Onimus, O.; Arrivet, F.; Le Borgne, T.; Perez, S.; Castel, J.; Ansoult, A.; Bertrand, B.; Mashhour, N.; de Almeida, C.; Bui, L.-C.; Vandecasteele, M.; Luquet, S.; Venance, L.; Heck, N.; Marti, F.; Gangarossa, G.

Reward-related processes have traditionally been ascribed to neural circuits centered on the dopamine (DA) system. While exteroceptive stimuli, such as food and drugs of abuse, are well-established activators of DA-neuron activity, growing evidence indicates that interoceptive signals also play a critical role in modulating reward. Among these, the gut-brain vagal axis has emerged as a key pathway, yet its precise contribution to mesolimbic DA-dependent signaling, dynamics and behaviors remains poorly defined. Here, we combine complementary ex vivo and in vivo approaches across multiple scales to investigate how the gut-brain vagal axis regulates DA dynamics and reward-related behaviors. We 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 drugs-induced reinforcement. These findings challenge the traditional brain-centric view of reward processing, supporting a more unified and integrated model in which gut-derived and vagus-mediated interoceptive signals are pivotal in intrinsically shaping motivation and reinforcement. By uncovering the influence of gut-brain vagal communication on mesolimbic DA functions, this work offers new insights into the neurobiological mechanisms underlying both adaptive and maladaptive reward processes, with broad implications for eating disorders and addiction.