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

Abstract

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 regions⁶ 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.