A food-predictive cue attributed with incentive salience engages subcortical afferents and efferents of the paraventricular nucleus of the thalamus
Introduction
The paraventricular nucleus of the thalamus (PVT) has recently been implicated in a variety of motivated behaviors (Hsu et al., 2014, Kirouac, 2015, Vertes et al., 2015), including reward-seeking behaviors (Martin-Fardon and Boutrel, 2012, James and Dayas, 2013, Haight and Flagel, 2014, Urstadt and Stanley, 2015). Much of the research surrounding the PVT and reward-seeking behaviors has focused on the role of the PVT in mediating responses to food- or drug-paired cues. For example, paired presentations of a discrete cue-light with a water reward leads to greater c-Fos induction in the PVT, relative to controls who received unpaired presentations of the cue and reward (Igelstrom et al., 2010). Enhanced levels of c-Fos are also found in the PVT in response to presentation of cocaine-paired cues (Matzeu et al., 2015a), as well as following cue-induced reinstatement of ethanol- and cocaine-seeking behavior (Wedzony et al., 2003, Dayas et al., 2008, James et al., 2011). In addition, transient inactivation of the PVT attenuates cue-induced reinstatement of cocaine-seeking behavior (Matzeu et al., 2015b) and the expression of cocaine conditioned place preference (Browning et al., 2014). While these findings demonstrate that the PVT is involved in mediating cue-motivated behaviors, its specific role in these processes is less well known.
Identifying the neural mechanisms underlying cue-motivated behaviors has been complicated by the fact that Pavlovian-conditioned cues can act as both predictive and incentive stimuli (Robinson and Berridge, 1993). A predictive stimulus acquires predictive properties, and thereby the ability to elicit a conditioned response (CR); whereas an incentive stimulus acquires both predictive and incentive motivational properties and thereby the ability to evoke complex emotional and motivational states (Stewart et al., 1984, Childress et al., 1993). Incentive stimuli are defined by three fundamental properties: (1) they can elicit approach behaviors upon presentation, (2) they can act as conditioned reinforcers such that individuals are willing to work for presentation of the stimulus alone, and (3) their presentation can enhance ongoing instrumental actions (Berridge, 2001, Cardinal et al., 2002a). Initially, it was thought that if a cue was predictive of reward delivery (i.e. a predictive stimulus) it was also imbued with incentive properties. Upon further study, however, it was discovered that individuals differ in the extent to which they attribute incentive motivational value or incentive salience to reward-predictive stimuli (Flagel et al., 2009, Robinson and Flagel, 2009). To study this phenomenon, we use a Pavlovian conditioned approach (PCA) procedure that allows us to capture individual variation in the propensity to attribute incentive salience to reward-paired cues, and to thereby explore the underlying neural mechanisms. In this model, where presentation of a discrete lever-cue (conditioned stimulus, CS) is followed by presentation of a food reward (unconditioned stimulus, US), some rats develop a sign-tracking CR. These rats, referred to as “sign-trackers (STs)” (Hearst and Jenkins, 1974), approach and engage the lever-CS upon presentation, and will work for presentation of the lever-CS, even in the absence of a food reward (Robinson and Flagel, 2009). Other rats develop a goal-tracking CR, and these rats, referred to as “goal-trackers (GTs)” (Boakes, 1977), rapidly approach and enter the location of food delivery upon lever-CS presentation, and are less motivated than STs to work for lever presentation in the absence of food reward. The remaining rats develop a mixed CR, vacillating between engagement with the lever-CS and the location of food delivery. Thus, for all individuals, the lever-CS serves as a predictive stimulus, but only for STs does the lever-CS also become an incentive stimulus (Robinson and Flagel, 2009).
The ST/GT animal model has been used to show that cortico-thalamic-striatal circuitry is engaged only when a reward cue is attributed with incentive value—that is, to a greater extent in STs than GTs (Flagel et al., 2011a, Yager et al., 2015). The PVT seems to represent a central node of this differential activity, as there are robust phenotypic differences in food- and drug-cue induced c-Fos in this region, and distinct patterns of correlated neural activity involving the PVT. In STs, food-cue induced c-Fos mRNA is correlated between the PVT and the shell of the nucleus accumbens (NAc); whereas in GTs, cue-induced c-Fos mRNA is correlated between areas of the prefrontal cortex (PFC), such as the prelimbic cortex (PrL), and the PVT (Flagel et al., 2011b, Haight and Flagel, 2014). Additional evidence supporting a role for the PVT in mediating the propensity to attribute incentive salience to reward cues comes from a lesion study in which we found that PVT lesions attenuate a goal-tracking CR, while concomitantly increasing a sign-tracking CR (Haight et al., 2015). These findings demonstrate a causal link between the PVT and the attribution of incentive salience to a reward cue, suggesting that the PVT may act as a “brake” on incentive salience attribution.
