modified rhythms
ultradian rhythms
mice
behavioural study

description: 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.