Primary food reward and reward-predictive stimuli evoke different patterns of phasic dopamine signaling throughout the striatum

Abstract

Phasic changes in dopamine activity play a critical role in learning and goal-directed behavior. Unpredicted reward and reward-predictive cues evoke phasic increases in the firing rate of the majority of midbrain dopamine neurons--results that predict uniformly broadcast increases in dopamine concentration throughout the striatum. However, measurement of dopamine concentration changes during reward has cast doubt on this prediction. We systematically measured phasic changes in dopamine in four striatal subregions [nucleus accumbens shell and core (Core), dorsomedial (DMS) and dorsolateral striatum] in response to stimuli known to activate a majority of dopamine neurons. We used fast-scan cyclic voltammetry in awake and behaving rats, which measures changes in dopamine on a similar timescale to the electrophysiological recordings that established a relationship between phasic dopamine activity and reward. Unlike the responses of midbrain dopamine neurons, unpredicted food reward and reward-predictive cues evoked a phasic increase in dopamine that was subregion specific. In rats with limited experience, unpredicted food reward evoked an increase exclusively in the Core. In rats trained on a discriminative stimulus paradigm, both unpredicted reward and reward-predictive cues evoked robust phasic dopamine in the Core and DMS. Thus, phasic dopamine release in select target structures is dynamic and dependent on context and experience. Because the four subregions assayed receive different inputs and have differential projection targets, the regional selectivity of phasic changes in dopamine has important implications for information flow through the striatum and plasticity that underlies learning and goal-directed behavior.

Figure 1

Histological verification of recording sites. Recordings were made in the Shell (blue), Core (green), DMS (orange) or DLS (red). Top: Location of recording sites for Experiment 1 examining phasic dopamine release evoked by unpredicted food reward. Bottom: Location of recording electrodes for Experiment 2 examining phasic dopamine release during the discriminative stimulus task and subsequent unpredicted food reward presentation. Numbers are distances in mm anterior to bregma. Rat atlas sections are adapted from The Rat Brain in Stereotaxic Coordinates by G. Paxinos and C. Watson, 1996, Sydney, Australia: Academic Press. Copyright 1996 by Academic Press. Adapted with permission.

Figure 2

Electrical stimulation of VTA/SNpc (24 pulses, 60 Hz) evokes phasic dopamine release in all striatal subregions. (A) Dopamine release in each subregion is shown using color plots, which show current changes (in color) across the applied voltages (E_app; ordinate) over time (abscissa). Dopamine is identified by its oxidation (green feature, ∼0.6 V) and reduction (dark blue/yellow feature, ∼-0.2 V) peaks that arise just after stimulation onset. (B) Average change in dopamine evoked by electrical stimulation in each subregion: Shell (blue), Core (green), DMS (orange) and DLS (red). The black bar on the x-axis denotes stimulation duration.

Figure 3

Individual trial examples of phasic dopamine evoked by electrical stimulation of the VTA/SNpc and by unpredicted food reward in the Core. (A) Electrical stimulation evokes a phasic change in dopamine. Top: Color plot shows current changes (in color) as a function of applied voltage over time, as described in Fig. 2. Bottom: Change in dopamine over time extracted from color plot above using PCA. Inset: Cyclic voltammogram plotted at the time of peak dopamine release. Cyclic voltammograms for dopamine and pH obtained after stimulation are used to build a training set for PCA. (B) In the same rat, unpredicted food reward (sugar pellet) evokes a phasic increase in dopamine. Top: Color plot shows current changes as a function of applied voltage over time. Dopamine is identified by its oxidation and reduction features occurring just after pellet delivery. Bottom: Change in dopamine extracted from the color plot above using PCA.

Figure 4

Unpredicted food reward evokes a regionally selective phasic dopamine response. Average dopamine (black line) ± SEM (gray vertical bars) in different striatal regions in response to unpredicted food reward (sugar pellet; time = 0). Insets: Average dopamine signal for each rat during both Baseline and Pellet epochs. Unpredicted food reward evokes phasic dopamine release in the Core (B) but not the Shell (A), DMS (C) or DLS (D). * P < 0.05 for Baseline versus Pellet epochs.

Figure 5

Discriminative stimuli differentially evoke phasic dopamine signaling across striatal subregions. Average dopamine (black line) ± SEM (gray vertical bars) to predictive cues in striatal subregions during the discriminative stimulus test. Top: A cue predictive of reward (DS+) selectively evokes phasic dopamine release in the Core (B) and DMS (C) but not the Shell (A) or DLS (D). Insets: Average dopamine signal for each rat during both Baseline and Cue epochs. Note that in the Core (B), the scale for the ordinate is 2 nA, twice that of the other striatal regions. * P < 0.05 for Baseline versus DS+ epoch. Bottom: A cue predictive of no reward (DS-) fails to alter phasic dopamine signaling in all striatal subregions. Insets: Average dopamine concentration for each rat during both Baseline and Cue epochs.

Figure 6

Cue-evoked dopamine is dependent on a cue-reward association. Average dopamine signal for each rat during both Cue (DS+ versus DS-) epochs. The DS+ evoked significantly greater dopamine relative to the DS- in the Core (B) and DMS (C). Note that in the Core (B), the scale for the ordinate is 2 nA, twice that of the other striatal regions. * P < 0.05 for DS+ versus DS- epochs. No differences were observed in the Shell (A) or DLS (D).

Figure 7

In rats trained in the discriminative stimulus paradigm, unpredicted food reward evokes a different pattern of phasic dopamine release across striatal subregions. Average dopamine (black line) ± SEM (gray vertical bars) in different striatal regions in response to unpredicted food reward (sugar pellet; time = 0). Insets: Average dopamine signal for each rat during both Baseline and Pellet epochs. Unpredicted food reward evokes phasic dopamine release in the Core (B) and DMS (C) but not the Shell (A) or DLS (D). Note that in the Core (B), the scale for the ordinate is 2 nA, twice that of the other striatal regions. * P < 0.05 for Baseline versus Pellet epochs.