Amplitude Model for the Effects of Mutations and Temperature on Period and Phase Resetting of the Neurospora Circadian Oscillator

Abstract

This paper analyzes published and unpublished data on phase resetting of the circadian oscillator in the fungus Neurospora crassa and demonstrates a correlation between period and resetting behavior in several mutants with altered periods: As the period increases, the apparent sensitivity to resetting by light and by cycloheximide decreases. Sensitivity to resetting by temperature pulses may also decrease. We suggest that these mutations affect the amplitude of the oscillator and that a change in amplitude is responsible for the observed changes in both period and resetting by several stimuli. As a secondary hypothesis, we propose that temperature compensation of period in Neurospora can be explained by changes in amplitude: As temperature increases, the compensation mechanism may increase the amplitude of the oscillator to maintain a constant period. A number of testable predictions arising from these two hypotheses are discussed. To demonstrate these hypotheses, a mathematical model of a time-delay oscillator is presented in which both period and amplitude can be increased by a change in a single parameter. The model exhibits the predicted resetting behavior: With a standard perturbation, a smaller amplitude produces type 0 resetting and a larger amplitude produces type 1 resetting. Correlations between period, amplitude, and resetting can also be demonstrated in other types of oscillators. Examples of correlated changes in period and resetting behavior in Drosophila and hamsters raise the possibility that amplitude changes are a general phenomenon in circadian oscillators.

Assessment of circadian function in fibroblasts of patients with bipolar disorder

“…90 It has been reported that reduced amplitude of circadian oscillators can increase the efficacy of perturbing agents such as light and other stimuli in causing phase shifts in various organisms. 89,[91][92][93] Although the observed reduction in the amplitude of circadian gene expression in BPI was subtle and only showed a trend for significance after correction for multiple comparisons, it is possible that the core clocks in bipolar patients are more vulnerable to external stimulation, which may contribute to unstable or more variable circadian rhythms as have been observed in bipolar patients. 13,94,95 Alterations in the overall expression level of core clock genes and clock-controlled genes can lead to anomalies in the circadian rhythmicity.…”

Period Robustness and Entrainability of the Kai System to Changing Nucleotide Concentrations

“…al. (4) and later in more detail by Hatakeyama and Kaneko (7,8). Here we present a specific manifestation of this mechanism at the level of individual hexamers.…”

“…This is a clear signature of another mechanism of period robustness: at higher phosphorylation rates, corresponding to higher α ATP , the rate at which a system goes through state space increases, yet the length of one cycle also increases (4,8). It is important to note that the phenomenon of the variation of the phosphorylation cycle with the bulk ATP level emerges as a prediction of the Paijmans model; we did not deliberately design the model to have this property.…”

“…However, such a clock would not be entrainable, and as a result of biochemical noise, it would inevitably run out of phase with the day-night rhythm. What the properties of an oscillator should be to fulfill both conditions has been studied in different systems, both experimentally and theoretically (4)(5)(6)(7)(8)(9)(10).…”

Semi-algebraic optimization of temperature compensation in a general switch-type negative feedback model of circadian clocks

“…Although molecular and theoretical explanations for many aspects of circadian oscillators have been developed over the past decade [6], there have been few attempts to describe temperature compensation on a mathematical kinetic basis [26]. For an overview on other or related attempts to explain temperature compensation the reader is referred to the following papers [12,13,[15][16][17][18]27,28]. However, a discussion of these various approaches on how to "balance P" is beyond the scope of this paper.…”