Network properties of interstitial cells of Cajal affect intestinal pacemaker activity and motor patterns, according to a mathematical model of weakly coupled oscillators

Abstract

What is the central question of this study? What are the effects of interstitial cells of Cajal (ICC) network perturbations on intestinal pacemaker activity and motor patterns? What is the main finding and its importance? Two-dimensional modelling of the ICC pacemaker activity according to a phase model of weakly coupled oscillators showed that network properties (coupling strength between oscillators, frequency gradient and frequency noise) strongly influence pacemaker network activity and subsequent motor patterns. The model explains motor patterns observed in physiological conditions and provides predictions and testable hypotheses for effects of ICC loss and frequency modulation on the motor patterns. Interstitial cells of Cajal (ICC) are the pacemaker cells of gut motility and are associated with motility disorders. Interstitial cells of Cajal form a network, but the contributions of its network properties to gut physiology and dysfunction are poorly understood. We modelled an ICC network as a two-dimensional network of weakly coupled oscillators with a frequency gradient and showed changes over time in video and graphical formats. Model parameters were obtained from slow-wave-driven contraction patterns in the mouse intestine and pacemaker slow-wave activities from the cat intestine. Marked changes in propagating oscillation patterns (including changes from propagation to non-propagating) were observed by changing network parameters (coupling strength between oscillators, the frequency gradient and frequency noise), which affected synchronization, propagation velocity and occurrence of dislocations (termination of an oscillation). Complete uncoupling of a circumferential ring of oscillators caused the proximal and distal section to desynchronize, but complete synchronization was maintained with only a single oscillator connecting the sections with high enough coupling. The network of oscillators could withstand loss; even with 40% of oscillators lost randomly within the network, significant synchronization and anterograde propagation remained. A local increase in pacemaker frequency diminished anterograde propagation; the effects were strongly dependent on location, frequency gradient and coupling strength. In summary, the model puts forth the hypothesis that fundamental changes in oscillation patterns (ICC slow-wave activity or circular muscle contractions) can occur through physiological modulation of network properties. Strong evidence is provided to accept the ICC network as a system of coupled oscillators.

Keywords: coupled oscillators; interstitial cells of Cajal; intestinal motility; mathematical modeling.