Gastrin-releasing peptide signaling in the nucleus accumbens medial shell regulates neuronal excitability and motivation

Neuropeptides are the largest class of neuromodulators. It has been shown that subpopulations of ventral tegmental area (VTA) dopamine neurons express mRNA for the neuropeptide Gastrin-releasing peptide (GRP); however, its functional relevance in mesolimbic circuits is unknown. Here we report that the GRP receptor (GRPR) is expressed in nucleus accumbens medial shell (NAc MSh) neurons, which are targeted by GRP-expressing inputs from the VTA, hippocampus, and amygdala. We show that NAc MSh GRPR-positive cells represent subpopulations of D2 receptor-expressing neurons, comprising both classical striatal projection neurons (SPNs) and eccentric SPNs. GRPR-expressing neurons have high intrinsic excitability and can be activated by GRP in vivo. NAc-specific deletion of Grpr in mice increases motivation in a progressive ratio test, demonstrating that GRPR regulates motivated behaviors. These experiments establish GRP/GRPR signaling as a potent modulator of mesolimbic circuits and advance our understanding of the diversity of cell types present in the NAc.