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

Abstract

SummaryNeuropeptides are the largest class of neuromodulators, which can be co-released together with classical neurotransmitters. 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, which have high intrinsic excitability and can be activated by GRPin vivo. Selective deletion ofGrprfrom the NAc MSh increases motivation in a progressive ratio test, indicating a role for GRPR in motivated behaviors. These experiments establish GRP/GRPR signaling as a novel regulator of mesolimbic circuits and advance our understanding of neuropeptides in the striatum.