Summary Communication between the gut and brain is critical for homeostasis, but how this communication is represented in the dynamics of feeding circuits is unknown. Here we describe nutritional regulation of key neurons that control hunger in vivo. We show that intragastric nutrient infusion rapidly and durably inhibits hunger-promoting AgRP neurons in awake, behaving mice. This inhibition is proportional to the number of calories infused but surprisingly independent of macronutrient identity or nutritional state. We show that three gastrointestinal signals – serotonin, CCK, and PYY – are necessary or sufficient for these effects. In contrast, the hormone leptin has no acute effect on dynamics of these circuits or their sensory regulation, but instead induces a slow modulation that develops over hours and is required for inhibition of feeding. These findings reveal how layers of visceral signals operating on distinct timescales converge on hypothalamic feeding circuits to generate a central representation of energy balance.

Highlights d InsCtx ongoing activity patterns reflect current bodily state, not behavioral state d Hypothalamic hunger/thirst neurons gate InsCtx responses to food/water cues d Hypothalamic hunger/thirst neurons do not gate InsCtx ongoing activity d Food/water cues drive transient ''simulations'' of future bodily states in InsCtx

The neural mechanisms underlying hunger are poorly understood. AgRP neurons are activated by energy deficit and promote voracious food consumption, suggesting these cells may supply the fundamental hunger drive that motivates feeding. However recent in vivo recording experiments revealed that AgRP neurons are inhibited within seconds by the sensory detection of food, raising the question of how these cells can promote feeding at all. Here we resolve this paradox by showing that brief optogenetic stimulation of AgRP neurons before food availability promotes intense appetitive and consummatory behaviors that persist for tens of minutes in the absence of continued AgRP neuron activation. We show that these sustained behavioral responses are mediated by a long-lasting potentiation of the rewarding properties of food and that AgRP neuron activity is positively reinforcing. These findings reveal that hunger neurons drive feeding by transmitting a positive valence signal that triggers a stable transition between behavioral states.DOI: http://dx.doi.org/10.7554/eLife.18640.001

Artificial stimulation of Agouti-Related Peptide (AgRP) neurons promotes intense food consumption, yet paradoxically during natural behavior these cells are inhibited before feeding begins. Previously, to reconcile these observations, we showed that brief stimulation of AgRP neurons can generate hunger that persists for tens of minutes, but the mechanisms underlying this sustained hunger drive remain unknown (Chen et al., 2016). Here we show that Neuropeptide Y (NPY) is uniquely required for the long-lasting effects of AgRP neurons on feeding behavior. We blocked the ability of AgRP neurons to signal through AgRP, NPY, or GABA, and then stimulated these cells using a paradigm that mimics their natural regulation. Deletion of NPY, but not AgRP or GABA, abolished optically-stimulated feeding, and this was rescued by NPY re-expression selectively in AgRP neurons. These findings reveal a unique role for NPY in sustaining hunger in the interval between food discovery and consumption.