Insights into mechanisms of intestinal segmentation in guinea pigs: a combined computational modeling and in vitro study

Abstract

Segmentation in the guinea pig small intestine consists of a number of discrete motor patterns including rhythmic stationary contractions that occur episodically at specific locations along the intestine. The enteric nervous system regulates segmentation, but the exact circuit is unknown. Using simple computer models, we investigated possible circuits. Our computational model simulated the mean neuron firing rate in the feedforward ascending and descending reflex pathways. A stimulus-evoked pacemaker was located in the afferent pathway or in a feedforward pathway. Output of the feedforward pathways was fed into a simple model to determine the response of the muscle. Predictions were verified in vitro by using guinea pig jejunum, in which segmentation was induced with luminal fatty acid. In the computational model, local stimuli produced an oral contraction and anal dilation, similar to in vitro responses to local distension, but did not produce segmentation. When the stimulus was distributed, representing a nutrient load, the result was either a tonic response or globally synchronized oscillations. However, when we introduced local variations in synaptic coupling, stationary contractions occurred around these locations. This predicts that severing the ascending and descending pathways will induce stationary contractions. An acute lesion in our in vitro model significantly increased the number of stationary contractions immediately oral and anal to the lesion. Our results suggest that spatially localized rhythmic contractions arise from a local imbalance between ascending excitatory and descending inhibitory muscle inputs and require a distributed stimulus and a rhythm generator in the afferent pathway.