Natural and Drug Rewards Engage Distinct Pathways that Converge on Coordinated Hypothalamic and Reward Circuits.

Motivated behavior is influenced by neural networks that integrate physiological needs. Here, we describe coordinated regulation of hypothalamic feeding and midbrain reward circuits in awake behaving mice. We find that alcohol and other non-nutritive drugs inhibit activity in hypothalamic feeding neurons. Interestingly, nutrients and drugs utilize different pathways for the inhibition of hypothalamic neuron activity, as alcohol signals hypothalamic neurons in a vagal-independent manner, while fat and satiation signals require the vagus nerve. Concomitantly, nutrients, alcohol, and drugs also increase midbrain dopamine signaling. We provide evidence that these changes are interdependent, as modulation of either hypothalamic neurons or midbrain dopamine signaling influences reward-evoked activity changes in the other population. Taken together, our results demonstrate that (1) food and drugs can engage at least two peripheral→central pathways to influence hypothalamic neuron activity, and (2) hypothalamic and dopamine circuits interact in response to rewards. • Alcohol and drugs inhibit hypothalamic neurons in a nutrient-independent manner • Nutrients and drugs inhibit AgRP neurons via vagal and non-vagal modes, respectively • Interdependent coordination of AgRP and DA circuits mediates response to rewards How does the brain process natural versus drug rewards? Alhadeff et al. demonstrate that food and drugs signal from the periphery to the hypothalamus via distinct pathways. Furthermore, bidirectional and coordinated interactions between hypothalamic and dopamine circuits potentiate responses to rewards. [ABSTRACT FROM AUTHOR]