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The modern obesogenic environment contains an abundance of food cues (e.g., sight, smell of food) as well cues that are associated with food through learning and memory processes. Food cue exposure can lead to food seeking and excessive consumption in otherwise food-sated individuals, and a high level of food cue responsivity is a risk factor for overweight and obesity. Similar food cue responses are observed in experimental rodent models, and these models are therefore useful for mechanistically identifying the neural circuits mediating food cue responsivity. This review draws from both experimental rodent models and human data to characterize the behavioral and biological processes through which food-associated stimuli contribute to overeating and weight gain. Two rodent models are emphasized - cue-potentiated feeding and Pavlovian-instrumental transfer - that provide insight in the neural circuits and peptide systems underlying food cue responsivity. Data from humans are highlighted that reveal physiological, psychological, and neural mechanisms that connect food cue responsivity with overeating and weight gain. The collective literature identifies connections between heightened food cue responsivity and obesity in both rodents and humans, and identifies underlying brain regions (nucleus accumbens, amygdala, orbitofrontal cortex, hippocampus) and endocrine systems (ghrelin) that regulate food cue responsivity in both species. These species similarities are encouraging for the possibility of mechanistic rodent model research and further human research leading to novel treatments for excessive food cue responsivity in humans.

Safety learning allows individuals to associate stimuli with the absence of threat, thus conferring the ability to suppress fear and anxiety in safe situations, and by consequence, maintain psychological and physiological well-being. Disrupted safety learning is thought to be a key component of anxiety-related disorders, but as yet, the basic mechanisms of safety learning remain incompletely understood and lack a formal theoretical definition. Across two studies of healthy adults, this thesis sought to examine the behavioural (Study 1) and neural (Study 2) basis of safety learning in humans. Based on long-standing principles of associative learning theory, a novel iteration of the Pavlovian conditioned inhibition paradigm was developed and implemented in lab-based and 7-Tesla functional magnetic resonance imaging (fMRI) settings. Study 1 (N = 73) was an investigation of the behavioural aspects of safety learning, and moreover, sought to validate the utility of the Pavlovian conditioned inhibition paradigm as an experimental model for safety learning, as well as examining individual differences in trait measures of anxiety. This paradigm trained a robust safety signal (the conditioned inhibitor, X) which was conditioned by delivering threat (loud noise) to a conditioned stimulus on its own (A+), but omitting threat when that stimulus was presented in conjunction with the inhibitor (AX-). As a control cue, two stimuli were similarly unreinforced in compound, but neither was presented alone on other trials (BC-). The paradigm also controlled for several possible confounds, including the use of a safety signal as a control cue, rather than using a novel or neutral cue, among other factors. Both the control safety signal and the conditioned inhibitor were shown to inhibit physiological and cognitive threat responses at test, when paired with aversive conditioned stimuli. However, the inhibitor conferred a significantly greater degree of inhibition for cognitive threat re

Rationale: The importance of reward-associated cues in eliciting behavior is well established, with stimuli associated with drugs of abuse known to play a crucial role in recidivism. Recently, Redish (2004) proposed that drugs, acting as unconditional stimuli (US), remain associable even after being fully predicted by a conditional stimulus (CS), meaning that they are not susceptible to the blocking effect [1]; if correct, this may represent a possible mechanism to explain exaggerated cue-controlled drug-seeking and reinstatement in nicotine dependence and substance dependence problems in general. Objectives: We tested whether pairings between nicotine and an environmental CS would convey conditioned reinforcement properties onto the CS, even when nicotine’s rewarding effects were already fully predicted by another cue (whether there was an absence of the blocking effect). Methods: 134 male Long-Evans rats were implanted with jugular catheters and assigned to either food- or nicotine-reward (0.06 mg/kg/inf) conditions. Each group was exposed to paired or unpaired presentations of their respective reward with one CS in 10 daily sessions; subsequently, they were exposed to 4 more daily sessions of paired presentations of the reward paired with a compound CS composed of the original CS and a second CS. Tests of the conditioned reinforcing value of both CSs using the active-lever-presses to total-presses ratio as an outcome were conducted following training. Results: Pressing for a blocked second CS (µ = 0.59, SD = 0.21) was significantly lower than pressing for an unblocked second CS (µ = 0.69, SD = 0.14) in the food-reward condition, but not in nicotine-rewarded animals, verifying the hypothesis that nicotine, but not food, is resilient to the blocking effect. Conclusion: The absence of blocking when nicotine is the reward may explain the powerful role for cues in supporting tobacco dependenceby allowing for the extension of nicotine’s rewarding value across numerous

