Stimulus-outcome Associations Research Articles

Adaptive responding to stimulus-outcome associations requires noradrenergic transmission in the medial prefrontal cortex.

A dynamic environment, such as the one we inhabit, requires organisms to continuously update their knowledge of the setting. While the prefrontal cortex is recognized for its pivotal role in regulating such adaptive behavior, the specific contributions of each prefrontal area remain elusive. In the current work, we investigated the direct involvement of two major prefrontal subregions, the medial prefrontal cortex (mPFC, A32D+A32V) and the orbitofrontal cortex (OFC, VO+LO), in updating Pavlovian stimulus-outcome (S-O) associations following contingency degradation in male rats. Specifically, animals had to learn that a particular cue, previously fully predicting the delivery of a specific reward, was no longer a reliable predictor. First, we found that chemogenetic inhibition of mPFC, but not of OFC, neurons altered the rats' ability to adaptively respond to degraded and non-degraded cues. Next, given the growing evidence pointing at noradrenaline (NA) as a main neuromodulator of adaptive behavior, we decided to investigate the possible involvement of NA projections to the two subregions in this higher-order cognitive process. Employing a pair of novel retrograde vectors, we traced NA projections from the locus coeruleus (LC) to both structures and observed an equivalent yet relatively segregated amount of inputs. Then, we showed that chemogenetic inhibition of NA projections to the mPFC, but not to the OFC, also impaired the rats' ability to adaptively respond to the degradation procedure. Altogether, our findings provide important evidence of functional parcellation within the prefrontal cortex and point at mPFC-NA as key for updating Pavlovian S-O associations.Significant statement The ability to update stimulus-outcome (S-O) associations is a key adaptive behavior, essential for surviving and thriving in an ever-changing environment. The prefrontal cortex is well-known for playing a key role in this process. The discrete contribution of each prefrontal subregion and of different neurotransmitters, however, remains unclear. In the current study, we show that inhibiting medial prefrontal (mPFC), but not orbitofrontal cortex (OFC), neurons impairs rats' ability to update S-O associations following contingency degradation. Moreover, we demonstrate that discrete noradrenergic projections to the two subregions exist and that inhibiting the ones projecting to the mPFC, but not to the OFC, once again impairs the animals' behavior, thereby implying a substantial contribution of noradrenaline in orchestrating this higher-order cognitive process.

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).

Supplemental Material for Stimulus–Outcome Associations Are Required for the Expression of Specific Pavlovian-Instrumental Transfer

Supplemental Material for Stimulus–Outcome Associations Are Required for the Expression of Specific Pavlovian-Instrumental Transfer

A test of the role of stimulus-response and stimulus-outcome associations in the effects of intermittent-access training

Increased reinforcer motivation in rats has been repeatedly demonstrated following intermittent-access (IntA) training, where the reinforcer is only available for brief periods during a session, compared to continuous-access (ContA) training where the reinforcer is available throughout the session. The present study investigated whether different associations learned during training on the two procedures contributes to the effect. Two experiments tested the importance of the stimulus-response (S-R) and stimulus-outcome (S-O) associations between the IntA availability cues and the training response and reinforcer, respectively. In Exp. 1, separate groups of rats were trained to lever press for saccharin on the IntA or ContA procedures. Increased motivation for saccharin was observed in the IntA group on a later progressive ratio test where nosepoking was the operant (but not when lever pressing was the operant). The outcome of the nosepoke test suggests that a potential S-R association formed during IntA training was not critical for the effect. In Exp. 2, increased saccharin motivation (on nosepoke tests) after IntA training (with lever pressing) was observed regardless of the presence or absence of IntA availability cues, indicating that the S-O association formed during training is not critical for the effect either. Overall, these results suggest that the elemental associations learned on IntA procedures may not be what drives increased motivation observed after IntA training.

