A circuit from lateral septum neurotensin neurons to tuberal nucleus controls hedonic feeding

Feeding behavior is regulated by both the homeostatic needs of the body and hedonic values of the food. Easy access to palatable energy-dense foods and the consequent obesity epidemic stress the urgent need for a better understanding of neural circuits that regulate hedonic feeding. Here, we report that neurotensin-positive neurons in the lateral septum (LS(Nts)) play a crucial role in regulating hedonic feeding. Silencing LS(Nts) specifically promotes feeding of palatable food, whereas activation of LS(Nts) suppresses overall feeding. LS(Nts) neurons project to the tuberal nucleus (TU) via GABA signaling to regulate hedonic feeding, while the neurotensin signal from LS(Nts)→the supramammillary nucleus (SUM) is sufficient to suppress overall feeding. In vivo calcium imaging and optogenetic manipulation reveal two populations of LS(Nts) neurons that are activated and inhibited during feeding, which contribute to food seeking and consumption, respectively. Chronic activation of LS(Nts) or LS(Nts)→TU is sufficient to reduce high-fat diet-induced obesity. Our findings suggest that LS(Nts)→TU is a key pathway in regulating hedonic feeding.