Anterior zona incerta to ventral tegmental area circuit controls compulsive eating in a binge-eating-disorder mouse model.

Compulsion is a defining feature of binge eating disorder (BED), yet the circuit basis sustaining compulsive binge eating remains unclear. Here, we identify tyrosine hydroxylase (TH)-BAC-Cre-labeled γ-aminobutyric acid (GABAergic) neurons in the anterior zona incerta (aZIT neurons) as a key population driving compulsive binge eating. In a mouse BED model, intermittent high-fat-diet training increases aZIT neuronal excitability, which is required for the development of compulsive intake. These neurons project to the ventral tegmental area (VTA), where they promote aversion-resistant food seeking and consumption. Mechanistically, BED training reduces inhibitory control from aZIT neurons onto VTA dopamine neurons via both direct and indirect pathways, and this effect results in enhanced dopamine release in the nucleus accumbens. Single-cell RNA sequencing and behavioral profiling further identify neurensin 2 (Nrsn2) as a genetic marker for aZI binge neurons that functionally contribute to compulsive binge eating. Together, these findings define a cell-type-specific ZI-VTA circuit that engages mesolimbic dopamine signaling to drive compulsive binge eating.