Stimulus-outcome associations are required for the expression of specific Pavlovian-instrumental transfer.

A series of experiments employed a specific Pavlovian-instrumental transfer (PIT) task in rats to determine the capacity of various treatments to undermine two outcome-specific stimulus-outcome (S-O) associations. Experiment 1 tested a random treatment, which involved uncorrelated presentations of the two stimuli and their predicted outcomes. This treatment disrupted the capacity of the outcome-specific S-O associations to drive specific PIT. Experiment 2 used a negative-contingency treatment during which the predicted outcomes were exclusively delivered in the absence of their associated stimulus. This treatment spared specific PIT, suggesting that it left the outcome-specific S-O associations relatively intact. The same outcome was obtained in Experiment 3, which implemented a zero-contingency treatment consisting of delivering the predicted outcomes in the presence and absence of their associated stimulus. Experiment 4 tested a mixed treatment, which distributed the predicted outcomes at an equal rate during each stimulus. This treatment disrupted the capacity of the outcome-specific S-O associations to drive specific PIT. We suggest that the mixed treatment disrupted specific PIT by generating new and competing outcome-specific S-O associations. By contrast, we propose that the random treatment disrupted specific PIT by undermining the original outcome-specific S-O associations, indicating that these associations must be retrieved to express specific PIT. We discuss how these findings inform our theoretical understanding of the mechanisms underlying this phenomenon. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

High fat diet allows food-predictive stimuli to energize action performance in the absence of hunger, without distorting insulin signaling on accumbal cholinergic interneurons.

Obesity can disrupt how food-predictive stimuli control action performance and selection. These two forms of control recruit cholinergic interneurons (CIN) located in the nucleus accumbens core (NAcC) and shell (NAcS), respectively. Given that obesity is associated with insulin resistance in this region, we examined whether interfering with CIN insulin signaling disrupts how food-predictive stimuli control actions. To interfere with insulin signaling we used a high-fat diet (HFD) or genetic excision of the insulin receptor (InsR) from cholinergic cells. HFD left intact the capacity of food-predictive stimuli to energize performance of an action earning food when mice were tested hungry. However, it allowed this energizing effect to persist when the mice were tested sated. This persistence was linked to NAcC CIN activity but was not associated with distorted CIN insulin signaling. Accordingly, InsR excision had no effect on how food-predicting stimuli control action performance. Next, we found that neither HFD nor InsR excision altered the capacity of food-predictive stimuli to guide action selection. Yet, this capacity was associated with changes in NAcS CIN activity. These results indicate that insulin signaling on accumbal CINs does not modulate how food-predictive stimuli control action performance and selection. However, they show that HFD allows food-predictive stimuli to energize performance of an action earning food in the absence of hunger.

Basal forebrain cholinergic signaling in the basolateral amygdala promotes strength and durability of fear memories.

The basolateral amygdala (BLA) complex receives dense cholinergic projections from the nucleus basalis of Meynert (NBM) and the horizontal limb of the diagonal band of Broca (HDB). The present experiments examined whether these projections regulate the formation, extinction, and renewal of fear memories. This was achieved by employing a Pavlovian fear conditioning protocol and optogenetics in transgenic rats. Silencing NBM projections during fear conditioning weakened the fear memory produced by that conditioning and abolished its renewal after extinction. By contrast, silencing HDB projections during fear conditioning had no effect. Silencing NBM or HDB projections during extinction enhanced the loss of fear produced by extinction, but only HDB silencing prevented renewal. Next, we found that systemic blockade of nicotinic acetylcholine receptors during fear conditioning mimicked the effects produced by silencing NBM projections during fear conditioning. However, this blockade had no effect when given during extinction. These findings indicate that basal forebrain cholinergic signaling in the BLA plays a critical role in fear regulation by promoting strength and durability of fear memories. We concluded that cholinergic compounds may improve treatments for post-traumatic stress disorder by durably stripping fear memories from their fear-eliciting capacity.

Sensory-Specific Satiety Dissociates General and Specific Pavlovian-Instrumental Transfer.

