Genetic resolution of dopamine systems for reward association and motivation

Abstract

The ventral tegmental area (VTA) dopamine system is a key regulator of reward and motivational processes. Through modulation of cortico- and amygdalo-striatal networks, VTA dopamine neurons facilitate and update stimulus- and response-outcome associations. They also provide a motivational signal that initiates and sustains approach behavior in response to reward-predictive stimuli. It has been proposed that these two components of reward behavior represent discrete dopamine systems, but the populations and pathways that comprise them remain unresolved. Based on gene enrichment data in midbrain dopamine neurons, we utilized neuropeptidergic markers to genetically isolate VTA dopamine subpopulations. Characterization revealed two primarily distinct subpopulations with unique projection patterns to mesolimbic targets, including the core and shell subdivisions of the nucleus accumbens (NAc). In vivo electrophysiological analysis during an instrumental reward paradigm demonstrated similar phasic responses to reward-related actions and stimuli, and a tonic rise in baseline firing preceding reward receipt during early learning. However, these responses diverged as training progressed indicating differential adaptations with extended conditioning. Optogenetic manipulation of these populations revealed dissociable roles in the formation of reward associations or the maintenance of learned reward behaviors, and that convergence of these associative and motivational systems is required to maximize reward reinforcement. Our findings begin to consolidate the operational roles of discrete dopamine populations and pathways, a crucial step in identifying more precise therapeutic targets for drug addiction and depression, disorders associated with aberrations in mesolimbic dopamine signaling.