Research report
Which cue to ‘want’? Opioid stimulation of central amygdala makes goal-trackers show stronger goal-tracking, just as sign-trackers show stronger sign-tracking

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Abstract

Pavlovian cues that have been paired with reward can gain incentive salience. Drug addicts find drug cues motivationally attractive and binge eaters are attracted by food cues. But the level of incentive salience elicited by a cue re-encounter still varies across time and brain states. In an animal model, cues become attractive and ‘wanted’ in an ‘autoshaping’ paradigm, where different targets of incentive salience emerge for different individuals. Some individuals (sign-trackers) find a predictive discrete cue attractive while others find a reward contiguous goal cue more attractive (location where reward arrives: goal-trackers). Here we assessed whether central amygdala mu opioid receptor stimulation enhances the phasic incentive salience of the goal-cue for goal-trackers during moments of predictive cue presence (expressed in both approach and consummatory behaviors to goal cue), just as it enhances the attractiveness of the predictive cue target for sign-trackers. Using detailed video analysis we measured the approaches, nibbles, sniffs, and bites directed at their preferred target for both sign-trackers and goal-trackers. We report that DAMGO microinjections in central amygdala made goal-trackers, like sign-trackers, show phasic increases in appetitive nibbles and sniffs directed at the goal-cue expressed selectively whenever the predictive cue was present. This indicates enhancement of incentive salience attributed by both goal trackers and sign-trackers, but attributed in different directions: each to their own target cue. For both phenotypes, amygdala opioid stimulation makes the individual's prepotent cue into a stronger motivational magnet at phasic moments triggered by a CS that predicts the reward UCS.

Highlights

DAMGO in CeA enhances motivational magnets. ► Mu opioid receptor stimulation in CeA enhances both sign-tracking and goal-tracking. ► DAMGO in CeA amplifies cue-evoked motivation.

Introduction

Reward cues (Pavlovian CSs) can carry incentive salience: eliciting craving for the reward, and making the cues themselves ‘wanted’, approached and even the target of consummatory acts such as ingestive licks, nibbles, and bites that normally belong to an associated food reward (UCS). Thus food cues can tempt a binge-eater to overindulge or drug cues can trigger relapse in a drug addict [1], [2], [3], [4], and such cues can attract appetitive-consummatory behaviors acting as ‘motivational magnets’ [5], [6], [7], [8].

However, reward cues are not always attractive, but rather vary across time in motivation potency. A cue's power to trigger temptation fluctuates especially when encountered in different physiological-brain states (e.g., drug intoxication, stress, hunger, satiety) [9], [10], [11]. Particular activations in mesocorticolimbic brain states, we will suggest, are why particular cue encounters may make addicts relapse into excessive consumption even after the same cue has been successfully resisted many times before [10], [11], [12], [13]. Some brain activations may also focus ‘wanting’ more narrowly onto a single target, as well as elevating intensity [19].

Useful individual differences in the target of incentive salience have been found in autoshaping or “sign-tracking” experiments in rats [14], [15], which model the ‘motivational magnet’ feature of incentive salience for Pavlovian cues. In one version of autoshaping, phasic presentation of a lever CS (CS+ Lever; sometimes called the sign) always predicts a reward UCS: a sucrose pellet delivered to a dish (CSdish; sometimes called the goal). After learning the Pavlovian CS–UCS association, many individual rodents, fish, pigeons, dogs, and people come to approach and bite the discrete CS+ sign and are known as “sign-trackers” [3], [8], [16], [17], [18], [19]. By contrast, other individuals come to approach the goal location where reward is delivered (CSdish) during the CS+ sign presentation and are known as “goal-trackers” [5], [16], [19]. Goal-tracking vs. sign-tracking differences emerge in the first few days of Pavlovian training in rats, and remain stable [9], [20], [21].

This difference in individual phenotype is related to underlying mesolimbic brain traits, but can also be experientially biased by environmental situations such as encountering uncertainty in CS–UCS contingencies, receiving reward UCS directly without needing to approach a goal, receiving amphetamine or related drugs, or having been previously sensitized by drugs administered weeks earlier [16], [22], [23], [24], [25], [26], [27], [28]. Some similarity in underlying mechanisms might be recruited in both sign-trackers and goal-trackers to attribute incentive salience to individualized targets, at least when mesocorticolimbic brain systems are in a stimulated state. Stimulation of mu opioid circuits in the central nucleus of the amygdala (CeA) was indicated to achieve that mesocorticolimbic state by an earlier study in our laboratory: producing elevation of incentive salience in both sign trackers and goal trackers, and simultaneously focusing that intense incentive salience onto a single Pavlovian target [21].

CeA has distinct inputs and outputs that distinguish it from other nuclei in amygdala [29], [30]. Anatomically, the CeA can be viewed as a serial output nucleus for basolateral amygdala (BLA) [31], as a serial starting point for the extended amygdala complex [32], [33], [34], or as a striatal-level structure within macrocircuits that organize cortico-striatal-pallidal networks to generate motivated behavior [35]. Functionally, CeA is a site where mu opioid stimulation via DAMGO microinjection can markedly increase motivation to seek and consume palatable food rewards, and CeA interacts with nucleus accumbens in opioid enhancements of food intake [36], [37], [38], [39]. CeA also plays special roles in translating learned Pavlovian information into active motivation [40], [41], [42], [43], [44], [45]. For example, stimulation of mu opioid receptors in the central nucleus of the amygdala (CeA) magnifies the ability of cues to trigger incentive motivation toward sucrose or sex incentives, and to act as CS motivational magnets [21], [46].