Pavlovian conditioning enables predictive stimuli to control action performance and action selection. The present experiments used sensory-specific satiety to examine the role of outcome value in these two forms of control. Experiment 1 employed a general Pavlovian-instrumental transfer design to show that a stimulus predicting a food outcome energizes the performance of an instrumental action earning another food outcome. This energizing effect was removed when the stimulus-predicted outcome or a novel outcome was devalued by sensory-specific satiety. Experiments 2 and 3 employed a specific Pavlovian-instrumental transfer design to demonstrate that a stimulus predicting a particular food outcome promotes the selection of an instrumental action earning the same, but not a different, food outcome. Remarkably, this effect was maintained when all or just one of the stimulus-predicted outcomes were devalued by sensory-specific satiety. These results indicate that satiety alone removes the expression of general PIT. By contrast, satiety or outcome-specific devaluation does not regulate the expression of specific PIT, which is insensitive to changes in outcome value. This dissociation is consistent with the view that general and specific PIT are two separate phenomena driven by distinct psychological mechanisms.

Acquisition and extinction of second-order context conditioned fear: Role of the amygdala.

Second-order fear conditioning has been demonstrated in protocols using discrete and simple stimuli, and much is now known about its behavioral and neural characteristics. In contrast, the mechanisms of second-order conditioning to more complex stimuli, such as contexts, are unknown. To address this gap in our knowledge, we conducted a series of experiments to investigate the neural and behavioral characteristics of second-order context fear conditioning in rats. We found that rats acquire fear to a context in which a first-order conditioned stimulus is presented (Experiment 1); neuronal activity in the basolateral amygdala (BLA) is required for the acquisition (Experiment 2) and extinction (Experiment 3) of second-order context fear; second-order context fear can be reduced by extinction of its first-order conditioned stimulus associate (Experiment 4); and that second-order fear reduced in this way is restored when fear of the first-order conditioned stimulus spontaneously recovers or is reconditioned (Experiment 5). Thus, second-order context fear requires neuronal activity in the BLA, and once established, tracks the level of fear to its first-order conditioned stimulus-associate. These results are discussed with respect to the substrates of second-order fear conditioning in other protocols, and the role of the amygdala in different forms of conditioning.

The role of the basolateral amygdala and infralimbic cortex in (re)learning extinction.

The basolateral amygdala complex (BLA) and infralimbic region of the prefrontal cortex (IL) play distinct roles in the extinction of Pavlovian conditioned fear in laboratory rodents. In the past decade, research in our laboratory has examined the roles of these brain regions in the re-extinction of conditioned fear: i.e., extinction of fear that is restored through re-conditioning of the conditioned stimulus (CS) or changes in the physical and temporal context of extinction training (i.e., extinction of renewed or spontaneously recovered fear). This paper reviews this research. It has revealed two major findings. First, in contrast to the acquisition of fear extinction, which usually requires neuronal activity in the BLA but not IL, the acquisition of fear re-extinction requires neuronal activity in the IL but can occur independently of neuronal activity in the BLA. Second, the role of the IL in fear extinction is determined by the training history of the CS: i.e., if the CS was novel prior to its fear conditioning (i.e., it had not been trained), the acquisition of fear extinction does not require the IL; if, however, the prior training of the CS included a series of CS-alone exposures (e.g., if the CS had been pre-exposed), the acquisition of fear extinction was facilitated by pharmacological stimulation of the IL. Together, these results were taken to imply that a memory of CS-alone exposures is stored in the IL, survives fear conditioning of the CS, and can be retrieved and strengthened during extinction or re-extinction of that CS (regardless of whether the extinction is first- or second-learned). Hence, under these circumstances, the initial extinction of fear to the CS can be facilitated by pharmacological stimulation of the IL, and re-extinction of fear to the CS can occur in the absence of a functioning BLA.

The conditions that regulate formation of a false fear memory in rats.

People and animals sometimes associate events that never occurred together. These false memories can have disastrous consequences, yet little is known about the conditions under which they form. In four experiments, we investigated how rats learn to fear a context in which they have never experienced danger (i.e., how they form a false context fear memory). In each experiment, rats were pre-exposed to a context on day 1, shocked in a similar-but-different context on day 2, and tested in the pre-exposed or explicitly-conditioned context on day 3. The results revealed that: (1) the true memory of the explicitly-conditioned context and false memory of the pre-exposed context develop simultaneously and independently; and (2) the conditions of pre-exposure on day 1 and time of shock exposure on day 2 interact to determine the strength of the false memory. These findings are anticipated by a recent computational model, the Bayesian Context Fear Algorithm/Automaton (BACON; Krasne, Cushman, & Fanselow, 2015). They are discussed in relation to this model and more general theories of context learning.

Role Played by the Passage of Time in Reversal Learning.

