The gut-brain vagal axis governs mesolimbic dopamine dynamics and reward events.

Reward processes have traditionally been ascribed to dopamine (DA)-associated circuits. While external stimuli, such as food and drugs of abuse, are activators of DA-neuron activity, growing evidence indicates that interoceptive signals also play a critical role. Among these, the gut-brain vagal axis has emerged as a key regulator, although its precise contribution to mesolimbic DA signaling and behavior remains unclear. Here, we combine complementary ex vivo and in vivo approaches across multiple scales to show that gut-brain vagal tone is essential for gating mesolimbic DA system activity and functions, modulating DA-dependent molecular and cellular processes, and scaling both food- and drug-induced reinforcement. These findings challenge the traditional brain-centric view of reward processing, supporting a more integrated model in which vagus-mediated interoceptive signals intrinsically shape motivation and reinforcement. By uncovering the influence of gut-brain vagal communication on DA functions, this work provides insights into the neurobiology of adaptive and maladaptive reward, with broad relevance for eating disorders and addiction.