Disentangling pleasure from incentive salience and learning signals in brain reward circuitry

Abstract

Multiple signals for reward-hedonic impact, motivation, and learned associative prediction-are funneled through brain mesocorticolimbic circuits involving the nucleus accumbens and ventral pallidum. Here, we show how the hedonic "liking" and motivation "wanting" signals for a sweet reward are distinctly modulated and tracked in this circuit separately from signals for Pavlovian predictions (learning). Animals first learned to associate a fixed sequence of Pavlovian cues with sucrose reward. Subsequent intraaccumbens microinjections of an opioid-stimulating drug increased the hedonic liking impact of sucrose in behavior and firing signals of ventral pallidum neurons, and likewise, they increased incentive salience signals in firing to the reward-proximal incentive cue (but did not alter firing signals to the learned prediction value of a reward-distal cue). Microinjection of a dopamine-stimulating drug instead enhanced only the motivation component but did not alter hedonic impact or learned prediction signals. Different dedicated neuronal subpopulations in the ventral pallidum tracked signal enhancements for hedonic impact vs. incentive salience, and a faster firing pattern also distinguished incentive signals from slower hedonic signals, even for a third overlapping population. These results reveal separate neural representations of wanting, liking, and prediction components of the same reward within the nucleus accumbens to ventral pallidum segment of mesocorticolimbic circuitry.

Fig. 1.

Design of experiments within a test day. In the serial Pavlovian design, two CS+ sounds (first CS+1 and then CS+2) predicted a sucrose UCS. In the simple Pavlovian design, a single CS+ sound predicted sucrose pellet delivery as a UCS. On test days conducted after rats had learned the Pavlovian associations, microinjections of DAMGO, amphetamine, or vehicle were made in the hedonic hotspot of the NAc shell to activate NAc-VP circuits immediately before the test, and VP neural firing was recorded to all stimuli. For serial Pavlovian tests, serial CS+ cues were presented in extinction to prevent relearning about the UCS (20–45 min postinjection), and sucrose UCS was tested alone in a second block (45–60 min) to isolate hedonic signals. Reinforced Pavlovian approach trials with the single CS+ were presented in a third block (60–75 min). Consumption of M&Ms was then used to verify increases of behavioral food wanting (75–105 min).

Fig. 2.

Incentive salience was amplified by opioid or dopamine stimulation of the NAc. (A) Neural firing in the VP was increased to the incentive CS+2 but never to the predictive CS+1 after either DAMGO (red line) or amphetamine (green) microinjections in the NAc compared with after vehicle (gray line). For each neuron, firing rate in sequential 0.5-s time windows was calculated as a percentage of its average rate 5 s before stimulus onset [baseline (BL) = 100%]. Lines represent mean normalized firing per drug, and lighter bands represent ± SEM. (B) Sequential 0.1-s windows at cue onset show that firing increases were driven by a fast and phasic burst, which tapered to baseline by 0.2–0.3 s after cue onset (note that the firing rise in A is averaged over the full 0.5 s, which dampens peak amplitude). (C) Behavioral intake of chocolate M&Ms was also increased by NAc amphetamine (A) or DAMGO (D) microinjection compared with vehicle (V) from ∼7 to 10 M&Ms eaten over 30 min. (D) VP firing to the control CS− that predicted nothing was never changed by dopamine or opioid stimulation of the NAc.

Fig. 3.

Hedonic liking for UCS was increased by opioid stimulation of the NAc hotspot but not by dopamine stimulation. (A) DAMGO microinjection in the NAc increased VP firing to the intraoral UCS sucrose taste (red line; mean firing rate over baseline ± SEM band as in Fig. 2) compared with after vehicle microinjection (gray line). Amphetamine microinjection in the NAc failed to enhance VP firing to the UCS (green line). x axis is as it is in Fig. 2. (B) Behavioral confirmation that DAMGO uniquely enhanced hedonic impact of sucrose was seen in increased orofacial liking reactions to the sucrose taste after opioid stimulation of the NAc but never after dopamine stimulation.

Fig. 4.

Distinct neural populations and firing signatures track liking vs. wanting enhancement. (A–D) Neuronal enhancements of firing to CS+2 vs. UCS induced by DAMGO. (A) Partly distinct DAMGO subpopulations encoded enhancement of firing above vehicle to the incentive CS+2 (but not to UCS), firing enhancement of hedonic UCS (but not of CS+2), or firing enhancements to both CS+2 and UCS. (B) Distinct temporal firing patterns tracked UCS liking vs. CS+2 wanting in the population that encoded both (patterns were also shared by the larger VP populations). Line graph shows firing to the CS+2 (green dashed) vs. UCS (red solid) during the first 5 s of stimulus presentation relative to prestimulus baseline levels. Time 0 equals tone onset for CS+2 and estimated arrival of sucrose in the mouth for UCS (0.5 s after pump onset because of infusion lag). DAMGO-induced elevation of CS+2-evoked firing was rapid and phasic, whereas DAMGO elevation of UCS firing was slower in latency to reach peak firing levels and was more sustained in duration. Shown also on the y axis are peak-firing levels to each stimulus in the vehicle condition (gray dash marks). A single example neuron is additionally shown below firing during the UCS and CS+2. (C) In the subpopulation of neurons in which DAMGO elevated firing to the incentive CS+2 only (and not to UCS), the elevated response was similarly rapid and phasic, although it was lower in magnitude and slightly more sustained compared with the dual-coding population in which DAMGO elevated both CS+2 and UCS firing. An example neuron is shown below. (D) In the subset of neurons in which DAMGO elevated firing to the liked UCS only (and not to CS+2), a gradual elevation of firing rate was observed to the UCS after opioid stimulation compared with vehicle levels. An example neuron is shown below. (E) Amphetamine-firing enhancements are neurons that fired at higher levels to the CS+2 compared with after vehicle, and they had a rapid and phasic peak elevation similar to DAMGO enhancement of CS+2 firing (but amphetamine never elevated UCS firing over vehicle).

Fig. P1.

Rats learned a serial cue sequence that separated moments of maximal reward signals: Pavlovian prediction (maximal to the first CS+1), incentive salience (maximal to the second CS+2), and hedonic impact (maximal to the UCS reward). Neural firing was recorded for each stimulus in the VP, whereas opioid and dopamine were stimulated by drug microinjections in the nucleus accumbens to modulate enhancement of specific reward signals. Raster histogram representations of neuronal firing to stimuli across trials are shown on the right. In this example, a neuron recorded after opioid stimulation shows enhanced phasic activity to the incentive CS+2 and enhanced sustained activity to the hedonic UCS. In other tests, dopamine stimulation enhanced firing only to the CS+2.