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Intrinsic Neural Reflexes Regulating Colonic Motility
AuthorHeredia, Dante J.
AdvisorSmith, Terence K.
Biochemistry and Molecular Biology
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The studies performed in this dissertation have examined the basic intrinsic neural reflexes regulating colonic motility and their relevance to chronic slow transit constipation. We were able to propose several enteric circuits that underlie different neural reflexes.With a variety of techniques we were able to thoroughly examine the following aspects involved in generation and propagation of colonic motility patterns; overall propulsive activity was characterized with video analysis followed by the construction of spatio temporal maps, mechanical contractile activity was recorded with isometric tension transducers, the activity of a syncytium of muscle fibers was recorded using intracellular microelectrodes and high-resolution calcium imaging allowed us to observe calcium activity in myenteric neurons and muscle fibers within the colon. Throughout this dissertation, we have learned that a fecal matter in the lumen of the colon activates local excitatory and inhibitory reflexes that determine the site of origin and propagation of the colonic migrating motor complex (CMMC), which is responsible for movement of colonic contents. The generation of the CMMC involves many processes; one of which is the excitatory component of contraction that requires the release of acetylcholine (ACh) and tachykinins from excitatory motor neurons to activate the smooth muscle and interstitial cells of Cajal (ICC). ACh and tachykinins activate muscarinic receptors (M2,3 on muscle and ICC), NK2 receptors (muscle) and NK1 receptors (ICC). The propagation of the CMMC requires the activation of inhibitory motor neurons that release purines and nitric oxide (NO) to relax the smooth muscle. Additionally, colonic elongation occurs naturally during colonic filling or accommodation. Colonic elongation releases NO from mechanosensative interneurons that depress the neural circuitry responsible for initiating, generating and propagating the CMMC. Therefore, elongation causes accommodation of fecal pellets and slows their transit through the colon. We have found that the colon is always under ongoing neural activity both between (tonic inhibition) and during CMMCs. 5-hydroxytryptomine (5-HT) appears to be essential for generating patterns of colonic motility. Between CMMCs, ongoing activity in descending serotonergic interneurons, which release both 5-HT and ACh to activate inhibitory motor neurons and provide tonic inhibition of the muscle. Spontaneous and evoked release of 5-HT from EC cells by fecal pellets is important in initiating and directing the propagation direction of the CMMC. Stools apply pressure to enterochromaffin (EC) cells that release 5-HT to activate 5-HT3 receptors on the mucosal endings of AH sensory neurons, which leads to the generation of the CMMC. Furthermore, we have shown that various 5-HT receptor subtypes (5-HT1A, 5-HT3, and 5-HT7 ) are involved in the initiation and generation of the CMMC by modulating the output of mucosally projecting AH neurons to interneurons underlying the CMMC. In our animal model of slow transit constipation, we found that the release of mucosal 5-HT and 5-HT released from descending serotonergic inhibitory pathway had been compromised leading to dysfunction of colonic motility. Collectively these studies demonstrate the complexity of the enteric nervous system beyond the simple basic idea of the "Law of the Intestine" (contraction behind and relaxation in front of a bolus) as first postulated by Bayliss & Starling (1899). Lessons learned from our observations of colonic motility in mice are likely applicable to both the normal physiology and pathology of the colon in humans, as humans (and most other mammals) have been observed to have similar CMMC patterns to mice.