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

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 (aZI^T neurons) as a key population driving compulsive binge eating. In a mouse BED model, intermittent high-fat-diet training increases aZI^T 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 aZI^T 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.