Differential Dopamine Release Dynamics in the Nucleus Accumbens Core and Shell Reveal Complementary Signals for Error Prediction and Incentive Motivation

Abstract

Mesolimbic dopamine (DA) is phasically released during appetitive behaviors, though there is substantive disagreement about the specific purpose of these DA signals. For example, prediction error (PE) models suggest a role of learning, while incentive salience (IS) models argue that the DA signal imbues stimuli with value and thereby stimulates motivated behavior. However, within the nucleus accumbens (NAc) patterns of DA release can strikingly differ between subregions, and as such, it is possible that these patterns differentially contribute to aspects of PE and IS. To assess this, we measured DA release in subregions of the NAc during a behavioral task that spatiotemporally separated sequential goal-directed stimuli. Electrochemical methods were used to measure subsecond NAc dopamine release in the core and shell during a well learned instrumental chain schedule in which rats were trained to press one lever (seeking; SL) to gain access to a second lever (taking; TL) linked with food delivery, and again during extinction. In the core, phasic DA release was greatest following initial SL presentation, but minimal for the subsequent TL and reward events. In contrast, phasic shell DA showed robust release at all task events. Signaling decreased between the beginning and end of sessions in the shell, but not core. During extinction, peak DA release in the core showed a graded decrease for the SL and pauses in release during omitted expected rewards, whereas shell DA release decreased predominantly during the TL. These release dynamics suggest parallel DA signals capable of supporting distinct theories of appetitive behavior.

Significance statement: Dopamine signaling in the brain is important for a variety of cognitive functions, such as learning and motivation. Typically, it is assumed that a single dopamine signal is sufficient to support these cognitive functions, though competing theories disagree on how dopamine contributes to reward-based behaviors. Here, we have found that real-time dopamine release within the nucleus accumbens (a primary target of midbrain dopamine neurons) strikingly varies between core and shell subregions. In the core, dopamine dynamics are consistent with learning-based theories (such as reward prediction error) whereas in the shell, dopamine is consistent with motivation-based theories (e.g., incentive salience). These findings demonstrate that dopamine plays multiple and complementary roles based on discrete circuits that help animals optimize rewarding behaviors.

Keywords: associative learning; fast-scan cyclic voltammetry; incentive salience; reinforcement learning; striatum; ventral tegmental area.

Figure 1.

A, Schematic of task design. During the chain schedule, one lever (SL) was extended into the test chamber at the same time as a cue light was illuminated above the lever (SL^O). SL^P extinguished the light and retracted the lever. After a delay, the other lever in the chamber (TL) was extended and associated cue light illuminated (TL^O). Following a press on the TL (TL^P) rats received food reinforcement after a delay (R). B, Extinction behavior in animals with FSCV recordings in the core or shell. Behavior and analysis in extinction was grouped by block based on the rat's behavior. Trials in the immediate preceding chain task were used to compare events in extinction. Early extinction was all trials until the first significantly delay response on the SL, whereas delay extinction was all trials between the first delayed SL^P and the first omitted press following SL^O presentation. Within the late extinction block, distinctions were made between whether the subject made a press or omitted a response. C, Histology of electrode placements within the core (black circles) and medial shell (gray circles).

Figure 2.

Performance of the chained schedule produced different DA release dynamics within the NAc. Dopamine release dynamics in the core (A) and shell (B) of the NAc aligned to the time of SL extension into the chamber (SL^O). Color plots each show averages from a representative subject in the core and shell, respectively. Average time (▴) of the TL extension (TL^O) and reward (R) and range (±2 SD) relative to SL^O are shown at bottom. C–E, Across-subject mean DA release across all recordings in core (black) and shell (gray) relative to (C) SL^O, (D) SL^P, and the extension of the TL^O 4 s later, and (E) TL^P, and the reward (R) food pellet delivered 2.5 s after press. Dashed line shows SEM of the average for each region. Bottom row (F–H) shows average peak DA release for each behavioral event. *p < 0.05 versus baseline; †p < 0.05 core versus shell.

Figure 3.

Changes in DA signaling between the beginning of the session (early; first 5 trials of the chain schedule) versus the end of the session (late; last 5 trials). A, Average DA concentrations in the NAc core from the averages of each subject's first five trials (light blue) and last five trials (purple). B, In the core, within-subjects peak DA signaling was unchanged between the beginning of the session and end. C, Average DA concentrations in the NAc shell from the averages of each subject's first five trials (red) and last five trials (orange). D, Shell DA showed a significant within-subjects decrease at both the SL^P and TL^P cues and reward (**p < 0.01), whereas the decrease at the SL^O cue was nearly significant (#p = 0.073). Error bars show SE of the difference (early vs late).

Figure 4.

Comparison of electrically stimulated versus cue-evoked DA signaling in the NAc core and shell. A, Average concentration of DA aligned to either the SL^O cue or electrical stimulation of VTA fiber onset. The timing of the onset of the TL^O cue and reward was estimated on a range of response times for those outcomes following SL^O (mean response time indicated by triangle; width indicates ±95% confidence interval). B, Comparison of average baseline (BL) DA concentrations to peak DA concentration within 1 s of SL^O or electrical stimulation (Stim/SL^O), and within the 95% confidence interval range for the times corresponding to the TL^O or reward epochs. C, Latency to peak concentration following SL^O or electrical stimulation (Peak Lat) and subsequent decay (clearance) following release in the core and shell. T₂₀ and T₈₀ are the times at which the signal has decayed 20% and 80% away from peak, respectively, whereas half-life is the latency following peak to the reach half-peak concentration. *p < 0.0001, electrical stimulation/SL^O versus baseline; †p < 0.0001, Shell: Cue greater [DA] than all other stimulation types; ‡ p < 0.0001, Shell: Cue greater latency to decay from peak than all other stimulation types. Error bars show SE of the difference (cue vs electric).

Figure 5.

Extinction behavior in animals with FSCV recordings in the core or shell. A, The number of trials before rats first showed a significant increase in response latency to shift from the early to delay phase of extinction (left) and response omission (right) for the SL (light gray) and TL (dark gray). Rats showed a latency shift for the TL in significantly fewer trials than the SL, though the number of trials before a trial was omitted was the same between seeking and taking responses. *p < 0.05 SL versus TL. B, Response latency to respond on the SL (left) and the TL (right) across phases of extinction. Response latency increased across blocks, and was significantly longer in the delay and late extinction blocks for the SL presses. Presses on the TL were reliably faster than those on the SL within each block. *p < 0.05, **p < 0.01 vs early Ext.

Figure 6.

DA release in the core (A–C) and shell (D–F) during extinction. A, Alignment to the SL^O in the core revealed a continuous decrease in core DA release to the cue over iterative extinction trials (blue lines) relative to rewarded chain sessions (black line). BvCore DA release to operant responses and reward during the reinforced chain schedule (black) and early extinction (blue) aligned to the TL^P event. Gray bar shows range of maximum and minimum concentrations of DA during the baseline period. C, Peak DA relative to the SL^P, TL^P, and reward in the reinforced schedule and early extinction. D, Alignment to the SL^O in the shell (red lines) revealed more discrete decreases in phasic DA release to the cue over iterative extinction trials relative to rewarded chain sessions (black line). E, DA signaling aligned to the TL^P in the shell in early extinction (red) and the reinforced chain schedule (black). F, Peak DA in the shell was unchanged at SL^P, but showed significant decreases at TL^P and reward. *p < 0.05, **p < 0.01, chain versus early extinction; †p < 0.05, omission less than baseline.