Macroscopic Models and Phase Resetting of Coupled Biological Oscillators

Abstract

This thesis concerns the derivation and analysis of macroscopic mathematical models for coupled biological oscillators. Circadian rhythms, heart beats, and brain waves are all examples of biological rhythms formed through the aggregation of the rhythmic contributions of thousands of cellular oscillations. These systems evolve in an extremely high-dimensional phase space having at least as many degrees of freedom as the number of oscillators. This high-dimensionality often contrasts with the low-dimensional behavior observed on the collective or macroscopic scale. Moreover, the macroscopic dynamics are often of greater interest in biological applications.

Therefore, it is imperative that mathematical techniques are developed to extract low-dimensional models for the macroscopic behavior of these systems. One such mathematical technique is the Ott-Antonsen ansatz. The Ott-Antonsen ansatz may be applied to high-dimensional systems of heterogeneous coupled oscillators to derive an exact low-dimensional description of the system in terms of macroscopic variables. We apply the Ott-Antonsen technique to determine the sensitivity of collective oscillations to perturbations with applications to neuroscience.

The power of the Ott-Antonsen technique comes at the expense of several limitations which could limit its applicability to biological systems. To address this we compare the Ott-Antonsen ansatz with experimental measurements of circadian rhythms and numerical simulations of several other biological systems. This analysis reveals that a key assumption of the Ott-Antonsen approach is violated in these systems. However, we discover a low-dimensional structure in these data sets and characterize its emergence through a simple argument depending only on general phase-locking behavior in coupled oscillator systems. We further demonstrate the structure's emergence in networks of noisy heterogeneous oscillators with complex network connectivity. We show how this structure may be applied as an ansatz to derive low-dimensional macroscopic models for oscillator population activity. This approach allows for the incorporation of cellular-level experimental data into the macroscopic model whose parameters and variables can then be directly associated with tissue- or organism-level properties, thereby elucidating the core properties driving the collective behavior of the system.

We first apply our ansatz to study the impact of light on the mammalian circadian system. To begin we derive a low-dimensional macroscopic model for the core circadian clock in mammals. Significantly, the variables and parameters in our model have physiological interpretations and may be compared with experimental results. We focus on the effect of four key factors which help shape the mammalian phase response to light: heterogeneity in the population of oscillators, the structure of the typical light phase response curve, the fraction of oscillators which receive direct light input and changes in the coupling strengths associated with seasonal day-lengths. We find these factors can explain several experimental results and provide insight into the processing of light information in the mammalian circadian system.

In a second application of our ansatz we derive a pair of low-dimensional models for human circadian rhythms. We fit the model parameters to measurements of light sensitivity in human subjects, and validate these parameter fits with three additional data sets. We compare our model predictions with those made by previous phenomenological models for human circadian rhythms. We find our models make new predictions concerning the amplitude dynamics of the human circadian clock and the light entrainment properties of the clock. These results could have applications to the development of light-based therapies for circadian disorders.