MODULATION OF DOPAMINE NEURONS IN VENTRAL TEGMENTAL AREA BY GLUCAGON-LIKE PEPTIDE 1 AGONIST

Understanding how the brain prioritizes competing innate rewards is central to unraveling the neural mechanisms underlying increased food consumption and obesity. Satiety-promoting glucagon-like peptide 1 receptor (GLP-1R) agonists, such as Exendin-4 (Exd4), reduce food intake and body weight. We investigated the effects of Exd4 on the activity of dopamine neurons in the ventral tegmental area (VTA^DA). We used a combination of calcium imaging, high-density electrophysiological recordings in freely behaving mice and patch-clamp recordings in vitro to characterize the effects of Exd4 at multiple scales. We found that Exd4 does not act uniformly across the reward system. It selectively inhibits a specific subpopulation of VTA^DA neurons identified by their unique physiological firing patterns and responses to food. Inhibition by Exd4 could be predicted from the responses of individual neurons to food and to voluntary exercise. Furthermore, our data suggest that these effects are mediated by specific pathways connecting the midbrain to downstream subcortical targets. These findings provide insight into action of GLP-1R agonists on a specific population of VTA^DA neurons to selectively reduce food-directed motivation.
We gratefully acknowledge support by the DFG (CRC1451, to T.K. and S.V., and EXC2030-CECAD, to T.K.).