Induction and organization of Ca2+ waves by enteric neural reflexes

The motility of the gastrointestinal tract consists of local, non-propulsive mixing (pendular or segmental) and propulsive (peristaltic) movements1,2,3,4,5. It is generally considered that mixing movements are produced by intrinsic pacemakers which generate rhythmic contractions4,5,6, and peristalsis by intrinsic excitatory and inhibitory neural reflex pathways1,2,3,4,5,7,8, but the relationship between mixing and peristalsis is poorly understood4,5,6. Peristalsis is compromised in mice lacking interstitial cells of Cajal9, suggesting that these pacemaker cells10,11,12,13,14 may also be involved in neural reflexes. Here we show that mixing movements within longitudinal muscle result from spontaneously generated waves of elevated internal calcium concentration which originate from discrete locations (pacing sites), spread with anisotropic conduction velocities in all directions, and terminate by colliding with each other or with adjacent neurally suppressed regions. Excitatory neural reflexes control the spread of excitability by inducing new pacing sites and enhancing the overall frequency of pacing, whereas inhibitory reflexes suppress the ability of calcium waves to propagate. We provide evidence that the enteric nervous system organizes mixing movements to generate peristalsis, linking the neural regulation of pacemakers to both types of gut motility.