Abstract
Cues in the environment can guide behavior in adaptive ways, leading one towards valuable resources such as food, water, or a potential mate. However, cues in the environment may also serve as powerful motivators that lead to maladaptive patterns of behavior, such as addiction. Importantly, and central to this article, there is considerable individual variation in the extent to which reward cues gain motivational control over behavior. Here we describe an animal model that captures this individual variation, allowing us to better understand the psychological and neurobiological processes that contribute to cue-evoked behaviors. When a discrete cue is paired with a food reward in a Pavlovian manner it acquires greater control over motivated behavior in some rats (“sign-trackers, STs) than in others (“goal-trackers”, GTs). We review studies that have exploited this animal model to parse the neurobiological mechanisms involved in learning associations between stimuli vs. those involved in attributing incentive salience to those same stimuli. The latter seems to be dependent on dopamine and subcortical circuits, whereas the former may engage more cortical “top-down” mechanisms.
Introduction
Cues (conditional stimuli, CSs) that predict the impending delivery of biologically significant events (unconditional stimuli, USs), such as a food reward, acquire the ability to control behavior, or produce a conditioned response (CR), via Pavlovian learning mechanisms [1]. The same is true for stimuli associated with aversive events, but here we will focus only on cues associated with rewards. The ability of a CS to evoke simple reflexive CRs, such as salivation in the case of Pavlov’s dogs, is well known. It is less well appreciated, however, that CSs can also acquire the ability to evoke complex emotional and motivational states [2–5]. This latter transformation is thought to occur if a CS is attributed with incentive salience and thus acquires the properties of an incentive stimulus [2–4, 6]. Incentive stimuli: 1) bias attention towards them and can elicit approach into close proximity with them; 2) become desirable themselves, in the sense that an animal will work for access to the stimulus alone (i.e., they act as conditioned reinforcers); and 3) can instigate or invigorate reward-seeking behavior (as in Pavlovian-to-instrumental transfer effects, PIT). Incentive stimuli can guide behavior in adaptive ways, leading one towards valuable resources such as food, water, or a potential mate. However, such cues may also serve as powerful motivators that lead to maladaptive patterns of behavior, as in over-eating and addiction. Importantly, there is considerable individual variation in the extent to which CSs act as incentive stimuli and gain motivational control over behavior [7].
In the laboratory, if a discrete and localizable Pavlovian CS, such as presentation of a lever, is reliably paired with presentation of a food reward, some rats come to approach the CS (Figure 1), even though no response is required for delivery of the reward [8]. This is called “sign-tracking” [9, 10]. In contrast, upon presentation of the lever-CS, other rats go to the location of impending reward delivery (Figure 1) [8]. This CR is called “goal-tracking” [11]. It is important to note that the lever-CS is an equally effective predictive stimulus (CS) in both sign-trackers (STs) and goal-trackers (GTs) – they learn their respective CRs at the same rate – but only in STs does the lever-CS acquire the properties of an incentive stimulus [12]. That is, for STs, the CS is more attractive and elicits approach towards it, is a more effective conditioned reinforcer, and is more effective at instigating reward-seeking behavior relative to GTs [12–14]. Importantly, this variation in the ability of a CS to acquire incentive salience is captured best by a localizable CS (i.e. lever or light) [15], and is not apparent when the CS is a tone [16]. Furthermore, tone stimuli paired with a food reward are attributed with less incentive value than a lever-CS [16, 17].
Sign-trackers are also more resistant to extinction of their CR than GTs [18] and will continue to approach the CS even if contact with it results in omission of the reward [19], indicating that approach behavior is not contingent upon subsequent food delivery or maintained via response reinforcement processes [20]. It has also been shown that sign-tracking behavior becomes more pronounced when the relationship between the CS and the reward is uncertain, such that the probability of the reward following CS presentation changes [21]. These findings provide further evidence for dissociation between the predictive vs. incentive value of the CS (see also [22]). Thus, a lever-CS acquires all of the properties of an incentive stimulus in some individuals (STs), but not others (GTs). Importantly, this individual variation in the propensity to attribute incentive salience to a discrete or localizable CS has been described not only for food predictive cues, but also for cues that predict drug rewards [7, 15]}. The current article will focus on what we have learned about the neurobiological mechanisms of stimulus-reward learning by exploiting this individual variation.
