Establishing sensory functions of pharyngeal enteric neurons in C. elegans

SUMMARY Interoception is a critically important process that allows animals to sense internal signals in order to appropriately regulate their behavior and physiology. Here we propose to address the fundamental question of how organisms sense and regulate these internal signals, focusing on the enteric neurons of the foregut (“pharynx”) of the nematode C. elegans as a model system. Across animal phylogeny, enteric nervous systems are autonomously acting circuits that are essential for integrating a diverse set of multimodal internal sensory cues and relaying them to other parts of the organism. Dysfunction of these processes results in systemic metabolic and physiological disorders including disorders of gut motility and function, as well as neurological and neuropsychiatric syndromes. However, despite the essential role of the enteric circuit, the cellular and molecular mechanisms by which enteric neurons detect and respond to internal cues are poorly understood. Here we bring together the complementary expertise of our labs to study the molecular and circuit mechanisms of three different sensory modalities that we have shown to be perceived by enteric neurons: a high salt-sensing sensory phenomenon, the sensation of a putative bacterial metabolite, and an internal proprioceptive sensory process that relates to the peristaltic movement of the foregut. For each of these sensory processes, we have identified a diverse set of conserved putative sensory receptors expressed in highly restricted sets of enteric neurons, and found that their disruption leads to defects in feeding behavior and physiological adaptation. The specific goals of this proposal are to investigate the localization, functions, and downstream signaling events that allow these molecules and enteric neurons to detect chemical and mechanical cues, and transmit these signals to alter behavior. Chemosensation and mechanosensation are conserved properties of enteric neurons in vertebrates including in humans. Thus, results from this proposed work will provide new insights into the mechanisms by which enteric neurons sense and relay information to maintain and modulate physiological homeostasis across species.