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 dopamine neurons express mRNA for the neuropeptide Gastrin-releasing peptide (GRP); however, its functional relevance in dopaminergic circuits is unknown. Here, we find that the GRP receptor (GRPR) is present in the nucleus accumbens medial shell (NAc MSh), which is targeted by GRP-expressing midbrain dopamine neurons as well as glutamatergic inputs from the hippocampus and amygdala. We show that the NAc MSh GRPR-positive cells are a subpopulation of D2 receptor-expressing neurons, comprising both classical indirect pathway striatal projection neurons (iSPNs) and eccentric SPNs (eSPNs), which have high intrinsic excitability, and can be activated by GRP in vivo. NAc-specific deletion of Grpr 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 neuropeptide actions in the brain.