Elucidating the Neurobiological Mechanisms Underlying Individual Differences in Stimulus-Reward Learning
Dopamine
There has been considerable research on the role of dopamine (DA) in stimulus-reward learning, and one popular hypothesis is that phasic DA signals serve as a prediction error signal necessary for learning associations (for recent review see [22]). Given that STs and GTs learn CS-US associations equally well, but differ in the degree to which they attribute incentive salience to the CS [12], we have used this animal model to parse the role of dopamine in stimulus-reward learning [23]. The classic evidence that DA provides a prediction error signal is the observation that a phasic DA signal transfers from the US to the CS over the course of learning [24]. We used in vivo voltammetry in the core of the nucleus accumbens to see if this shift in DA occurred as STs and GTs learned their respective CRs [23]. We found that the transfer of DA occurs only in rats that learned a sign-tracking CR, suggesting that the role of DA is to encode the incentive properties of reward cues, not the predictive properties [23] (for additional discussion see [22]). In agreement, Parker et al. [25] found that mice with disrupted phasic dopamine signaling were perfectly capable of learning a goal-tracking CR, even though there was no apparent transfer in dopamine signaling from the US to the CS.
Furthermore, a series of pharmacological studies support the notion that dopamine signaling is important for sign-tracking, but not goal-tracking behavior. Systemic injections of flupenthixol, a non-specific dopamine receptor antagonist, blocked the acquisition of a ST CR, but had no effect on the acquisition of a goal-tracking CR [23]. Similarly, flupenthixol administered directly into the core of the nucleus accumbens [26] attenuated the performance of an already learned sign-tracking CR, but not a goal-tracking CR. This effect appears to be due to DA antagonism degrading the incentive value of the cue, which is necessary for it to elicit approach behavior, because the effect was evident on the very first trial and therefore could not be due to new learning [26]. In support, DA antagonism had no effect on the performance of a different CR, conditioned orienting behavior, in either STs or GTs [27]. This latter finding suggests that DA blockade does not degrade the CS-US association, even in STs. Lastly, flupenthixol administered in the core of the accumbens also attenuates cue-evoked reinstatement of cocaine-seeking and does so preferentially in STs [28]; while enhancing DA activity by local injection of amphetamine increases both cue-evoked reinstatement of cocaine-seeking [28], and approach to a lever-CS [29] in STs. Taken together, these findings demonstrate that dopamine signaling, specifically in the core of the nucleus accumbens (Figure 2), is critical for the attribution of incentive salience to reward cues, and not for encoding the predictive value.
One source of variation in DA signaling in STs and GTs may be that these phenotypes differ in DA transporter (DAT) and/or dopamine receptor expression and function [29–31]. Indeed, STs show greater surface DAT expression in the ventral striatum, and this is associated with faster DA uptake in the core of the accumbens. Also, systemic amphetamine administration inhibits DA uptake to a greater extent in STs than GTs [29], which could contribute to its selective effects on approach and cue-induced reinstatement described above [28]. There are also data to suggest that STs have lower levels of dopamine D2 receptor mRNA in the nucleus accumbens [30, 31], and pharmacological studies suggest that antagonism of this receptor disrupts sign-tracking, without affecting goal-tracking behavior [32]. However, the expression of both sign- and goal-tracking CRs were attenuated with systemic administration of flupenthixol [23] or antagonists acting with greater selectivity at D2/D3 receptors [33, 34], and agonists of these receptors have similar effects [33]. Thus, while dopamine signaling clearly plays a role in the propensity to attribute incentive salience to reward cues, it is not yet clear which receptors are mediating these signals; although recent evidence suggests that D3 and D4 receptors are not selectively involved [33, 35]. Further investigation is also needed to determine whether or not inherent differences in expression patterns or efficacy of the dopamine system are playing a role. Moreover, the role of dopamine and/or which dopamine receptors are involved changes over the course of training [35], such that effects on acquisition may differ from those on the expression of the conditioned response [36].
