Defining gastric vagal mechanisms underlying emetic activation using novel electrophysiological and optical mapping technology

Nausea and vomiting occur with numerous medical treatments and diseases, including cancer chemotherapy and diabetic gastroparesis, which can lead to reduced appetite and nutritional imbalance. Activation of a gastric vagal neural circuit i believed to play a primary role in emetic signaling; however, gastric vagal emetic signaling essentially remains a "black box." The following fundamental mechanistic questions are unanswered: (1) how are emetic signals coded in the vagus by activation of specific fiber subtypes, temporal patterns, or gastric receptive fields? (2) Do different emetic stimuli produce the same vagal emetic "message"? (3) What are the mechanisms responsible for the history-dependence of the gastric emetic system? The goal of this project is to develop joint electrophysiology and infrared (IR) technology that will permit detailed functional neural circuit mapping for the control of the gastric emetic pathway as a potential therapy for nausea and emesis. Our team has the unique expertise to achieve this goal. Dr. Horn has developed a system to interrogate and analyze the activity of individual vagal units while recording the emetic reflex in the musk shrew (emetic reflexes are absent in rats and mice). Drs. Jenkins and Chiel have initiated work using an IR technology that can stimulate or inhibit sub-populations of axons with high spatial precision. Dr. Lewis has expertise in selectively activating/inhibiting vagal su-populations and in monitoring the molecular biological mechanisms associated with vagal activity. We will complete two AIMS: (1) Develop electrophysiology/IR mapping technology and apply it to characterize the topography and fiber types of gastric afferents within the vagus. To determine how fibers carrying gastric afferent signals are organized topographically within the vagus, we will develop a novel electrophysiology/IR mapping technology. We will develop a multi-optical fiber device that allows illumination of different regions circumferentially, and combine this with an electrophysiological technique that examines individual units in vagal fascicles. (2) Extend the electrophysiology/IR technology to determine and control temporal patterns of vagal activity in response to classical versus clinically relevant emetogenic stimuli. We will examine the patterning of activity in the vagus, and role of IR laser inhibition, in response to stomach-related emetic stimuli, mechanical distension, chemical irritation (using copper sulfate), and the cancer chemotherapy agent cisplatin. Our approach is innovative because we are combining cutting edge electrophysiology and IR technology to develop spatial and temporal maps of the gastric vagal organ system. This project is significant because it will elucidate precise vagal emetic mechanisms that must be modulated to control emesis; therefore, producing the critical knowledge base urgently needed to facilitate the development of new strategies to treat patients with intractable nausea and vomiting. More generally, the technology could have great utility for understanding other aspects of vagal and peripheral nerve function.