Dynamic computation of incentive salience: "wanting" what was never "liked"

Abstract

Pavlovian cues for rewards become endowed with incentive salience, guiding "wanting" to their learned reward. Usually, cues are "wanted" only if their rewards have ever been "liked," but here we show that mesocorticolimbic systems can recompute "wanting" de novo by integrating novel physiological signals with a cue's preexisting associations to an outcome that lacked hedonic value. That is, a cue's incentive salience can be recomputed adaptively. We demonstrate that this recomputation is encoded in neural signals coursing through the ventral pallidum. Ventral pallidum neurons do not ordinarily fire vigorously to a cue that predicts the previously "disliked" taste of intense salt, although they do fire to a cue that predicts the taste of previously "liked" sucrose. Yet we show that neural firing rises dramatically to the salt cue immediately and selectively when that cue is encountered in a never-before-experienced state of physiological salt depletion. Crucially, robust neural firing to the salt cue occurred the first time it was encountered in the new depletion state (in cue-only extinction trials), even before its associated intense saltiness has ever been tasted as positively "liked" (salt taste had always been "disliked" before). The amplification of incentive salience did not require additional learning about the cue or the newly positive salt taste. Thus dynamic recomputation of cue-triggered "wanting" signals can occur in real time at the moment of cue re-encounter by combining previously learned Pavlovian associations with novel physiological information about a current state of specific appetite.

Figure 1.

Methods: A 5 s tone cue (CS_sucrose) predicted an infusion of sucrose solution into the mouth as UCS. A different tone cue (CS_salt) predicted concentrated NaCl taste infusion. A third tone (CS−) predicted no infusion. Tones were counterbalanced between animals. Trials with actual tastes, used for training and phase 2 of testing, are shown at the top (“CS plus UCS”). Each test day began with an extinction phase (“CS only,” middle) and was identical except that the CS tones were not followed by UCS taste infusions. At the beginning of each test phase (bottom time line), 5 CS− control cues were presented, followed by 10 sucrose and salt trials in a random mix, followed by 5 more CS− control trials. The experiment consisted of two test days: (1) normal homeostasis and (2) sodium-depleted. Time axis truncated and not to scale.

Figure 2.

Examples of neural responses in two units to 5 s cue tones (CS_sucrose and CS_salt) during baseline-replete (day 1, left column unit) and sodium depletion (day 2, right column unit). Most VP neurons responded within 100 ms of cue onset, and firing peaks lasted ∼500 ms although the tone lasted 5 s. Each row in the raster represents spike activity in an individual trial. Histograms average activity across trials in 50 ms bins. Note that the homeostatic day 1 unit fired robustly to the cue for sucrose but not to the cue for salt. By contrast, the unit recorded on sodium-depleted day 2 rose in response to the cue for salt, firing as robustly to it as to the cue for sucrose.

Figure 3.

Population coding during extinction testing (“CS alone”). This “Venn-style” diagram uses rectangles rather than circles to represent sizes of neural populations responsive to the different cues (CS_salt,, CS_sucrose, and CS−). The area of each rectangle is proportional to the population size. The gray background represents the total of all neurons tested and the area of exposed gray represents the proportion of unresponsive neurons. The overlap between rectangles indicates the intersection among populations with one, two or, three responses. For example, the overlap between red and blue rectangles represents the proportion of neurons with responses to both CS_salt and CS−. Unique responses overlap gray background alone. Normal homeostasis test day is on the left and test after salt depletion is on the right. Only the proportion of neurons responsive to salt cues grew on the salt depletion test day (*p < 0.05, χ² test of independence) (Siegel, 1956).

Figure 4.

Sodium depletion selectively potentiates an initial burst of activity to CS_salt in extinction trials. These histograms show averaged, normalized firing rates of responsive VP neurons during extinction tests. a, Normal homeostasis test on day 1 (20 s period from 5 s before cue onset to 15 s after cue offset; 500 ms bins). b, Sodium depletion test on day 2. c, Analysis with 250 ms bins confirms faster firing rates to CS_sucrose than to CS_salt during the baseline-replete test day 1 (left), but no difference during depletion day 2 (right). d, Control tone CS− response. In each diagram, the green time line marks the occurrence of the tone cue. The dashed line and hatching (“no infusion”) in a and b marks the period during which an infusion would have occurred in rewarded trials, but does not in these extinction trials. In a–c, solid red lines and shading indicate salt cue firing and blue lines and shading indicate sucrose cue firing. The gray shading in a marks a significant decrease in firing rate relative to the precue baseline (p = 0.007) in salt cue trials. During “no-infusion” period, rates were faster after a salt cue than the sucrose cue (line and “*” marks), but there was no significant difference during depletion (b). d, Firing rates to the onset of control cue transiently increase slightly during depletion, but firing rates to CS− overall are lower than to the other CS cues. “*” indicates significant difference (p < 0.05).

Figure 5.

Comparison of VP firing to CS_salt across extinction trials in normal homeostasis (red) versus salt appetite (blue). Lines depict mean ± SEM firing (normalized to precue background) across 10 extinction trials. Firing to CS_salt during salt appetite was significantly elevated above normal in the very first trials, including the very first CS_salt presentation after depletion (trial 1). This firing elevation was generally robust across extinction trials. *p < 0.05.

Figure 6.

VP firing rate coding of CS and UCS during phase two on day 1 (normal homeostasis) and day 2 (sodium depletion) during trials “CS plus UCS” with actual taste reward infusions. On normal day 1, VP neurons fire to CS_sucrose and to sucrose taste UCS, but not significantly to CS_salt or salt taste. On sodium-depleted day 2, neurons fire to CS_salt as well as CS_sucrose, and fire even more vigorously to salt taste than to sucrose taste. The format follows Figure 4, with the brown line indicating the timing of actual taste infusions. *p < 0.05.

Figure 7.

Taste reactivity to UCS actual taste infusions. a, b, Sucrose taste elicited stronger positive hedonic reactions (a) on the normal homeostasis test of day 1, when NaCl taste instead elicited many negative aversive reactions (b). Conversely, after sodium depletion on day 2, NaCl elicits predominantly positive hedonic reactions, similar to the sucrose taste.