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Efforts to stem the global rise in obesity have been minimally effective, perhaps in part because our understanding of the psychological and behavioral drivers of obesity is limited. It is well established that stimuli that are paired with palatable foods can powerfully influence food-seeking and feeding behaviors. However, how consumption of sugary, fatty “junk-foods” affects these motivational responses to food cues is poorly understood. Here, we determined the effects of short- and long-term “junk-food” consumption on the expression of cue potentiated feeding and conditioned food cup approach to Pavlovian conditioned stimuli (CS). Further, to determine the degree to which effects of “junk-food” were selective to Pavlovian motivational processes, we varied the predictive validity of the CS by including training groups conditioned with unique CS-US contingencies ranging from −1.0 to +1.0. “Junk-food” did not enhance cue potentiated feeding in any group, but expression of this potentiation effect varied with the CS-US contingency independent of diet. In contrast, “junk-food” consistently enhanced conditioned approach to the food cup; this effect was dependent on the previously established CS-US contingency. That is, consumption of “junk-food” following training enhanced approach to the food cup only in response to CSs with previously positive CS-US contingencies. This was accompanied by reduced motivation for the US itself. Together these data show that “junk-food” consumption selectively enhances incentive motivational responses to previously established food CSs, without altering cue potentiated feeding induced by these same CSs, and in the absence of enhanced motivation for food itself.

Urges to consume food can be driven by stimuli in the environment that are associated with previous food experience. Identifying adaptations within brain reward circuits that facilitate cue-induced food seeking is critical for understanding and preventing the overconsumption of food and subsequent weight gain. Utilizing electrophysiological, biochemical, and DiI labeling, we examined functional and structural changes in the nucleus accumbens (NAc) and prefrontal cortex (PFC) associated with time-dependent increases in food craving (‘incubation of craving’). Rats self-administered 60% high fat or chow 45 mg pellets and were then tested for incubation of craving either 1 or 30 days after training. High fat was chosen for comparison to determine whether palatability differentially affected incubation and/or plasticity. Rats showed robust incubation of craving for both food rewards, although responding for cues previously associated with high fat was greater than chow at both 1 and 30 days. In addition, previous experience with high-fat consumption reduced dendritic spine density in the PFC at both time points. In contrast, incubation was associated with an increase in NAc spine density and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated transmission at 30 days in both groups. Finally, incubation of craving for chow and high fat was accompanied by an increase in calcium-permeable and calcium-impermeable AMPARs, respectively. Our results suggest that incubation of food craving alters brain reward circuitry and macronutrient composition specifically induces cortical changes in a way that may facilitate maladaptive food-seeking behaviors.

BACKGROUND: Pavlovian stimuli can influence instrumental behaviors via phenomena such as Pavlovian-to-instrumental transfer (PIT). PIT arises via dissociable processes as Sensory-Specific-PIT (SS-PIT) and General-PIT. The basolateral amygdala (BLA) mediates SS-PIT, but not General-PIT. However, the specific BLA neuronal populations involved are unknown. AIMS: To determine the contribution of glutamatergic BLA neurons to the expression of SS-PIT and to the recall of sensory-specific properties of stimulus-outcome associations. METHODS: BLA neurons were transduced with virus containing either GFP or hM4Di, driven by the CamKII promoter. Rats were then tested for SS- and General-PIT and subsequently for expression of Pavlovian outcome devaluation effects and conditioned taste aversion following injections of Vehicle or Clozapine-n-oxide (CNO, the hM4Di-agonist). RESULTS: CNO selectively blocked SS-PIT in the hM4Di-expressing group, but not controls, without altering expression of Pavlovian outcome devaluation or sensory-specific taste aversion in either group. Unexpectedly, CNO disrupted General-PIT in both groups. CONCLUSIONS: CamKII BLA neurons mediate the expression of SS-PIT by enabling Pavlovian stimuli to trigger recall of the correct action-outcome associations rather than by mediating recall of the sensory-specific properties of the stimulus-outcome association. Separately our data demonstrate that CNO alone is sufficient to disrupt affective, but not sensory-specific processes, an effect that was not due to generalized motor disruption. This nonspecific effect on General PIT may be related to CNO induced shifts in internal state. Together these data identify BLA CamKII neurons as critical for the expression of SS-PIT, and reveal important considerations for using CNO to study general affective motivation.