Here we explore further the idea that in autoshaping the two Pavlovian CSs (sign and goal) have potentially distinct roles: acting as (1) the trigger to elicit a phasic pulse of intense incentive salience, vs. as (2) the target of focused incentive salience attribution (that becomes the most ‘wanted’ Pavlovian object of desire). That is, CeA opioid stimulation may make sign-trackers ‘want’ the CS+ Lever more, and similarly make goal-trackers ‘want’ the CSdish more, each in a phasic pulse when triggered by CS+ encounter [21]. We hypothesize that the CS+ acts as the trigger in both sign-trackers and goal-trackers to evoke a temporary surge in the intensity of CeA-amplified incentive salience, which lasts seconds. However, the target CS that is attributed with focused incentive salience differs between sign-trackers and goal-trackers during a state of CeA opioid stimulation. For sign-trackers, the target is the same trigger or CS+ Lever that predicts sucrose. By contrast, for goal-trackers the target is the CSdish object/location where the UCS is delivered. Finally, we hypothesize that the breadth of focus for incentive salience attribution on the individualized target is also narrowed by CeA stimulation in a winner-take-all fashion. That is, individualized Pavlovian information-to-motivation links are amplified to make the most ‘wanted’ target even more intensely attractive after CeA opioid stimulation, while alternative targets may even decline in relative attractiveness.

However, a potential problem for our hypothesis is that goal-trackers may essentially lack incentive salience, as only sign-trackers appear to show high cue-triggered ‘wanting’ [8], [47]. Sign-trackers have been suggested to model addiction-like features of incentive salience much more than goal-trackers [14], [15], [48], [49], whereas goal-trackers might approach their dish using non-‘wanting’ mechanisms, such as cognitive expectancy mechanisms or via simpler S–R habit mechanisms [9], [48]. A potential reconciliation between such evidence and our hypothesis might be achieved if it could be shown that specific mesocorticolimbic states (e.g., CeA opioid stimulation) produce the higher intensities and sharper focus of incentive salience in goal-trackers. Specifically, our hypothesis is that CeA stimulated states cause goal-trackers to show pulses of high incentive salience that are equal in intensity to sign-trackers, though focused on a different target: the dish.

To test this hypothesis, it is necessary that goal-trackers in a state of mesocorticolimbic activation show the full cue-triggered sequence of motivated appetitive-consummatory behaviors that characterizes a ‘motivational magnet.’ For a sucrose pellet UCS, these are sequences of approach, nibble, sniff, grasps and bite behaviors directed to the metal object (CSdish or CS+ Lever). That sequence was not completely confirmed for goal-trackers in the earlier Mahler and Berridge study because the opaque metal wall of the goal dish precluded a clear camera view of actions inside, so that it was not possible to observe a goal-tracker's mouth performing nibble, sniff and bite behaviors in the dish [21].

Here we aimed to more stringently test whether CeA stimulation enhances incentive salience using an additional close-up camera focused on the inside surface of the dish. This measured the full appetitive-consummatory sequences of approach, nibbles, sniffs, grasps and bites of the CSdish in goal-trackers. We also aimed to more closely examine the winner-take-all aspect of narrower focusing on a single target induced by CeA DAMGO, in individuals that show nearly balanced mixtures of goal-tracking vs. sign-tracking, as well as in the more extreme phenotypes. Our results here confirm that CeA stimulation does make goal-trackers approach and ‘consume’ their metal CSdish more, and in more focused fashion. The intensity and focus of the enhancement in goal-trackers’ behavior is comparable to sign-trackers’ enhanced behavior toward CS+ Lever, consistent with the trigger vs. target hypothesis for Pavlovian incentive salience.

Section snippets

Subjects

Sprague Dawley rats (n = 28; female) weighing 280–340 g at the start of the experiment were pair housed on a reverse light/dark cycle. Water was provided ad libitum; food was provided ad libitum except during weeks containing autoshaping training or test sessions, when rats were restricted to 90% free feeding weight and fed about 12 g of standard laboratory chow daily after each training session. All experiments were conducted in accordance with protocols approved by the University of Michigan

Overview: mu opioid stimulation of central amygdala potently enhanced approach and appetitive-consummatory actions of goal-trackers toward dish but of sign-trackers toward lever

In goal-trackers, DAMGO microinjections in CeA potently increased the number of appetitive-consummatory sequences directed toward their CSdish. The increase was selective to moments when the CS+ Lever was physically present. The increased sequences were always initiated by CS+-triggered approaches to the dish, followed by nibbles and sniffs of the dish rim and internal surface. In sign-trackers, these CeA DAMGO enhancements were matched by increased numbers of approaches and

Central nucleus of the amygdala focuses incentive salience

Goal-trackers and sign-trackers ordinarily differ in their targets of incentive salience, so that it has been suggested that sign-trackers may uniquely attribute incentive salience to discrete CSs for reward in ways relevant to addiction [8], [9], [14], [15], [48]. Our results add a degree of richness to this picture by confirming that goal-trackers can achieve similar high intensities of incentive salience pulses, though focused on a different type of Pavlovian CS target, especially when their

Acknowledgments

We thank Terry Robinson, Benjamin Saunders, and Aaron Garcia for helpful comments on earlier versions of this manuscript. This work was supported by Grants DA015188 and MH63649 to KCB and DA007267 to AGD.

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