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.

Dynamic slow‐wave interactions in the rabbit small intestine defined using high‐resolution mapping

“…Lammers et al also demonstrated these events in the in vivo canine small intestine and proposed the dissociations could be an effect of anesthetic induction. Previous studies have shown that an increased prevalence of dissociated activity (where the wave terminates without an apparent cause of the block) is associated with a steeper slow‐wave frequency gradient . We have now shown in spatiotemporal detail that dissociated activity can reorganize over time.…”

“…Sarna et al specified this event as “amyogenesia” to indicate the dissociations in the small intestine as the resultant effect of specified anesthesia. Wei et al suggested the dissociations may happen if the corresponding ICC have insufficient coupling strength within the adjacent ICC for the entrainment. Lammers et al also demonstrated these events in the in vivo canine small intestine and proposed the dissociations could be an effect of anesthetic induction.…”

Acute Cholecystitis Reduces Interstitial Cells of Cajal in Porcine Gallbladder Through Decreased mRNA Synthesis

“…ICCs were first described in detail in the gastrointestinal tract by Santiago Ramo´n y Cajal in 1893 [18,19], and they express the specific marker, c-kit [20]. ICCs in the gastrointestinal tract are the pacemaker cells of gut motility and are related to motility disorders [21]. Recent studies have shown that reduced biliary system ICCs, ICC injury or loss of function, and compromises in the and c-kit/SCF pathway may play important roles in biliary system motility diseases, including cholelithiasis [16,17] and may be closely connected to malignant tumors in the biliary system.…”

Decrease of Nitrergic Innervation in the Esophagus of Patients with Chagas Disease: Correlation with Loss of Interstitial Cells of Cajal

“…It is well known that, like other cells, the number of ICCs is controlled by several factors that regulate proliferation and death and that ICCs continuously undergo apoptosis in the GI tract of healthy individuals [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31]. Because neurons produce Stem Cell Factor (SCF), which activates the c-kit receptor and stimulates the proliferation, survival…”

“…This process is essential for muscle relaxation during peristalsis and it allows for the passage of gut contents [14,15]. Commonly observed in several regions of the GI tract, the ICCs are responsible for generating and propagating "slow waves" to the muscle layers, constituting the pacemaker system [16,17]. This system regulates the membrane potential of smooth muscle cells.…”