Reward Signaling in the Gut-Brain Axis

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PROJECT SUMMARY Obesity is not only a leading cause of death in the US, but also a risk factor for nearly all other top causes of death including heart disease, pulmonary disease, stroke, and cancer. Overconsumption of high-fat high-sugar foods is a driver of obesity, but the mechanism for this is unclear. Nodose ganglia (NG) neurons of the vagus nerve transmit post-ingestive signals for fats and sugars from the gut to the brain to regulate food intake and reinforce food choice. Previous studies have demonstrated that vagal activity in response to post-ingestive signals is reduced in obesity, which may lead to increased food intake. To understand how altered macronutrient signaling may lead to obesity requires understanding its basic physiology, which has not been fully elucidated. My preliminary data reveals distinct neuronal populations in the vagus nerve are required for post-ingestive fat or sugar signaling, but whether these signals are sufficient to reinforce conditioned behavior is unclear. I have previously shown that ablation of neurons expressing cholecystokinin receptor (CCKR) affects fat- but not sugar-mediated satiation, indicating CCKR may be a specific marker for fat responsive vagal afferent neurons. Accordingly, I hypothesize that fats and sugars activate phenotypically and functionally distinct vagal ensembles in the gut-brain axis, which are sufficient to reinforce conditioned behavior, and this activation is reduced in obesity. To address these hypotheses, we will use FosTRAP mice, an activity-dependent genetic targeting model, to selectively target vagal sensory neurons that respond to either fat or sugar. In aim 1, we will test whether optogenetic activation of fat or sugar sensing vagal neurons is sufficient to trigger nigrostriatal dopamine release, and for animals to learn to self-stimulate, two hallmarks of reward. In aim 2, we will test the necessity of CCK receptor expressing vagal sensory neurons in fat, but not sugar reward, by performing a flavor-nutrient conditioning experiment with and without selective ablation of vagal afferents expressing CCKR, using the conjugated neurotoxin CCK-Saporin. In aim 3, we will test how high-fat high-sugar diet intake disrupts nutrient sensing by using FosTRAP mice to compare neural responses to intragastric stimuli before and after the onset of obesity within the same animal. This work will for the first time characterize nutrient-specific signaling in the gut-brain reward circuitry in lean and obese conditions for future study and possible therapeutic targets.