Continually rising global obesity rates present a major challenge to human health. The contribution of Pavlovian motivational processes to overeating and obesity has become increasingly apparent. In humans, brain and behavioral reactivity to food-related stimuli positively correlates with subsequent weight gain. In concordance with this, selectively bred obesity-prone rats show stronger single-outcome Pavlovian-to-instrumental transfer (SO PIT) than obesity-resistant rats, providing support for the hypothesis that enhanced Pavlovian motivation is a pre-existing phenotype of obesity-susceptibility. However, whether obesity-susceptibility in outbred rats is associated with similar enhancements in PIT was unknown. Moreover, given that SO PIT does not distinguish between sensory specific and general affective motivational processes, it was unclear which of these was linked to obesity-susceptibility. Thus, here we determined whether obesity-susceptibility is associated with enhanced Sensory Specific (SS) PIT versus General PIT using both outbred and selectively bred populations. Rats were trained with two action-outcome and three stimulus-outcome associations; two of the Pavlovian and instrumental associations shared a common outcome. During PIT testing, the influence of the Pavlovian stimuli on the two instrumental responses were measured simultaneously. In outbred rats, expression of General PIT was positively correlated with subsequently determined obesity-susceptibility. In selectively bred rats, General PIT was stronger in obesity-prone versus obesity-resistant rats. Jointly, these data show that enhanced affective Pavlovian motivation is tightly linked to obesity vulnerability, supporting a role for phenotypic differences in incentive motivation in vulnerability to obesity. This has important implications for obesity prevention and for the specific neurocircuitry underlying enhanced food-seeking in vulnerable populations.

When discrete localizable stimuli are used during appetitive Pavlovian conditioning, “sign-tracking” and “goal-tracking” responses emerge. Sign-tracking is observed when conditioned responding is directed toward the CS, whereas goal-tracking manifests as responding directed to the site of expected reward delivery. These behaviors seem to rely on distinct, though overlapping neural circuitries, and, possibly, distinct psychological processes as well, and are thought to be related to addiction vulnerability. One currently popular view is that sign-tracking reflects an incentive motivational process, whereas goal-tracking reflects the influence of more top-down cognitive processes. To test these ideas, we used illness-induced outcome-devaluation and Kamin blocking procedures to determine whether these behaviors rely on similar or distinct underlying associative mechanisms. In Experiments 1 and 2 we showed that outcome-devaluation reduced sign-tracking responses, demonstrating that sign-tracking is controlled by reward expectancies. We also observed that post-CS goal-tracking in these animals is also devaluation sensitive. To test whether these two types of behaviors rely on similar or different prediction error mechanisms, we next tested whether Kamin blocking effects could be observed across these two classes of behaviors. In Experiment 3 we asked if sign-tracking to a lever CS could block the development of goal-tracking to a tone CS; whereas in Experiment 4, we examined whether goal-tracking to a tone CS could block sign-tracking to a lever CS. In both experiments blocking effects were observed suggesting that both sign- and goal-tracking emerge via a common prediction error mechanism. Collectively, the studies reported here suggest that the psychological mechanisms mediating sign- and goal-tracking are more similar than is commonly acknowledged.

