A molecularly defined NAcSh D1 subtype controls feeding and energy homeostasis

Abstract

Understanding the mechanism of energy homeostasis is expected to lead to effective treatment to obesity and metabolic diseases1,2. However, energy homeostasis is a complicated process largely controlled by neuronal circuits in the hypothalamus and brainstem3-5, whereas reward and motivation of food intake are mainly controlled by the limbic regions6and cerebral cortex7,8. Although the limbic and hypothalamus connection like Nucleus Accumbens shell (NAcSh) to the lateral hypothalamus (LH) circuit has been reported to regulate feeding9,10, the neuron subtypes involved, and how do the humoral/neuronal signals coordinate to direct feeding behavior remain unknown. Here we show that the projection from dopamine receptor D1(Drd1)- andSerpinb2-expressing subtype to leptin receptor (LepR) expressing neurons in LH modulates food seeking and consumption. We demonstrate that theSerpinb2+neuronal activity is dynamically modulated during feeding. Conversely, chemo/optogenetics-mediated modulation ofSerpinb2+neurons bidirectionally regulate food seeking and consumption. Importantly, circuitry stimulation revealed the NAcShSerpinb2→LHLepRprojection controls refeeding and overcomes leptin-mediated feeding suppression. Ablation of NAcShSerpinb2neurons could decrease body weight. Together, our study reveals a molecularly distinct accumbal-to-lateral hypothalamic neural circuit that controls internal state-dependent food consumption, which provides a promising therapeutic target for anorexia and obesity.