Rationale: By 2018, 31 states had an obesity rate ≥30% and none <20%. Costs due to obesity are estimated at $190B/yr. 72% of Veterans are overweight (45%) or obese (27%), of which 66% have hypertension and 31% have diabetes. Researchers use vagal nerve stimulation (VNS) to treat a number of conditions, including obesity. Sensory afferents in the vagus nerves innervate the stomach and relay information about the state of the stomach, particularly the degree of stomach wall stretch associated with increased stomach volume. However, VNS parameters vary widely and it is unknown how changes in stimulus parameters alter outcomes. Until the parameter-to-outcome relationship is mapped, developing optimal stimulus waveforms is impossible. Objective: The objectives of this study are to map the relationship between stimulus parameters and 1) nerve recruitment, 2) brain activity in regions associated with satiety, and 3) food consumption. Further, a novel stimulus waveform and interface for delivering more effective bilateral VNS will be evaluated. Numerous hypotheses will be tested through a series of animal experiments over a period of 4 years. Research Plan and Methodology: During Aim 1, the subdiaphragmatic vagus nerve will be implanted with a nerve cuff electrode in rats. The rats will remain healthy or become obese depending on their diet. Once per month, the animal will receive subdiaphragmatic VNS (sVNS) while an fMRI image of brain activity is acquired. The effects of VNS intensity, VNS waveform, diet type, and time on activation of the brain in key regions responsible for satiety and reward will be determined. During Aim 2, the subdiaphragmatic vagus nerve will be implanted with a nerve cuff electrode in rats. The rats will have simultaneous access to three diet types. Each week VNS will be provided for multiple days. The amount and type of food consumed as well as the overall activity of the rat during days of stimulation will be compared to days without stimulation. The effects of VNS intensity and waveform on food consumption and activity will be determined. During Aim 3, a novel cuff that wraps around the esophagus and delivers bilateral VNS will be implanted. As with Aim 2, the rats will have simultaneous access to three diet types and both food consumption and activity during days of stimulation will be compared to days without stimulation. The effects of VNS intensity on food consumption and activity will be determined and compared to those found in Aim 2. Esophageal resistance to distension and histology will be used to assess if the implant remains safe after 6 months. Additionally, the map between VNS stimulus intensity and axon recruitment within the vagus nerve will be mapped. Expected Outcomes: This study provides the necessary data to facilitate understanding how sVNS effects the system at three levels by generating a map that links sVNS parameters to: 1) axon recruitment within the vagus nerves; 2) brain activation; and 3) short-term...