Reversal learning is thought to involve an extinction-like process that inhibits the expression of the initial learning. However, behavioral evidence for this inhibition remains difficult to interpret as various procedures have been employed to study reversal learning. Here, we used a discrimination task in rats to examine whether the inhibition produced by reversal learning is as sensitive to the passage of time as the inhibition produced by extinction. Experiment 1 showed that when tested immediately after reversal training, rats were able to use the reversed contingencies to solve the discrimination task in an outcome-specific manner. This ability to use outcome-specific information was lost when a delay was inserted between reversal training and test. However, interpretation of these data was made difficult by a potential floor effect. This concern was addressed in Experiment 2 in which it was confirmed that the passage of time impaired the ability of the rats to use the reversed contingencies in an outcome-specific manner to solve the task. Further, it revealed that the delay between initial learning and test was not responsible for this impairment. Additional work demonstrated that solving the discrimination task was unaffected by Pavlovian extinction but that the discriminative stimuli were able to block conditioning to a novel stimulus, suggesting that Pavlovian processes were likely to contribute to solving the discrimination. We therefore concluded that the expression of reversal and extinction learning do share the same sensitivity to the effect of time. However, this sensitivity was most obvious when we assessed outcome-specific information following reversal learning. This suggests that the processes involved in reversal learning are somehow distinct from those underlying extinction learning, as the latter has usually been found to leave outcome-specific information relatively intact. Thus, the present study reveals that a better understanding of the mechanisms supporting reversal training requires assessing the impact that this training exerts on the content of learning rather than performance per se.

The infralimbic cortex encodes inhibition irrespective of motivational significance.

Evidence indicates that the infralimbic cortex (IL) encodes and retrieves the inhibitory memory produced by fear extinction. Recently, we have shown that the IL is also involved in the inhibitory memory generated by stimulus pre-exposure that causes latent inhibition. These results are surprising because a stimulus undergoing fear extinction carries aversive motivational value, whereas a pre-exposed stimulus is neutral. The present experiments tested the hypothesis that the IL encodes inhibition irrespective of the motivational information about the stimulus. Using rats, we first confirmed that IL activity during stimulus pre-exposure is required for latent inhibition. Then, we found that pharmacological stimulation of the IL facilitated aversive extinction to a stimulus that had been trained and extinguished as an appetitive stimulus. This facilitation was stimulus specific and required appetitive extinction. The same facilitation was found when appetitive extinction was replaced with random presentations of the stimulus and an appetitive outcome. Together, these findings indicate that non-reinforced stimulus presentations establish an inhibitory memory that is reactivated and strengthened in the IL during subsequent aversive extinction. This is consistent with the view that the IL encodes inhibition irrespective of motivational value, suggesting that this brain region plays a general role in inhibitory learning.

Extinction of relapsed fear does not require the basolateral amygdala.

It is well established that extinguished fears are restored with the passage of time or a change in physical context. These fear restoration phenomena are believed to mimic the conditions under which relapse occurs in patients that have been treated for anxiety disorders by means of cue-exposure therapy. Here, we used a rodent model to extinguish relapsed fear and assess whether this new extinction prevents further relapse. We found that activity in the basolateral amygdala (BLA) is required to initially extinguish conditioned fear, but this activity was not necessary to subsequently extinguish relapsed fear. That is, extinction of spontaneously recovered or renewed fear was spared by BLA inactivation. Yet, this BLA-independent learning of extinction did not protect against further relapse: extinction of relapsed fear conducted without BLA activity was still likely to return after the passage of time or a shift in physical context. These findings have important clinical implications. They indicate that pharmacological agents with anxiolytic properties may disrupt initial cue-exposure therapy but may be useful when therapy is again needed due to relapse. However, they also suggest that these agents will not protect against further relapse, implying the need for developing drugs that target other brain regions involved in fear inhibition.

Extinction and Latent Inhibition Involve a Similar Form of Inhibitory Learning that is Stored in and Retrieved from the Infralimbic Cortex.

Extinction and latent inhibition each refer to a reduction in conditioned responding: the former occurs when pairings of a conditioned stimulus (CS) and an unconditioned stimulus (US) are followed by repeated presentations of the CS alone; the latter occurs when CS alone presentations precede its pairings with the US. The present experiments used fear conditioning to test the hypothesis that both phenomena involve a similar form of inhibitory learning that recruits common neuronal substrates. We found that the initial inhibitory memory established by extinction is reactivated in the infralimbic (IL) cortex during additional extinction. Remarkably, this reactivation also occurs when the initial inhibitory memory had been established by latent inhibition. In both cases, the inhibitory memory was strengthened by pharmacological stimulation of the IL. Moreover, NMDA receptor blockade in the IL disrupted the weakening in conditioned responding produced by either latent inhibition or extinction. These findings, therefore, indicate that latent inhibition and extinction produce a similar inhibitory memory that is retrieved from the IL. They also demonstrate that the IL plays a wide role in fear regulation by promoting the retrieval of inhibitory memories generated by CS alone presentations either before or after this CS has been rendered dangerous.