Rationale: The importance of reward-associated cues in eliciting behavior is well established, with stimuli associated with drugs of abuse known to play a crucial role in recidivism. Recently, Redish (2004) proposed that drugs, acting as unconditional stimuli (US), remain associable even after being fully predicted by a conditional stimulus (CS), meaning that they are not susceptible to the blocking effect [1]; if correct, this may represent a possible mechanism to explain exaggerated cue-controlled drug-seeking and reinstatement in nicotine dependence and substance dependence problems in general. Objectives: We tested whether pairings between nicotine and an environmental CS would convey conditioned reinforcement properties onto the CS, even when nicotine’s rewarding effects were already fully predicted by another cue (whether there was an absence of the blocking effect). Methods: 134 male Long-Evans rats were implanted with jugular catheters and assigned to either food- or nicotine-reward (0.06 mg/kg/inf) conditions. Each group was exposed to paired or unpaired presentations of their respective reward with one CS in 10 daily sessions; subsequently, they were exposed to 4 more daily sessions of paired presentations of the reward paired with a compound CS composed of the original CS and a second CS. Tests of the conditioned reinforcing value of both CSs using the active-lever-presses to total-presses ratio as an outcome were conducted following training. Results: Pressing for a blocked second CS (µ = 0.59, SD = 0.21) was significantly lower than pressing for an unblocked second CS (µ = 0.69, SD = 0.14) in the food-reward condition, but not in nicotine-rewarded animals, verifying the hypothesis that nicotine, but not food, is resilient to the blocking effect. Conclusion: The absence of blocking when nicotine is the reward may explain the powerful role for cues in supporting tobacco dependenceby allowing for the extension of nicotine’s rewarding value across numerous

Overeating in individuals with obesity is hypothesized to be partly caused by automatic action tendencies to food cues that have the potential to override goal-directed dietary restriction. Individuals with obesity are often characterized by alterations in the processing of such rewarding food, but also of non-food stimuli, and previous research has suggested a stronger impact on the execution of goal-directed actions in obesity. Here, we investigated whether Pavlovian cues can also corrupt the learning of new approach or withdrawal behavior in individuals with obesity. We employed a probabilistic Pavlovian-instrumental learning paradigm in which participants (29 normal-weight and 29 obese) learned to actively respond (Go learning) or withhold a response (NoGo learning) in order to gain monetary rewards or avoid losses. Participants were better at learning active approach responses (Go) in the light of anticipated rewards and at learning to withhold a response (NoGo) in the light of imminent punishments. Importantly, there was no evidence for a stronger corruption of instrumental learning in individuals with obesity. Instead, they showed better learning across conditions than normal-weight participants. Using a computational reinforcement learning model, we additionally found an increased learning rate in individuals with obesity. Previous studies have mostly reported a lower reinforcement learning performance in individuals with obesity. Our results contradict this and suggest that their performance is not universally impaired: Instead, while previous studies found reduced stimulus-value learning, individuals with obesity may show better action-value learning. Our findings highlight the need for a broader investigation of behavioral adaptation in obesity across different task designs and types of reinforcement learning., Peer Reviewed

A recent study by Saunders, Richard, Margolis, and Janak (2018) shows that there is a great deal left to learn about what different mesotelencephalic dopamine circuits contribute to learning about the motivational significance of reward-related cues. Their findings suggest that nigrostriatal and mesolimbic dopamine pathways support distinct reinforcement processes that independently push and pull animals toward their goals.

The expectation of reward is known to enhance a consolidation of long-term memory for events. We tested whether this effect is driven by positive valence or action requirements tied to expected reward. Using a functional magnetic resonance imaging (fMRI) paradigm in young adults, novel images predicted gain or loss outcomes, which in turn were either obtained or avoided by action or inaction. After 24 h, memory for these images reflected a benefit of action as well as a congruence of action requirements and valence, namely, action for reward and inaction for avoidance. fMRI responses in the hippocampus, a region known to be critical for long-term memory function, reflected the anticipation of inaction. In contrast, activity in the putamen mirrored the congruence of action requirement and valence, whereas other basal ganglia regions mirrored overall action benefits on long-lasting memory. The findings indicate a novel type of functional division between the hippocampus and the basal ganglia in the motivational regulation of long-term memory consolidation, which favors remembering events that are worth acting for.

