Cholecystokinin receptors in lateralized vagal reward signaling

About This Grant

PROJECT SUMMARY The vagus nerves transmit sensory information from the gastrointestinal tract to the brain, playing a crucial role in the neural control of feeding and energy homeostasis. These signals are conveyed to brain systems that regulate both the homeostatic control of feeding and the cognitive aspects of food reward. The gut-innervating afferent fibers of the vagus nerve demonstrate lateralized activation of midbrain “reward” circuitry, with projections through the right, but not the left, vagus nerve driving reward-related behaviors and dopamine release. One key hormone involved in feeding regulation is cholecystokinin (CCK), a peptide released in the gut in response to food intake. Acting through the vagus nerve, CCK signaling is traditionally known to promote satiety, a physiological state in which feelings of fullness signal the cessation of eating. However, recent research has shown that CCK also plays a critical role in the vagal signaling pathways that drive post-ingestive macronutrient preference. The ability of vagal CCK signaling to reinforce food-seeking behaviors suggests that it may play a role in vagally-mediated reinforcement. The central hypothesis of this proposal is that asymmetrically expressed CCK receptor-expressing vagal neurons critically contribute to lateralized interoceptive reward signaling. The goal of this project is to determine the extent to which these neurons contribute to lateralized vagus-mediated reinforcement of appetitive behaviors. In Aim 1, we test the hypothesis that right vagal neurons are more responsive to CCK than left vagal neurons. In Aim 2, we test the necessity of right versus left CCK receptor-expressing vagus neurons in the development of fat preference. In Aim 3, we determine the extent to which CCK receptor-expressing vagal neurons are required for the reinforcement of learned behaviors by right vagus nerve stimulation (VNS). These experiments will reveal new insights into the mechanisms underlying lateralized interoceptive reward signaling. In doing so, the proposed work will critically inform the development and optimization of VNS and other therapeutic approaches for the treatment of obesity and metabolic disorders.