Rationale The paraventricular nucleus of the thalamus (PVT) has been shown to mediate cue-motivated behaviors, such as sign- and goal-tracking, as well as reinstatement of drug-seeking behavior. However, the role of the PVT in mediating individual variation in cue-induced drug-seeking behavior remains unknown. Objectives To determine if inactivation of the PVT differentially mediates cue-induced drug-seeking behavior in sign-trackers and goal-trackers. Methods Rats were characterized as sign-trackers (STs) or goal-trackers (GTs) based on their Pavlovian conditioned approach behavior. Rats were then exposed to 15 days of cocaine self-administration, followed by a 2-week forced abstinence period and then extinction training. Rats then underwent tests for cue-induced reinstatement and general locomotor activity, prior to which they received an infusion of either saline (control) or baclofen/muscimol (B/M) to inactivate the PVT. Results Relative to control animals of the same phenotype, GTs show a robust increase in cue-induced drug-seeking behavior following PVT inactivation, whereas the behavior of STs was not affected. PVT inactivation did not affect locomotor activity in either phenotype. Conclusion In GTs, the PVT appears to inhibit the expression of drug seeking, presumably by attenuating the incentive value of the drug cue. Thus, inactivation of the PVT releases this inhibition in GTs, resulting in an increase in cue-induced drug-seeking behavior. PVT inactivation did not affect cue-induced drug-seeking behavior in STs, suggesting that the role of the PVT in encoding the incentive motivational value of drug cues differs between STs and GTs.
Rationale: Prior research suggests that inputs from the lateral hypothalamic area (LHA) to the paraventricular nucleus of the thalamus (PVT) contribute to the attribution of incentive salience to Pavlovian-conditioned reward cues. However, a causal role for the LHA in this phenomenon has not been demonstrated. In addition, it is unknown which hypothalamic neurotransmitter or peptide system(s) are involved in mediating incentive salience attribution.Objectives: To examine: 1) the role of the LHA in the propensity to attribute incentive salience to reward cues, and 2) the role of orexinergic signaling in the PVT on the expression of Pavlovian conditioned approach (PavCA) behavior, a reflection of incentive salience attribution. Methods: Male Sprague-Dawley rats received bilateral excitotoxic lesions of the LHA prior to the acquisition of Pavlovian conditioned approach (PavCA) behavior. A separate cohort of male rats acquired PavCA behavior and were characterized as sign-trackers (STs) or goal-trackers (GTs) based on their conditioned response. The orexin 1 receptor (OX1r) antagonist SB-334867, or the orexin 2 receptor (OX2r) antagonist TCS-OX2-29, were then administered directly into the PVT to assess the effects of these pharmacological agents on the expression of PavCA behavior and on the conditioned reinforcing properties of the Pavlovian reward cue. Results: Lesions of the LHA before training attenuated the development of leverdirected (sign-tracking) behaviors in the PavCA paradigm, without affecting magazinedirected (goal-tracking) behaviors. In STs, administration of the OX1r antagonist into the PVT reduced lever-directed behaviors and increased magazine-directed behaviors; while administration of the OX2r antagonist only reduced lever-directed behaviors.Further, OX2r, but not OX1r, antagonism was able to reduce the incentive motivational value of the conditioned stimulus on a conditioned reinforcement test in STs. The behavior of GTs was unaffected by orexinergic antagonism in the PVT. Conclusions:The LHA is necessary for the attribution of incentive salience to reward cues and, thereby, the development of a sign-tracking conditioned response..
Rationale Relapse often occurs when individuals are exposed to stimuli or cues previously associated with the drug-taking experience. The ability of drug cues to trigger relapse is believed to be a consequence of incentive salience attribution, a process by which the incentive value of reward is transferred to the reward-paired cue. Sign-tracker (ST) rats that attribute enhanced incentive value to reward cues are more prone to relapse compared to goal-tracker (GT) rats that primarily attribute predictive value to such cues. Objectives The neurobiological mechanisms underlying this individual variation in relapse propensity remains largely unexplored. The paraventricular nucleus of the thalamus (PVT) has been identified as a critical node in the regulation of cue-elicited behaviors in STs and GTs, including cue-induced reinstatement of drug-seeking behavior. Here we used a chemogenetic approach to assess whether "top-down" cortical input from the prelimbic cortex (PrL) to the PVT plays a role in mediating individual differences in relapse propensity. Results Chemogenetic inhibition of the PrL-PVT pathway selectively decreased cue-induced reinstatement of drug-seeking behavior in STs, without affecting behavior in GTs. In contrast, cocaine-primed drug-seeking behavior was not affected in either phenotype. Furthermore, when rats were characterized based on a different behavioral phenotype-locomotor response to novelty-inhibition of the PrL-PVT pathway had no effect on either cue-or drug-induced reinstatement. Conclusions These results highlight an important role for the PrL-PVT pathway in vulnerability to relapse that is consequent to individual differences in the propensity to attribute incentive salience to discrete reward cues.
