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Programme
Contents
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The small intestine exhibits several motor patterns that are seen in distinctly different physiological circumstances. After a meal, the duodenum and jejunum enter the ‘fed state', a mix of stationary constrictions of the circular muscle, constrictions that propagate slowly for short distances and constrictions that propagate rapidly over long distances. The first two are generally termed segmentation, the last are propulsive and usually termed peristalsis. The proportions of segmenting (mixing) and propulsive constrictions depend on the nutrient content of the meal. In fasting animals, migrating motor complexes (MMCs) replace the fed state in small intestine. Each pattern requires coordinated activity of many neuron subtypes in the enteric neural circuitry.
We have used several different computational models to investigate various aspects of the neural regulation of motility. We began using anatomically realistic models incorporating leaky-integrate-and-fire neurons with appropriate after-potentials to simulate intrinsic sensory neurons (ISNs). This showed that the ISNs, which are interconnected via slow excitatory synaptic potentials in recurrent excitatory feedback loops, can operate in two distinct states as either encoding ongoing sensory stimuli or as “driver” neurons that propagate the activity front of MMCs. A simpler model showed that the rate of propagation of MMCs is too slow for this to be carried via conventional interneurons within enteric circuits.
We built on these realistic models by constructing more abstracted models to ask key questions about the motor activity in the fed state. In vitro data indicate that a one motor pattern evoked by intraluminal nutrient involves rhythmic constrictions that appear simultaneously over 4 - 6 mm of duodenum or jejunum, but do not propagate. However, enteric neural pathways are polarized with excitatory pathways running orally and inhibitory pathways running anally. We used a reduced model to identify conditions under which a polarized circuit, repeated as regular overlapping units, could produce the rhythmic stationary contractions characteristic of the fed state. The activity of the muscle at any point was given by the sum of the activity of the excitatory and inhibitory motor neurons innervating that point. A local stimulus at a single point along the intestine produced polarized reflexes similar to the ascending excitation and descending inhibition, identified 120 years ago. After incorporation of newly identified anatomical connections between descending interneurons and ascending interneurons, localized stimuli also evoked a descending excitatory reflex similar to that recently identified in guinea-pig ileum. However, when the stimulus was distributed along the intestinal segment, mimicking the presence of nutrients after a meal, then local irregularities in synaptic connections led to stationary segmenting activity. Predictions of this model were tested in in vitro experiments, which confirmed its predictive validity.
Most recently, we used an abstracted model to examine the role of the slow after-hyperpolarizing potentials (AHPs) of ISNs in setting the timing of contractile activity in the fed state. This model omitted the ascending and descending projections of the enteric neurons, but incorporated contraction activated positive feedback from the muscle and fast and slow excitatory transmission from ISNs to excitatory and inhibitory motor neurons, respectively. We found that the alternating patterns of contractile activity and quiescence seen with nutrient induced segmentation could be explained by this model as could the effects of blocking the AHPs.
We are now developing more realistic single neuron models and testing the predictions of our models with further in vitro experimentation.