Reflex pathways in the control of intestinal motility

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DESCRIPTION (provided by applicant): Abnormal changes in colonic smooth muscle tone and motility are pathological indicators of GI disorders. However the relationship between muscle tone, enteric neural activity and propulsion is unclear. The release of excitatory and inhibitory neurotransmitters regulates tone of both the longitudinal (LM) and circular muscle (CM) layers. It is generally unappreciated that muscle tone itself can alter activity in the enteric nervous system. Our novel preliminary findings suggest that both tone dependent and tone independent (stretch activated) motility patterns exist, but these motor activities are different in proximal and distal isolated colon. These different motor patterns will provide us with an important window of opportunity to dissect out, for the first time, the tone dependent and independent neural circuitry underlying colonic motor activity. We demonstrate that these motor patterns appear to be regulated by two different intrinsic sensor/neurons: IPANS {AH-neurons) that are sensitive to muscle tone and contraction and ascending interneurons whose activity is stretch dependent but independent of muscle tone. Therefore, sensory transduction in the ENS is analogous to that in the somatic nervous system where Golgi tendon organs and muscle spindles provide complementary information regarding muscle tension and muscle length respectively. Furthermore, we show that the sensory processes of these two neurons appear to be located within the CM but not the LM. We will use the isolated guinea-pig proximal and distal colon, to determine: AIM 1: how stretch activates muscle tone dependent and tone independent neural reflex pathways that underlie propulsive activities in proximal and distal colon. AIM 2: the extent of activation of LM cells and myenteric neurons around the circumference of the colon during stretch induced motor reflexes. AIM 3: whether the LM or CM is necessary for sensory transduction underlying motor activities in the large intestine. AIM 4: the role and firing patterns of myenteric AH and S neurons and submucosal neurons in colonic motor activities. Several new techniques will be used, which indclude: 1) Simultaneous intracellular recordings from LM or CM cells and from myenteric or submucosal neurons. 2) Video imaging of movements of the gut wall. 3) Calcium imaging of neurons and muscle. 4) Intracellular recording from Dil retrogradely labeled mechanosensitive ascending interneurons.