Mechanosensitivität im enterischen Nervensystem:Mechanotransduktion und sensoscher Schaltkreis
Anatomie und Physiologie
Zusammenfassung der Projektergebnisse
The gastrointestinal tract is a complex system, which needs to be regulated by a neuronal network, located directly within its walls, communicating with the brain but not overloading it. The enteric nervous system (ENS) fulfills this role coordinating sensory-motor reflex pathways, which are the basis for gastrointestinal motility and secretory functions. Understanding basic circuits, their mechanistic and modulation will help to targeted threat gastrointestinal dysfunctions, as inflammatory bowel disease or neurodegenerative disorders, which show comorbidity with gut disorders, as Parkinson´s disease. In the first funding period of this project we focused on previously identified mechanosensitive enteric neurons (MEN). As a first step we characterized their properties in different regions and species (from guinea pig gastric corpus to human colon) and their responses to different mechanical stimuli (shear versus normal stress). Results reinforced our novel concept of sensory processing in the ENS, which is conserved across regions and species. This idea highlights the cooperative activity of multifunctional neurons acting as part of a sensory network. These neurons are compression- or tension-sensitive or both compression and tension-sensitive. Shear stress does not play a role in the neuronal control of motility but normal stress and strain. These data led to nine original publications in international recognized peer reviewed journals, one review and one PhD thesis. In the second funding period we identified and characterized submucosal MEN, which are likely to play a role in distension-mediated secretory functions. We also focused on revealing the key elements of mechanotransduction in MEN. Results of the pharmacological experiments indicate that different channels/mechanisms are involved. Gadolinium3+-sensitive channels and TRPC channels play a role in compression-sensitive enteric neurons mechanosensitivity. Further experiments are needed to characterize mechanotransduction of tension-sensitive MEN. Finally, we designed and developed a completely new set up for wide-field imaging, which we will be used to study crosstalk between neuronal and non-neuronal cells as well as consecutive neuronal activation in order to unravel sensory-motor reflex circuits. Data of the second funding period led (until today) to one original publication in Cell and Tissue Research and two Master and one PhD thesis. Two more manuscripts are in preparation. Thanks to this funding, new national and international collaborations started and a new Neurogastroenterology working group was established.
