A cortical-hypothalamic neural circuit for compulsive eating in mice.

Binge-eating disorder (BED) is the most common eating disorder and is strongly associated with obesity. The medial prefrontal cortex (mPFC) has been implicated in compulsive behavior and is known to project to multiple hypothalamic cell types implicated in maladaptive feeding. How the mPFC engages hypothalamic networks and whether such interactions are relevant for human disease remain unknown. Here, using a binge-eating-induced compulsive eating (BiCOM) paradigm in mice, we demonstrate that rostral zona incerta γ-aminobutyric acid (GABAergic) neurons (rZIGABA) drive compulsive eating. Manipulating either rZIGABA neurons or their mPFC inputs bidirectionally modulated compulsive eating. In vivo imaging showed that BiCOM modified mPFC neural dynamics, creating persistent attractor states driven by, and with sustained selectivity for, palatable food. Moreover, human fMRI showed that mPFC-rostral zona incerta (rZI) connectivity correlated with body weight and binge eating. Together, these results identify a cortical-hypothalamic mechanism for compulsive eating in mice and highlight potential targets for intervention in BED and obesity.