Circuit Level Differences
There have been numerous studies examining the neural systems involved in cue-motivated behaviors, most of which support the notion that there is a widespread and overlapping network of “reward circuits” mediating the response to many different classes of rewards (e.g., food, sex, drugs) and reward cues (e.g., discrete cues, contexts) (for review see [4, 37–39]). This “motive circuit” includes cortico-striato-pallido-thalamic loops with cortical and subcortical networks converging on the nucleus accumbens [37–40]. What has been less clear, however, is exactly which properties of a reward cue are responsible for activating this circuit. In most learning studies the predictive and incentive value of cues are confounded, and they tend to change together, making it difficult to separate the neurobiological processes involved in learning associations vs. those involved in attributing incentive salience to a cue. However, the sign-tracker/goal-tracker model allows us to do this [12], and here we describe initial studies in which we have exploited this individual variation to better understand the circuitry underlying these different forms of stimulus-reward learning.
One of our first efforts was to determine which brain regions are engaged by presentation of a food cue in STs and GTs, using c-fos as a marker of neuronal activity [41]. Interestingly, a food cue induced c-fos expression throughout the so-called motive circuit in STs but not GTs, including the dorsal (caudate-putamen) and ventral striatum (accumbens), lateral habenula and midline thalamus, and similar effects have been described upon presentation of a drug (opioid) cue [27] (Figure 2). These findings demonstrate that the predictive value of a cue is not sufficient to engage these brain regions; it must also be attributed with incentive salience.
Furthermore, an examination of interregional cue-induced c-fos mRNA levels within each phenotype revealed distinct patterns of correlated neural activity, with subcortical patterns of activation in STs, and evidence for cortical engagement in GTs [41]. In particular, STs showed correlated cue-induced activity between the paraventricular nucleus of the thalamus (PVT) and the ventral striatum; whereas GTs showed a strong pattern of correlated activity between the prefrontal cortex (PFC) and paraventricular nucleus of the thalamus (PVT) [41, 42]. These findings, and the fact that the PVT shows pronounced differences in cue-induced c-fos activity between STs and GTs [27, 41] (Figure 2), has prompted further investigation into the role of the PVT and related circuitry in sign- and goal-tracking behaviors [42, 43].
When the PVT is lesioned prior to the acquisition of a conditioned response, the initial learning of the CS-US association is not affected, but the differences in the expressed CR are amplified, with an increase in sign-tracking behavior in STs and decrease in goal-tracking behavior in GTs [43]. When lesions occur after rats have acquired a CR, effects are only evident in GTs who, following PVT lesions, show increased sign-tracking behavior [43]. These results suggest that the PVT may act to suppress the attribution of incentive salience to reward cues, at least in GTs, as disruption of the functional activity of this nucleus enhances the tendency to sign-track.
To better understand the circuitry surrounding the PVT in these cue-motivated behaviors, we conducted dual-labelling (c-fos and flourogold) studies to identify which cells communicating with the PVT are activated in response to a food cue [44]. The findings suggest that the pathway from the prelimbic cortex (PrL) to the PVT may play a primary role in encoding the predictive properties of reward cues; whereas subcortical activity – both inputs to the PVT from amygdalar and hypothalamic subregions (Figure 2), and outputs from the PVT to the ventral striatum – are mediating the attribution of incentive salience to reward cues.
Using chemogenetics, we (SBF) are now targeting some of these circuits to further explore their role in sign- and goal-tracking behaviors. We are especially interested in the PrL-PVT circuit, as depletion of serotonin in the mPFC enhances sign-tracking behavior in C57 mice [45]; and deficits in mPFC cholinergic activity have been associated with poor attentional control in STs [46]. STs are also more impulsive than GTs [30, 47], another trait inherent to these phenotypes that may be mediated by aberrant top-down executive control. Thus, we hypothesize that the PrL-PVT circuit may act to inhibit incentive salience attribution, and while this is effective in GTs, in STs the subcortical drive may override the cortical control, contributing to maladaptive tendencies.
Other Regions of Interest
The findings reviewed above which are, admittedly, primarily from our own work, provide evidence for the involvement of dopamine and specific nodes of the “motive circuit” in the attribution of incentive salience to reward cues. Support for these findings comes from other studies, such as that by DiFeliceantonio and Berridge [48], demonstrating that the dorsolateral striatum can act to enhance the incentive salience of a Pavlovian reward cue. It is important to note that other brain regions and neurotransmitter systems, known to interact with the dopamine system (for review see [40]), have also been studied within this realm.
