Optogenetic analysis of circuitry formation in the enteric nervous system in health and in a model of gastrointestinal dysmotility.

Digestive function relies on the orchestrated activity of the enteric nervous system, a precisely wired network of neurons and their support cells embedded in the wall of the gut. The enteric nervous system is vital for coordinating the muscle contractions that control the mixing and propulsion of food in the gut, and is able to do this without input from the brain. In order to do this, enteric neurons must be meticulously wired together in a specific fashion. However, almost nothing is known about how this wiring process is actually organized during development. There are many gastrointestinal motility disorders with a considerable human and economic burden, some of which are believed to arise from defective wiring of enteric neurons. Therefore, it is crucial to investigate how and when the different types of enteric neurons get connected to form functional circuits. In this project we will use newly developed optogenetic tools to map how enteric neurons are connected. We will examine how erroneous wiring can occur and will investigate, for the first time, how and when enteric neurons develop functional connections between each other. Our approach, which combines modern genetic, neurophysiological and novel microscopic techniques, provides crucial and powerful means to unravel enteric neuron circuit assembly.