A molecularly distinct accumbal-to-lateral hypothalamic circuit modulates food seeking and consumption

Understanding the mechanism of energy homeostasis is expected to lead to effective treatment to obesity and metabolic diseases(1,2). However, energy homeostasis is a complicated process largely controlled by neuronal circuits in the hypothalamus and brainstem(3–5), whereas reward and motivation of food intake are mainly controlled by the limbic regions(6) and cerebral cortex(7,8). Although the limbic and hypothalamus connection like Nucleus Accumbens shell (NAcSh) to the lateral hypothalamus (LH) circuit has been reported to regulate feeding(9,10), 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)- and Serpinb2-expressing subtype to leptin receptor (LepR) expressing neurons in LH modulates food seeking and consumption. We demonstrate that the Serpinb2(+) neuronal activity is dynamically modulated during feeding. Conversely, chemo/optogenetics-mediated modulation of Serpinb2(+) neurons bidirectionally regulate food seeking and consumption. Importantly, circuitry stimulation revealed the NAcSh(Serpinb2)→LH(LepR) projection controls refeeding and overcomes leptin-mediated feeding suppression. Ablation of NAcSh(Serpinb2) neurons 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.