Fabien Ducrocq

Université de Bordeaux, INRAE, Bordeaux INP, NutriNeuro, 33000, Bordeaux, France

Title

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

Abstract

Hyperactivity is a persistent symptom of anorexia nervosa (AN) that often precedes occurrence of the disease, and constitutes a major barrier to recovery. Alteration of mesolimbic dopamine transmission has been hypothesized as a critical factor for the development and maintenance of AN and hyperactivity. However, the nature of dopamine dysfunction in AN, and the underlying mechanisms remain unclear. We therefore aimed at i) characterizing the impact of the activity-based anorexia (ABA) model on ventral tegmental area dopamine (VTADA) neurons and ii) determining whether restoring activity of VTA neural network is protective in the ABA model. Using ex-vivo electrophysiology in mice exposed to the ABA model, we found that VTADA neurons displayed increased firing frequency. This was paralleled with reduced GABAergic inputs onto VTADA neurons. This reduction was at least in part attributable to local VTAGABA neurons. Indeed, using electrophysiological recording coupled with optogenetic manipulations, we found that VTAGABA neurons were less excitable, displayed a lower firing frequency and a reduced probability of release onto VTADA neurons. Restoring the excitability of VTAGABA neurons via chemogenetic activation rescued mice from starvation by decreasing hyperactivity. In summary, we found that caloric restriction together with running leads to dysregulation of VTAGABA transmission on VTADA neurons that reinforces maladaptive behaviors such as hyperactivity. This study uncovers new mechanisms linked to the disturbed dopamine system characterizing AN, identifying a role of decreased local GABAergic control over VTADA neuron output in this process.