The present thesis examined the role of the rodent lateral orbitofrontal cortex (LO) in controlling performance in Pavlovian cue-outcome learning and placed the function of LO in the broader context of the entire orbitofrontal cortex (OFC) region. We found that functional inactivation of LO disrupted the retention of between- but not within-session extinction behaviour. This finding was not due to the disruption of post-session memory consolidation processes by the functional inactivation of LO or impaired acquisition of Pavlovian conditioned inhibition learning. These data confirmed that LO is necessary for the acquisition of Pavlovian extinction learning.In a second set of experiments we investigated the role of LO in guiding behaviour using the sensory specific properties of expected outcomes. Pre-training LO lesions were found to disrupt Pavlovian devaluation by taste aversion but not specific satiety or instrumental devaluation by conditioned taste aversion, or the specific Pavlovian-to-instrumental transfer effect. These findings rule out an explanation of LO function in simply representing the sensory specific properties of expected outcomes.The third set of experiments examined the role of LO in the acquisition of simple Pavlovian learning. Pre-training LO lesions increased conditioned responding whereas post-training lesions and functional inactivation of LO decreased conditioned responding. A blocking procedure revealed that decreased responding following LO inactivation did not affect the subsequent blocking of new learning at test. Furthermore, LO inactivation impaired the use of current relative value of outcomes to modulate behaviour. This suggested a role for LO in the expression of conditioned responding but not initial Pavlovian learning.A final set of experiments examined the role of LO in a novel Pavlovian differential outcomes expectancy task. Pre-training LO lesions were found to decrease whereas post-training lesions were found to increase resp

Reward-seeking actions can be guided by external cues that signal reward availability. For instance, when confronted with a stimulus that signals sugar, rats will prefer an action that produces sugar over a second action that produces grain pellets. Action selection is also sensitive to changes in the incentive value of potential rewards. Thus, rats that have been prefed a large meal of sucrose will prefer a grain-seeking action to a sucrose-seeking action. The current study investigated the dependence of these different aspects of action selection on cholinergic transmission. Hungry rats were given differential training with two unique stimulus-outcome (S1-O1 and S2-O2) and action-outcome (A1-O1 and A2-O2) contingencies during separate training phases. Rats were then given a series of Pavlovian-to-instrumental transfer tests, an assay of cue-triggered responding. Before each test, rats were injected with scopolamine (0, 0.03, or 0.1 mg/kg, intraperitoneally), a muscarinic receptor antagonist, or mecamylamine (0, 0.75, or 2.25 mg/kg, intraperitoneally), a nicotinic receptor antagonist. Although the reward-paired cues were capable of biasing action selection when rats were tested off-drug, both anticholinergic treatments were effective in disrupting this effect. During a subsequent round of outcome devaluation testing-used to assess the sensitivity of action selection to a change in reward value--we found no effect of either scopolamine or mecamylamine. These results reveal that cholinergic signaling at both muscarinic and nicotinic receptors mediates action selection based on Pavlovian reward expectations, but is not critical for flexibly selecting actions using current reward values.

The selection of actions, and the vigor with which they are executed, are influenced by the affective valence of predicted outcomes. This interaction between action and valence significantly influences appropriate and inappropriate choices and is implicated in the expression of psychiatric and neurological abnormalities, including impulsivity and addiction. We review a series of recent human behavioral, neuroimaging, and pharmacological studies whose key design feature is an orthogonal manipulation of action and valence. These studies find that the interaction between the two is subject to the critical influence of dopamine. They also challenge existing views that neural representations in the striatum focus on valence, showing instead a dominance of the anticipation of action., AuthorCount:4

Decision-making involves two fundamental axes of control namely valence, spanning reward and punishment, and action, spanning invigoration and inhibition. We recently exploited a go/no-go task whose contingencies explicitly decouple valence and action to show that these axes are inextricably coupled during learning. This results in a disadvantage in learning to go to avoid punishment and in learning to no-go to obtain a reward. The neuromodulators dopamine and serotonin are likely to play a role in these asymmetries: Dopamine signals anticipation of future rewards and is also involved in an invigoration of motor responses leading to reward, but it also arbitrates between different forms of control. Conversely, serotonin is implicated in motor inhibition and punishment processing. To investigate the role of dopamine and serotonin in the interaction between action and valence during learning. We combined computational modeling with pharmacological manipulation in 90 healthy human volunteers, using levodopa and citalopram to affect dopamine and serotonin, respectively. We found that, after administration of levodopa, action learning was less affected by outcome valence when compared with the placebo and citalopram groups. This highlights in this context a predominant effect of levodopa in controlling the balance between different forms of control. Citalopram had distinct effects, increasing participants' tendency to perform active responses independent of outcome valence, consistent with a role in decreasing motor inhibition. Our findings highlight the rich complexities of the roles played by dopamine and serotonin during instrumental learning., AuthorCount:8