Rationale: Prior research suggests that inputs from the lateral hypothalamic area (LHA) to the paraventricular nucleus of the thalamus (PVT) contribute to the attribution of incentive salience to Pavlovian-conditioned reward cues. However, a causal role for the LHA in this phenomenon has not been demonstrated. In addition, it is unknown which hypothalamic neurotransmitter or peptide system(s) are involved in mediating incentive salience attribution. Objectives:To examine: 1) the role of the LHA in the propensity to attribute incentive salience to reward cues, and 2) the role of orexinergic signaling in the PVT on the expression of Pavlovian conditioned approach (PavCA) behavior, a reflection of incentive salience attribution. Methods: MaleSprague-Dawley rats received bilateral excitotoxic lesions of the LHA prior to the acquisition of Pavlovian conditioned approach (PavCA) behavior. A separate cohort of male rats acquired PavCA behavior and were characterized as sign-trackers (STs) or goal-trackers (GTs) based on their conditioned response. The orexin 1 receptor (OX1r) antagonist SB-334867, or the orexin 2 receptor (OX2r) antagonist TCS-OX2-29, were then administered directly into the PVT to assess the effects of these pharmacological agents on the expression of PavCA behavior and on the conditioned reinforcing properties of the Pavlovian reward cue. Results: Lesions of the LHA before training attenuated the development of leverdirected (sign-tracking) behaviors in the PavCA paradigm, without affecting magazinedirected (goal-tracking) behaviors. Administration of the OX1r antagonist into the PVT reduced lever-directed behaviors and increased magazine-directed behaviors in STs; while administration of the OX2r antagonist only reduced lever-directed behaviors.Further, OX2r, but not OX1r, antagonism was able to reduce the incentive motivational value of the conditioned stimulus on a conditioned reinforcement test in STs. The behavior of GTs was unaffected by orexinergic antagonism in the PVT. Conclusions:The LHA is necessary for the attribution of incentive salience to reward cues and, thereby, the development of a sign-tracking conditioned response.treat the reward-cue primarily as a predictive stimulus and approach the location of impending reward delivery upon presentation of the cue (Flagel et al., 2007; Flagel et al., 2009). Thus, while both STs and GTs attribute predictive value to the reward-cue, only STs attribute it with incentive salience (Robinson & Flagel, 2009).The ST-GT model has provided a unique platform to investigate the neurobiology that contributes to the attribution of predictive vs. incentive value to reward-cues. Research thus far suggests that GT rats rely primarily on "top-down" cortical mechanisms to guide their behavior (Flagel et al.
Cues, or stimuli in the environment, attain the ability to guide behavior via learned associations. As predictors, cues can elicit adaptive behavior and lead to valuable resources (e.g., food). For some individuals, however, cues are transformed into incentive stimuli and can elicit maladaptive behavior. The goal-tracker/sign-tracker animal model captures individual differences in cue-motivated behaviors, with reward-associated cues serving as predictors of reward for both goal-trackers and sign-trackers, but becoming incentive stimuli only for sign-trackers. While these distinct phenotypes are characterized based on Pavlovian conditioned approach behavior, they exhibit differences on a number of behaviors of relevance to psychopathology. To further characterize the neurobehavioral endophenotype associated with individual differences in cue-reward learning, we investigated neuroendocrine and behavioral profiles associated with negative valence in male goal-trackers, sign-trackers, and intermediate responders. We found that baseline corticosterone increases with Pavlovian learning, and that this increase is positively associated with the development of sign-tracking. We did not observe significant differences between goal-trackers and sign-trackers in behavior during an elevated plus maze or open field test, nor did we see differences in the corticosterone response to the open field test or physiological restraint. We did, however, find that sign-trackers have greater glucocorticoid receptor mRNA expression in the ventral hippocampus, with no phenotypic differences in the dorsal hippocampus. These findings suggest that goal-trackers and sign-trackers do not differ on indices of negative valence; rather, differences in neuroendocrine measures between these phenotypes can be attributed to distinct cue-reward learning styles.
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