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

ABSTRACT Anorexia nervosa (AN) has the highest mortality among psychiatric diseases. Hyperactivity is a persistent symptom, which is difficult to control for patients and a major barrier to recovery as it interferes with weight gain. Alteration of mesolimbic dopamine transmission has been hypothesized as a critical factor for the development and maintenance of the disease and for hyperactivity. At what level the changes in dopamine occur in anorexic states and 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 unknown. We hypothesize that combining caloric restriction with exercise, such as in the activity-based anorexia (ABA) model, 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 ABA model on plasticity of the dopamine reward system. In ex-vivo brain slices of mice exposed to this model, ventral tegmental area dopamine (VTA DA ) neurons displayed a higher firing frequency compared to control mice supporting that the midbrain dopamine system undergoes plasticity. This coincided with reduced GABAergic transmission on VTA DA neurons. This reduction was at least in part attributable to local VTA GABA (VTA GABA ) neurons. Indeed, VTA GABA neurons were less excitable, displayed a lower firing frequency and a lower probability of release onto VTA DA neurons. Restoring the excitability of VTA GABA 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 VTA GABA transmission on VTA DA neurons that reinforces maladaptive behaviors such as excessive exercise. 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.