A key question in neuroscience is how memory is selectively allocated to neural networks in the brain. This question remains a significant research challenge, in both rodent models and humans alike, because of the inherent difficulty in tracking and deciphering large, highly dimensional neuronal ensembles that support memory (i.e., the engram). In a previous study we showed that consolidation of a new fear memory is allocated to a common topography of amygdala neurons. When a consolidated memory is retrieved, it may enter a labile state, requiring reconsolidation for it to persist. What is not known is whether the original spatial allocation of a consolidated memory changes during reconsolidation. Knowledge about the spatial allocation of a memory, during consolidation and reconsolidation, provides fundamental insight into its core physical structure (i.e., the engram). Using design-based stereology, we operationally define reconsolidation by showing a nearly identical quantity of neurons in the dorsolateral amygdala (LAd) that expressed a plasticity-related protein, phosphorylated mitogen-activated protein kinase, following both memory acquisition and retrieval. Next, we confirm that Pavlovian fear conditioning recruits a stable, topographically organized population of activated neurons in the LAd. When the stored fear memory was briefly reactivated in the presence of the relevant conditioned stimulus, a similar topography of activated neurons was uncovered. In addition, we found evidence for activated neurons allocated to new regions of the LAd. These findings provide the first insight into the spatial allocation of a fear engram in the LAd, during its consolidation and reconsolidation phase.

Chaîne opératoire, as both an analytical approach and a sociotechnical perspective, has had a presence in material culture literature for some considerable time. However despite the longevity of the concept, its full potential for the comparative study of material culture production and consumption has not really been realized within archaeology. Here, Farbstein explores this area through looking at the production of mobiliary art in a range of raw materials at Pavlovian Upper Paleolithic sites.

Activation of N-methyl-D-aspartate receptors (NMDAr) in the basolateral complex of the amygdala (BLA) is crucial for the acquisition and extinction of Pavlovian first-order fear. It is unknown whether these substrates also mediate higher-order fear. Higher-order fear has been observed using two procedures. In second-order conditioning, pairings of a tone (S1) and shock are followed by pairings of a light (S2) and the tone (S1); in sensory preconditioning, pairings of a light (S2) and tone (S1) are followed by pairings of the tone (S1) and shock. In each procedure, test presentations of the light alone elicit fear responses which extinguish across such presentations. This thesis examined whether activation of NMDAr in the BLA is necessary for the acquisition and extinction of higher-order fear. Inactivation of the BLA via infusion of the GABAA agonist muscimol, systemic injection of the NMDAr antagonist MK-801, and BLA infusion of the NMDAr NR2B subunit selective antagonist ifenprodil, disrupted acquisition and extinction of second-order fear. Extinction of sensory preconditioned fear was impaired by BLA infusion of muscimol or ifenprodil and by systemic MK-801. Acquisition of the neutral S2-S1 association and extinction of this association before conditioning of S1 was impaired by MK-801 but not by BLA infusion of muscimol. The final experiment examined the role of the perirhinal cortex (PRh) in the acquisition of higher-order fear. Muscimol inactivation of the PRh prior to S2-S1 pairings blocked sensory preconditioning but not second-order conditioning. These findings can be summarised as follows. First, activation of BLA NMDAr is necessary for the acquisition and extinction of second-order fear. Second, the acquisition and pre-extinction of sensory preconditioning requires NMDAr activity but not BLA activation. Third, once the fear circuit is engaged, learning to inhibit sensory preconditioned fear becomes dependent on BLA NMDAr activation. Finally, the PRh is nec

The endogenous opioid peptides and their receptors play important roles in Pavlovian fear conditioning in many species, including mice, rats, and humans. These roles are best viewed as regulating the conditions for fear learning by determining the actions of predictive error on association formation. Evidence will be reviewed showing such roles for opioid receptors in ventrolateral quadrant of the midbrain periaqueductal gray (vlPAG). These roles are shared across mammalian species because many of the effects of opioid receptor manipulations on fear learning first reported in rodents have now been documented in humans.

