Dissecting the Mechanism of Gut-brain Oscillations Underlying the C.elegans Enteric Clock

Central pattern generators (CPGs) are networks that produce intrinsic oscillatory activities underlying most rhythmic motor behaviors such as breathing, heartbeat and locomotion in almost all animals studied to date, including humans. However, the innerworkings and modulations of CPGs are diverse and poorly understood across different systems. The ancient enteric nervous system plays a role not only in digestion, but in the broader regulation of physiology and behavior. The C. elegans defecation motor program(DMP), consisting of a series of stereotyped motor sequences activated every 45 sec, is a particularly well-studied behavior regulated by the gut and the enteric nervous system. Previous work has established that internal clock underlying the C. elegans DMP relieson inositol triphosphate receptor (IP3R) oscillations of intestinal calcium. However, how the intestinal clock is self-generated and modulated by neural inputs and linked to rhythmic activities within the central nervous system are fundamental questions yet tobe addressed.This proposal aims to determine the mechanisms of gut-brain communications that generate and regulate the rhythmic defecation behavior in C. elegans. Our central hypothesis is that enteric neural oscillations and the coupled calcium and membranepotential oscillations in the intestine are mutually entrained by the gut-brain axis to function as a CPG underlying rhythmic motor pattern generation in C. elegans. We plan to attain our overall research goal by determining the ionic mechanisms underlying theintestinal action potential and pacemaker potential using electrophysiological, calcium and voltage fluorescent imaging approach. We will also develop quantitative models to reconstruct the intestinal oscillation to simulate the enteric clock underlying thedefecation motor behavior. The proposed research is expected to contribute in-depth understanding of how the C. elegans gut-brain axis modulates a well-defined rhythmic behavior from molecular mechanisms to cellular physiology and circuit property. Thiscontribution will be significant because it is expected to develop and test novel models to connect two key aspects of neuroscience with mounting interests - central pattern generation and gut-brain communication - within a simple physiological circuit that canbe mapped to quantifiable behaviors at single-cell resolution. Since the connection between the gut and the nervous system is an area of increasing excitement in neuroscience, the outcomes of this project are expected not only to advance our fundamental understanding of broader functions of gut-brain axis in behavior generation and modulation, but also to stimulate future thinking and modeling of central pattern generation in other systems.