Studies in humans suggest that stronger incentive motivational responses to Pavlovian food cues may drive over-consumption leading to and maintaining obesity, particularly in susceptible individuals. However, whether this enhanced incentive motivation emerges as a consequence of obesity or rather precedes obesity is unknown. Moreover, while human imaging studies have provided important information about differences in striatal responsiveness between susceptible and non-susceptible individuals, the neural mechanisms mediating these behavioral differences are unknown. The Nucleus Accumbens (NAc) mediates cue-triggered reward seeking and activity in the NAc is enhanced in obesity-susceptible populations. Therefore here, we used selectively-bred obesity-prone and obesity-resistant rats to examine intrinsic differences in incentive motivation, and the role of NAc AMPARs in the expression of these behaviors prior to obesity. We found that obesity-prone rats exhibit robust cue-triggered food-seeking (Pavlovian-to-instrumental transfer, PIT). Using intra-NAc infusion of AMPAR antagonists, we show that this behavior is selectively mediated by CP-AMPARs in the NAc core. Additionally, biochemical data suggest that this is due in part to experience-induced increases in CP-AMPAR surface expression in the NAc of obesity-prone rats. In contrast, in obesity-resistant rats PIT was weak and unreliable and training did not increase NAc AMPAR surface expression. Collectively, these data show that food cues acquire greater incentive motivational control in obesity-susceptible populations prior to the development of obesity. This provides support to the idea that enhanced intrinsic incentive motivation may be a contributing factor, rather than a consequence of obesity. In addition, these data demonstrate a novel role for experience-induced up-regulation of NAc CP-AMPARs in PIT, pointing to potential mechanistic parallels between the processes leading to addiction and to obesity.

Three experiments with male and female rats were conducted to examine the effects of Pavlovian extinction training on Pavlovian-to-instrumental transfer (PIT) in a task in which the unconditioned stimulus (US) was presented at an early time point within an extended conditioned stimulus (CS). Two instrumental responses were trained with different reinforcing outcomes (R1-O1, R2-O2) and then, independently, 2 stimuli were trained with those outcomes (S1-O1, S2-O2). One group then underwent an extinction treatment (S1-, S2-) and a second was merely exposed to the experimental contexts without any stimulus events. Finally, the effects of the 2 stimuli on instrumental responding were assessed in PIT tests. Across experiments we varied the number of Pavlovian training trials prior to extinction (8, 16, or 64 trials) and the length of time following extinction prior to test (i.e., 1 or 21 days, in a test for spontaneous recovery). We observed that outcome-specific PIT was reduced by extinction in all of our training conditions and that this extinction effect was durable, surviving a 3-week spontaneous recovery interval even though conditioned magazine approach spontaneously recovered over this interval. Although extinction reduced the magnitude of PIT, the temporal expression of PIT was mostly unaffected. We found these effects in both male and female rats, though in 1 study females were extinction-resistant. These data suggest that under the conditions studied here Pavlovian extinction may permanently weaken the ability of Pavlovian cues to retrieve a representation of their associated outcomes without impacting the temporal organization of responding. This suggests that different features of learning may be differentially sensitive to extinction. (PsycINFO Database Record

Genetically modified mice have become standard tools in neuroscience research. Our understanding of the basal ganglia in particular has been greatly assisted by BAC mutants with selective transgene expression in striatal neurons forming the direct or indirect pathways. However, for more sophisticated behavioral tasks and larger intracranial implants, rat models are preferred. Furthermore, BAC lines can show variable expression patterns depending upon genomic insertion site. We therefore used CRISPR/Cas9 to generate two novel knock-in rat lines specifically encoding Cre recombinase immediately after the dopamine D1 receptor (Drd1a) or adenosine 2a receptor (Adora2a) loci. Here, we validate these lines usingin situhybridization and viral vector mediated transfection to demonstrate selective, functional Cre expression in the striatal direct and indirect pathways, respectively. We used whole-genome sequencing to confirm the lack of off-target effects and established that both rat lines have normal locomotor activity and learning in simple instrumental and Pavlovian tasks. We expect these new D1-Cre and A2a-Cre rat lines will be widely used to study both normal brain functions and neurological and psychiatric pathophysiology.