Process-Oriented Geometric Singular Perturbation Theory and Calcium Dynamics

TL;DR

This paper develops a process-oriented geometric singular perturbation theory approach to analyze complex calcium dynamics in biological systems, identifying multiple small parameters and proving the existence of stable multi-scale oscillations.

Contribution

It introduces a heuristic for identifying small parameters in multi-scale ODE models, especially with switching, and applies GSPT with blow-up to prove stable oscillations in calcium dynamics.

Findings

Identified five small parameters related by a polynomial scaling law.

Proved existence and uniqueness of stable relaxation oscillations with three time-scales.

Provided estimates for oscillation periods and onset scenarios.

Abstract

Phenomena in chemistry, biology and neuroscience are often modelled using ordinary differential equations (ODEs) in which the right-hand-side is comprised of terms which correspond to individual 'processes' or 'fluxes'. Frequently, these ODEs are characterised by multiple time-scale phenomena due to order of magnitude differences between contributing processes and the presence of switching, i.e., dominance or sub-dominance of particular terms as a function of state variables. We outline a heuristic procedure for the identification of small parameters in ODE models of this kind, with a particular emphasis on the identification of small parameters relating to switching behaviours. This procedure is outlined informally in generality, and applied in detail to a model for intracellular calcium dynamics characterised by switching and multiple (more than two) time-scale dynamics. A total of five small parameters are identified, and related to a single perturbation parameter by a polynomial scaling law based on order of magnitude comparisons. The resulting singular perturbation problem has a time-scale separation which depends on the region of state space. We prove the existence and uniqueness of stable relaxation oscillations with three distinct time-scales using a coordinate-independent formulation of GSPT in combination with the blow-up method. We also provide an estimate for the period of the oscillations, and consider a number of possibilities for their onset under parameter variation.