Reduced GABA transmission onto ventral tegmental area dopamine neurons underlies vulnerability to a mouse model of Anorexia Nervosa

Abstract Anorexia nervosa (AN) has the highest mortality among psychiatric diseases. Hyperactivity is a persistent symptom and alteration of mesolimbic dopamine transmission has been linked to the development and maintenance of the disease and of hyperactivity. However, whether local mesolimbic neurocircuit plasticity is causally involved remains unclear. Especially the role of local GABA control over dopamine neurons, a powerful regulator of the dopamine system, in an AN context is unresolved. We hypothesize that combining caloric restriction with exercise alters dopamine transmission via GABA disinhibition that, in turn, facilitates the expression of maladaptive behaviors such as hyperactivity. Therefore, we characterized the impact of the activity-based anorexia (ABA) model on the plasticity of the dopamine reward system using ex-vivo electrophysiology coupled with optogenetic manipulations. Ventral tegmental area dopamine (VTADA) neurons displayed a higher firing frequency in ABA-exposed animals compared to control mice. This coincided with reduced GABAergic transmission on VTADA neurons, at least in part attributable to decreased excitability of local VTA GABA (VTAGABA) neurons. Restoring the excitability of VTAGABA neurons via chemogenetic activation rescued mice from starvation, by decreasing running wheel activity. In summary, we found that the anorexic state leads to dysregulation of VTAGABA transmission on VTADA neurons that reinforces maladaptive behaviors such as hyperactivity. We uncovered a new mechanism linked to the disturbed dopamine system in ABA-exposed animals, identifying a hitherto unknown role of decreased local GABAergic control over VTA dopamine neuron output.