Corticotropin-Releasing Factor Release From a Unique Subpopulation of Accumbal Neurons Constrains Action-Outcome Acquisition in Reward Learning.

Abstract

Background: The nucleus accumbens (NAc) mediates reward learning and motivation. Despite an abundance of neuropeptides, peptidergic neurotransmission from the NAc has not been integrated into current models of reward learning. The existence of a sparse population of neurons containing corticotropin-releasing factor (CRF) has been previously documented. Here, we provide a comprehensive analysis of their identity and functional role in shaping reward learning.

Methods: Our multidisciplinary approach included fluorescent in situ hybridization (n = ≥3 mice), tract tracing (n = 5 mice), ex vivo electrophysiology (n = ≥30 cells), in vivo calcium imaging with fiber photometry (n = ≥4 mice), and use of viral strategies in transgenic lines to selectively delete CRF peptide from NAc neurons (n = ≥4 mice). Behaviors used were instrumental learning, sucrose preference, and spontaneous exploration in an open field.

Results: We showed that the vast majority of NAc CRF-containing neurons are spiny projection neurons (SPNs) comprising dopamine D₁-, D₂-, or D₁/D₂-containing SPNs that primarily project and connect to the ventral pallidum and to a lesser extent the ventral midbrain. As a population, they display mature and immature SPN firing properties. We demonstrated that NAc CRF-containing neurons track reward outcomes during operant reward learning and that CRF release from these neurons acts to constrain initial acquisition of action-outcome learning and at the same time facilitates flexibility in the face of changing contingencies.

Conclusions: CRF release from this sparse population of SPNs is critical for reward learning under normal conditions.