Role of membrane potential Instabilities in Irritable Bowel Dysease

Irritable bowel syndrome (IBS) is one of the most prevalent gastrointestinal disorders with a prevalence of 4-10% worldwide, characterized by recurrent abdominal pain. Pain is tightly related with noxious stimulus detection carried out by peripheral sensory neurons (PSNs). However, how those neurons generate ongoing activity, encoding constant or slow stimuli is still uncertain, and the current textbook model for sensory transduction and encoding fails to explain it. During the last years, many authors have proposed membrane potential instabilities (MPIs), a voltage dependent phenomenon that consists in subthreshold membrane potential fluctuations, as the mechanism underlying ongoing activity and demonstrated its upregulation in pathologies coursing with neuropathic and bone cancer pain, both in animal models and patients. Nevertheless, the role of MPIs in visceral pain remains completely unexplored. In this project we aim to characterize the role of MPIs and excitability changes in the development of IBS pain, as well as its underlying mechanisms. Furthermore, we will develop a new model to study the subcellular distribution of MPIs and action potential encoding in this pathology, using voltage optical recordings. Finally, to assure the translatability of our results, we will study sensory neurons from IBS patients and the possibility to treat them through MPIs pharmacological disruption, opening new treatment approaches. In the long-term, RIIBS action will lead to increased insight in sensory information encoding, the pathophysiology of IBS and ultimately to improved clinical management of visceral pain. This is the adequate moment to carry this action, as the host institution counts with top-notch facilities to make it feasible, the host supervisors have recently generated a novel animal model reproducing IBS and have access to clinical patients, and voltage optical recordings have been living an exponential refinement in the last years.