Superstitions are beliefs that are not supported by empirical evidence, or beliefs that persist in the face of contradictory empirical evidence (Zebb & Moore, 2003). Both cultural and personal superstitions are pervasive in the general population (Vyse, 1997) and appear to influence not only the clinically ill, but healthy individuals as well as successful sportspeople, businesspeople, and politicians. The history of superstition research is traced from the Skinner's seminal (1948) explanation of superstitious learning as the result of accidental pairings of events, or adventitious conditioning. Contemporary human superstitious learning research (e.g. Matute, 1994, 1995) has demonstrated that non-contingent delivery of reinforcers can lead to illusion of control if the person is actively making instrumental responses to gain those reinforcers. Superstitious beliefs appear to play a role in clinical anxiety disorders such as OCD, social phobia, and PD. Specifically, avoidance of threatening situations and engaging in in-situation safety behaviours (e.g. Salkovskis, D. M. Clark & Gelder, 1996), prevent non-occurrence of the feared outcome from disconfirming the threat belief and eventual fear extinction. Quite the opposite, instrumental attempts to prevent imminent catastrophe lead non-occurrence of the feared outcome to be perceived as confirmation that the threat is real. A human avoidance learning paradigm (P. Lovibond, 2006; P. Lovibond et al., 2008) was adapted for a laboratory investigation of superstitious learning using a threat-relevant stimulus (mild electric shock). A series of five experiments using undergraduate participants demonstrated that participants‟ expectations of task structure modulated their tendency to develop maintained stereotyped responding. Approximately half the participants maintained a chosen instrumental response to a target cue and maintained higher threat beliefs towards that cue even though it had never been paired with shock.

The experiments reported in this thesis studied the mechanisms of expression of overexpectation of conditioned fear, as measured by freezing. In Stage I, rats were conditioned to fear a tone and a flashing light conditioned stimulus (CS) through pairings with a 0.5 mA, 1 s shock. In Stage II, overexpectation was trained by the reinforcement of a compound of these CSs with a shock of the same magnitude. Two compound – shock pairings produced an overexpectation effect, as measured by freezing to presentations of the tone alone, while further Stage II training caused over-training of overexpectation. Expression of the overexpectation effect produced by two compound – shock pairings could be prevented by pre-test injection of the benzodiazepine partial inverse agonist FG7142. This effect was dose-dependent and not due to state-dependent memory. Control experiments suggested that it was also not due to any general effect of FG7142 on the Pavlovian freezing response. Freezing to a tone that had been conditioned, but not subjected to any decremental training procedures, was unaffected by administration of FG7142 before either the conditioning or test session. FG7142 also did not affect freezing to a tone that had been subjected to an associative blocking procedure. The hypothesis that overexpectation of conditioned fear may be context-dependent was also tested. However, renewal was not observed. Rats that received Stage II training in a context distinct from the Stage I training context showed equivalent expression of overexpectation regardless of whether testing was conducted in the Stage I or Stage II training context. These results are consistent with the hypothesis that overexpectation, like extinction, leads to the imposition of a GABAA receptor-mediated mask on the fear CR. Moreover, they suggest that this masking of fear is the specific consequence of negative predictive error.

The bed nucleus of the stria terminalis (BNST) is believed to be a critical relay between the central nucleus of the amygdala (CE) and the paraventricular nucleus of the hypothalamus in the control of hypothalamic–pituitary– adrenal (HPA) responses elicited by conditioned fear stimuli. If correct, lesions of CE or BNST should block expression of HPA responses elicited by either a specific conditioned fear cue or a conditioned context. To test this, rats were subjected to cued (tone) or contextual classical fear conditioning. Two days later, electrolytic or sham lesions were placed in CE or BNST. After 5 days, the rats were tested for both behavioral (freezing) and neuroendocrine (corticosterone) responses to tone or contextual cues. CE lesions attenuated conditioned freezing and corticosterone responses to both tone and con- text. In contrast, BNST lesions attenuated these responses to contextual but not tone stimuli. These results suggest CE is indeed an essential output of the amygdala for the expres- sion of conditioned fear responses, including HPA re- sponses, regardless of the nature of the conditioned stimu- lus. However, because lesions of BNST only affected behav- ioral and endocrine responses to contextual stimuli, the results do not support the notion that BNST is critical for HPA responses elicited by conditioned fear stimuli in general. Instead, the BNST may be essential specifically for contex- tual conditioned fear responses, including both behavioral and HPA responses, by virtue of its connections with the hippocampus, a structure essential to contextual condition- ing. The results are also not consistent with the hypothesis that BNST is only involved in unconditioned aspects of fear and anxiety.