Oxytocin signaling in basolateral and central amygdala nuclei differentially regulates the acquisition, expression, and extinction of context-conditioned fear in rats.

The present study investigated how oxytocin (OT) signaling in the central (CeA) and basolateral (BLA) amygdala affects acquisition, expression, and extinction of context-conditioned fear (freezing) in rats. In the first set of experiments, acquisition of fear to a shocked context was impaired by a preconditioning infusion of synthetic OT into the CeA (Experiment 1) or BLA (Experiment 2). In the second set of experiments, expression of context fear was enhanced by a pre- or post-extinction CeA infusion of synthetic OT (Experiments 3-6) or a selective OT receptor agonist, TGOT (Experiment 4). This enhancement of fear was blocked by coadministration of an OT receptor antagonist, OTA (Experiment 5) and context fear was suppressed by administration of the antagonist alone (Experiment 6). In the third set of experiments, expression of context fear was suppressed, not enhanced, by a preextinction BLA infusion of synthetic OT or a selective OT receptor agonist, TGOT (Experiments 7 and 8). This suppression of fear was blocked by coadministration of the OT receptor antagonist, OTA (Experiment 8). Taken together, these findings show that the involvement of the CeA and BLA in expression and extinction of context-conditioned fear is dissociable, and imply a critical role for oxytocin signaling in amygdala-based regulation of aversive learning.

Habits as action sequences: hierarchical action control and changes in outcome value.

Goal-directed action involves making high-level choices that are implemented using previously acquired action sequences to attain desired goals. Such a hierarchical schema is necessary for goal-directed actions to be scalable to real-life situations, but results in decision-making that is less flexible than when action sequences are unfolded and the decision-maker deliberates step-by-step over the outcome of each individual action. In particular, from this perspective, the offline revaluation of any outcomes that fall within action sequence boundaries will be invisible to the high-level planner resulting in decisions that are insensitive to such changes. Here, within the context of a two-stage decision-making task, we demonstrate that this property can explain the emergence of habits. Next, we show how this hierarchical account explains the insensitivity of over-trained actions to changes in outcome value. Finally, we provide new data that show that, under extended extinction conditions, habitual behaviour can revert to goal-directed control, presumably as a consequence of decomposing action sequences into single actions. This hierarchical view suggests that the development of action sequences and the insensitivity of actions to changes in outcome value are essentially two sides of the same coin, explaining why these two aspects of automatic behaviour involve a shared neural structure.

Amygdala central nucleus interacts with dorsolateral striatum to regulate the acquisition of habits.

The role of the amygdala central nucleus (CeN) in habit learning was assessed in two experiments. First, we examined the effects of bilateral lesions of the anterior CeN on an overtraining-induced lever press habit evaluated using an outcome devaluation protocol. Overtraining generated habitual performance and rendered sham lesioned rats insensitive to outcome devaluation, an effect that was also found in rats given control lesions of the posterior CeN. In contrast, rats with lesions of the anterior CeN did not show normal habit acquisition and their performance remained goal-directed and sensitive to outcome devaluation. Nevertheless, lesions of either the posterior or the anterior CeN abolished the general excitatory influence of a Pavlovian conditioned stimulus on instrumental performance. Second, we assessed the functional interaction between the CeN and dorsolateral striatum (DLS), a region previously implicated in the acquisition of habits, using asymmetrical lesions to disconnect these structures. Rats were given a unilateral lesion of anterior CeN and a unilateral lesion of the DLS, made either ipsilateral (control) or contralateral (disconnection) to the CeN lesion, and given overtraining followed by outcome devaluation. Although the ipsilateral lesioned rats were insensitive to devaluation, the contralateral CeN-DLS lesion impaired habit acquisition, rendering performance sensitive to the devaluation treatment. These results are the first to implicate the CeN and its connection with a circuit involving DLS in habit learning. They imply that, in instrumental conditioning, regions of amygdala parse the instrumental outcome into the reward and reinforcement signals mediating goal-directed and habitual actions, respectively.