One such region is the lateral habenula, an area that showed enhanced cue-induced c-fos activity in STs relative to GTs [27, 41]. DA neuron firing is strongly modulated by inputs from the lateral habenula (LHb), such that increasing LHb activity decreases DA activity, whereas decreasing LHb activity does the opposite (for review see [49]). In an interesting study, Danna and colleagues [50] showed that lesions of the LHb outputs (increased DA) increased sign-tracking; whereas stimulation of the same outputs (decreased DA) attenuated sign-tracking. Neither manipulation had any influence on goal-tracking. These data further support the idea that DA is important for the performance of sign-tracking, but not goal-tracking behavior, and demonstrate a role for the lateral habenula in incentive salience attribution (Figure 2).
Another region that showed robust Fos expression in STs relative to GTs in response to both a food and opioid cue is the basolateral amygdala (BLA; [27], Figure 2). Consistent with this finding, it has been shown that lesions of the BLA attenuate sign-tracking behavior after the CR is acquired [51]. Interestingly, in the same study, it was shown that lesions of the nucleus accumbens impaired the initial acquisition of sign-tracking behavior, and when communication between the BLA and nucleus accumbens was disrupted with disconnection lesions, there were deficits in both the initial acquisition and expression of sign-tracking behavior [51]. These findings suggest that different brain regions within a circuit may mediate different aspects (i.e. acquisition vs. performance) of stimulus-reward learning.
In recent years, the ventral pallidum has become a focus of great interest as a mechanism of incentive motivation [52, 53]. In support, Chang and colleagues [54], using a chemogenetic approach, showed that transient disruption of neurons in the ventral pallidum impaired the acquisition of sign-tracking, but did not affect goal-tracking. Furthermore, using single-unit in vivo electrophysiology, Ahrens et al. [55], recently demonstrated that, during CS presentation, there are a greater number of responsive neurons in the ventral pallidum, and they show greater changes in activity in STs than GTs. Furthermore, this activity is strongly correlated with the degree of attraction to the reward cue, demonstrating that neural activity in the ventral pallidum largely reflects the degree to which the reward cue is attributed with incentive salience (Figure 2).
Conclusions
We have provided a review of converging data that implicate several brain regions and possible circuits in mediating the attribution of incentive salience to reward cues (Figure 2). Using the sign-tracker/goal-tracker animal model, we, and others, have demonstrated that the role of dopamine is to encode the incentive—and not the predictive—properties of reward cues. Furthermore, the corticostriato-pallido-thalamic loops of the “motive circuit” are engaged only when a reward cue is attributed with incentive salience. Based on the existing data, we postulate that the ability of reward cues to gain motivational control over behavior (as in STs) is regulated by subcortical networks; whereas “top-down” cortical circuits act to inhibit this process (as in GTs). This animal model has been invaluable in allowing us to parse the neurobiological mechanisms underlying stimulus-reward learning and incentive motivation, providing a better understanding of the neural processes that go awry in psychopathology. It is hoped that this model will continue to be utilized across disciplines [56, 57] to further advance our understanding and potentially lead to novel therapeutic targets for the treatment of addiction and related disorders.
Highlights.
There is considerable individual variation in conditioned responses to reward cues
Cues can evoke simple conditioned responses and/or complex motivational states
When a reward cue becomes an incentive stimulus it can elicit maladaptive behavior
We can exploit variation to elucidate the neurobiology of cue-elicited behavior
Distinct neural circuits are engaged when a cue has incentive vs. predictive value
Acknowledgments
We would like to thank the former and present members of the Robinson and Flagel laboratories who contributed to some of the studies reviewed here and who prompted insightful discussions surrounding the topic.
FUNDING SOURCES
Support for the authors and the studies reviewed in this manuscript is provided by grants from the National Institute on Drug Abuse (NIDA): P01 DA031656 (SBF, TER), P50 DA037844 (SBF, TER) and R01 DA038599 (SBF).
Footnotes
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Conflict of interest
The authors have no conflicts of interest to declare.
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