5-HT recruits distinct neurocircuits to inhibit hunger-driven and non-hunger-driven feeding

Obesity is primarily a consequence of consuming calories beyond energetic requirements, but underpinning drivers have not been fully defined. 5-Hydroxytryptamine (5-HT) neurons in the dorsal Raphe nucleus (5-HT(DRN)) regulate different types of feeding behavior, such as eating to cope with hunger or for pleasure. Here, we observed that activation of 5-HT(DRN) to hypothalamic arcuate nucleus (5-HT(DRN) → ARH) projections inhibits food intake driven by hunger via actions at ARH 5-HT(2C) and 5-HT(1B) receptors, whereas activation of 5-HT(DRN) to ventral tegmental area (5-HT(DRN) → VTA) projections inhibits non-hunger-driven feeding via actions at 5-HT(2C) receptors. Further, hunger-driven feeding gradually activates ARH-projecting 5-HT(DRN) neurons via inhibiting their responsiveness to inhibitory GABAergic inputs; non-hunger-driven feeding activates VTA-projecting 5-HT(DRN) neurons through reducing a potassium outward current. Thus, our results support a model whereby parallel circuits modulate feeding behavior either in response to hunger or to hunger-independent cues.