To better elucidate the role of the PVT in mediating the propensity to attribute incentive salience to reward cues, it is crucial to examine the afferent and efferent circuitry of this nucleus. The PVT is situated on the dorsal midline of the thalamus in the rat, directly underneath the 3rd ventricle, and has numerous connections with cortical, limbic and motor areas. Specifically, the PVT receives dense cortical input from much of the anterior-posterior gradient of the PrL, as well as the infralimbic (IL) and cingulate cortices (Vertes, 2004, Li and Kirouac, 2012). Subcortical afferents are widely distributed, and arise from the hypothalamus, ventral subiculum (vSub), and the central and medial amygdala (MeA), among other areas (Chen and Su, 1990, Canteras et al., 1995, Van der Werf et al., 2002, Kirouac et al., 2005, Kirouac et al., 2006, Vogt et al., 2008, Hsu and Price, 2009, Li and Kirouac, 2012, Li et al., 2014, Lee et al., 2015). In addition to its diverse inputs, the PVT sends efferent fibers to a variety of cortical and subcortical structures, including the PrL and IL, NAc core and shell, parts of the bed nucleus of the stria terminalis, and the central and basolateral amygdala, among other areas (Jones et al., 1989, Berendse and Groenewegen, 1990, Su and Bentivoglio, 1990, Moga et al., 1995, Van der Werf et al., 2002, Pinto et al., 2003, Parsons et al., 2006, Parsons et al., 2007, Li and Kirouac, 2008, Vertes and Hoover, 2008). Importantly, several of the sources of afferents, as well as the efferent targets, of the PVT have been implicated in cue- and context-motivated behaviors, including the PrL and IL (Willcocks and McNally, 2013, Moorman and Aston-Jones, 2015), hypothalamus (Petrovich et al., 2012, Cole et al., 2015), amygdala (Parkinson et al., 2000, Mahler and Berridge, 2009), vSub (Sun and Rebec, 2003, Kufahl et al., 2009), and NAc (Cardinal et al., 2002b, Bossert et al., 2007).
The neuroanatomical location of the PVT allows it to integrate cortical and subcortical inputs and send this information to the NAc to control motivated behavior (Kelley et al., 2005b). We postulate that the PVT acts as a central node to modulate the attribution of incentive salience to reward cues, with STs being more susceptible to subcortical motivational processes and GTs being biased toward greater cortical control of behavior (Haight and Flagel, 2014). Specifically, given that GTs perform better than STs on behavioral tests dependent on cortical processes, including sustained attention (Paolone et al., 2013) and impulsive action (Flagel et al., 2010, Lovic et al., 2011), we hypothesize that, following presentation of a reward-predictive cue, these rats will show greater activation of PrL afferents to the PVT, representing greater top-down control of behavior. In contrast, we hypothesize that STs will show greater cue-induced activation of subcortical inputs to the PVT, including those from the hypothalamus, amygdala, and vSub. In addition, we expect greater activation of PVT efferents to the NAc in STs, as the sign-tracking, but not the goal-tracking, response has been shown to be dependent on dopamine transmission in the NAc (Flagel et al., 2011b, Saunders and Robinson, 2012), which can be influenced by projections from the PVT (Parsons et al., 2006). These hypotheses were examined by assessing engagement of specific PVT afferent and efferent circuits in response to presentation of a predictive (i.e. for STs and GTs) or incentive (i.e. for STs only) stimulus associated with a food reward.
Section snippets
Experimental procedures
All experiments were conducted in accordance with the National Institute of Health Guide for the Care and Use of Laboratory Animals: Eighth Edition, revised in 2011. In addition, all procedures were approved by the University of Michigan Institutional Animal Care and Use Committee.
PCA behavior
Similar to previous reports (Flagel et al., 2009, Meyer et al., 2012, Haight et al., 2015), considerable variation was seen in the CRs acquired by individual rats following five sessions of PCA training. Some rats directed their behavior toward the lever-CS, and were classified as STs (n = 15; PCA Index range +0.3 to +0.93), while others directed their behavior toward the location of US delivery upon lever-CS presentation, and were classified as GTs (n = 12; PCA Index range −0.34 to −0.91). In
Discussion
The current study measured c-Fos expression in specific PVT afferent and efferent neuronal populations in response to presentation of a predictive and incentive stimulus (in STs), or a predictive-only stimulus (in GTs). This was accomplished using a combination of retrograde tracing and immunohistochemical analyses in a rat model that captures individual variation in PCA behavior. Results indicate that presentation of a reward-predictive stimulus increases activation of PrL cells that project
Conclusion
The current data lend further support to the theory that a hypothalamic–thalamic–striatal axis underlies cue-motivated behavior, by showing that presentation of an incentive stimulus elicits activity specifically in the dorsomedial/lateral hypothalamic-PVT-NAc circuit. In addition, inputs from the MeA likely contribute to the neural circuitry underlying these behaviors. Last, it seems that the PrL to PVT circuit is activated by the predictive, but not the incentive, qualities of a CS. Since the
Acknowledgments
The authors would like to acknowledge Dr. Terry Robinson for commenting on a previous version of this manuscript, and Dr. Brady West from the Consulting for Statistics, Computing and Analytics Research team at The University of Michigan for his helpful input on statistical modeling of the data. JLH and SBF designed the experiments. JLH, ZLF and KMF conducted the experiments and collected data. JLH and ZLF analyzed the data. JLH, ZLF and SBF wrote the paper. This work was supported by the
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