Reduced Ventral Tegmental Area GABA neuron output contributes to hyperactivity in the activity-based anorexia model in female mice

Anorexia nervosa (AN) has the highest mortality among psychiatric disorders, with hyperactivity being one of the most persistent and deleterious symptoms. Increased dopamine transmission is linked to AN and hyperactivity, though the underlying mechanisms remain unclear. Local GABAergic neurons powerfully regulate the dopamine system but their involvement in AN is unknown. Using the activity-based anorexia (ABA) mouse model, we found that GABAergic transmission onto ventral tegmental area dopamine (VTA_DA) neurons modulates hyperactivity in female mice. Indeed, female mice exposed to the ABA model displayed higher firing rates in VTA_DA compared to controls, along with reduced GABAergic transmission onto VTA_DA cells and decreased excitability of VTA_GABA neurons. Chemogenetic stimulation of GABA neurons excitability in the midbrain reduced hyperactivity and body weight loss in ABA mice, while reducing GABA neuron activity worsened this phenotype. In summary, decreased GABAergic control over VTA dopamine neurons contributes to development of hyperactivity in the ABA model.