Intrinsic sensory-motor circuits regulating gastric motility

• Applicant: Professorin Gemma Mazzuoli-Weber, Ph.D.
• Subject Area: Nutritional Sciences ; Anatomy and Physiology ; Gastroenterology
• Term: from 2020 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 441752749

The peristaltic reflex, as described more than a century ago, applies to the small and large intestine: activate reflex pathways in the enteric nervous system (ENS), which trigger coordinated oral excitatory and anal inhibitory muscle responses. This “law of the intestine” is relevant for proximal to distal transport of intestinal content but seem not to be operative in the stomach. Our hypothesis is that the particular structural, functional, neurochemical and neurophysiological features of the stomach is associated with a so far undiscovered “law of the stomach”. Numerous evidences support this idea: classical sensory neurons are virtually absent in the gastric ENS which rather contains multifunctional neurons but their role in reflex activity is still unknown. Electric and synaptic properties vastly differ between gastric and intestinal ENS neurons. Despite the presence of polarized innervation pathways, the gastric peristaltic wave is independent of the classical peristaltic reflex activity. This means that those pathways must fulfil other, yet to be discovered functions. One hint may be the finding that distention of the gastric corpus evokes cholinergic excitatory muscle responses proximally, distally and locally at the site of stimulation. We propose that such an excitatory response, which is modulated by inhibitory input at any level, is critical for normal gastric motility because it determines the muscle tone proximal, distal and at the site of the contractile wave. This delicate neural control would, according to our concept, adjust propulsion and retropulsion and thereby mixing, grinding and transport of content towards the pylorus, and consequently gastric emptying rate. Our aim is to study those sensory-motor circuits in the gastric ENS which are responsible for gastric motility under normal and pathological conditions. We apply various neuroimaging techniques using voltage and calcium sensitive dyes to monitor neuronal and muscle activity and to reveal their coordinated activity in time and space. Specifically, we shall define particular pathways and identify their neural components including their synaptic activation. Moreover, we intend to determine the sensory and motor neurons of the reflex arcs as well as the myogenic mechanisms relevant for gastric phasic and tonic muscle activity. As experimental model we use the guinea pig stomach, which is a well-established animal model in Neurogastroenterology and in our hands a very good model for the human stomach. This project is aimed to identify and characterize the “law of the stomach” as the basis to understand the control of gastric motility and emptying. This should eventually reveal new biomarkers and targets to treat gastric motility disorders.

• DFG Programme: Research Grants