Ghrelin Recruits Specific Subsets of Dopamine and GABA Neurons of Different Ventral Tegmental Area Sub-nuclei

Ghrelin is a stomach-derived hormone that regulates rewarding behaviors and reinforcement by acting on the ventral tegmental area (VTA). The VTA is a complex midbrain structure mainly comprised of dopamine (DA) and gamma-aminobutiric acid (GABA) neurons that are distributed in several VTA sub-nuclei. Here, we investigated the neuroanatomical distribution and chemical phenotype of ghrelin-responsive neurons within the VTA. In wild-type mice, we found that: (1) ghrelin binding cells are present in most VTA sub-nuclei but not in its main target, the nucleus accumbens (Acb); (2) systemically injected ghrelin increases food intake but does neither affect locomotor activity nor the levels of the marker of neuronal activation c-Fos in the VTA sub-nuclei; (3) centrally injected ghrelin increases food intake, locomotor activity and c-Fos levels in non-DA neurons of all VTA sub-nuclei; (4) intra-VTA-injected ghrelin increases food intake, locomotor activity and c-Fos levels in non-DA neurons of all VTA sub-nuclei; (5) both centrally and intra-VTA-injected ghrelin increase c-Fos levels in DA neurons of the parabrachial pigmented VTA sub-nucleus. In genetically modified mice in which a subset of GABA neurons expresses the red fluorescent protein tdTomato, we found that centrally injected ghrelin increases c-Fos levels in GABA neurons of the interfascicular VTA sub-nucleus. These results suggest that ghrelin can recruit specific subsets of VTA neurons in order to modulate food intake and locomotor activity.