Dopaminergic D2-like receptor stimulation affects attention on contextual information and modulates BOLD activation of extinction-related brain areas

Contextual information is essential for learning and memory processes and plays a crucial role during the recall of extinction memory, and in the renewal effect, which is the context-dependent recovery of an extinguished response. The dopaminergic system is known to be involved in regulating attentional processes by shifting attention to novel and salient contextual cues. Higher dopamine levels are associated with a better recall of previously learned stimulus-outcome associations and enhanced encoding, as well as retrieval of contextual information which promotes renewal. In this fMRI study, we aimed to investigate the impact of processing contextual information and the influence of dopaminergic D2-like receptor activation on attention to contextual information during a predictive learning task as well as upon extinction learning, memory performance, and activity of extinction-related brain areas. A single oral dose of 1.25 mg bromocriptine or an identical-looking placebo was administered to the participants. We modified a predictive learning task that in previous studies reliably evoked a renewal effect, by increasing the complexity of contextual information. We analysed fixations and dwell on contextual cues by use of eye-tracking and correlated these with behavioural performance and BOLD activation of extinction-related brain areas. Our results indicate that the group with dopaminergic D2-like receptor stimulation had higher attention to task-relevant contextual information and greater/lower BOLD activation of brain regions associated with cognitive control during extinction learning and recall. Moreover, renewal responses were almost completely absent. Since this behavioural effect was observed for both treatment groups, we assume that this was due to the complexity of the altered task design.

The emergence of task-relevant representations in a nonlinear decision-making task

This paper describes the relationship between performance in a decision-making task and the emergence of task-relevant representations. Participants learnt two tasks in which the appropriate response depended on multiple relevant stimuli and the underlying stimulus-outcome associations were governed by a latent feature that participants could discover. We divided participants into good and bad performers based on their overall classification rate and computed behavioural accuracy for each feature value. We found that participants with better performance had a better representation of the latent feature space. We then used representation similarity analysis on Electroencephalographic (EEG) data to identify when these representations emerge. We were able to decode task-relevant representations in a time window emerging 700 ms after stimulus presentation, but only for participants with good task performance. Our findings suggest that, in order to make good decisions, it is necessary to create and extract a low-dimensional representation of the task at hand.

Cortisol decreases activation in extinction related brain areas resulting in an impaired recall of context-dependent extinction memory

Conditioned responding gradually stops during successful extinction learning. The renewal effect is defined as the recovery of a extinguished conditioned response when the context of extinction is different from acquisition. The stress hormone cortisol is known to have an influence on extinction memory and associative learning. Different effects of cortisol on behaviour and brain activity have been observed with respect to stress timing, duration, and intensity. However, the influence of cortisol prior to the initial encoding of stimulus-outcome associations on extinction learning, renewal and its behavioural and neurobiological correlates is still largely unknown. In our study, 60 human participants received 20 mg cortisol or placebo and then learned, extinguished, and recalled the associations between food stimuli presented in distinct contexts and different outcomes in three subsequent task phases. Learning performance during acquisition and extinction phases was equally good for both treatment groups. In the cortisol group, significantly more participants showed renewal compared to placebo. In the subgroup of participants with renewal, cortisol treated participants showed significantly better extinction learning performance compared to placebo. Participants showing renewal had in general difficulties with recalling extinction memory, but in contrast to placebo, the cortisol group exhibited a context-dependent impairment of extinction memory recall. Imaging analyses revealed that cortisol decreased activation in the hippocampus during acquisition. The cortisol group also showed reduced dorsolateral prefrontal cortex activation when extinction learning took place in a different context, but enhanced activation in inferior frontal gyrus during extinction learning without context change. During recall, cortisol decreased ventromedial prefrontal cortex activation. Taken together, our findings illustrate cortisol as a potent modulator of extinction learning and recall of extinction memory which also promotes renewal.

Threat learning in space: how stimulus-outcome spatial compatibility modulates conditioned skin conductance response

A central question in Pavlovian conditioning concerns the critical conditions that drive the acquisition and maintenance of the stimulus-outcome association. The spatial relationship between the conditioned (CS) and unconditioned (US) stimuli is considered to exert strong effects on learning. However, how spatial information modulates Pavlovian learning remains mostly unexplored in humans. Here, we test how the compatibility between the CS and the US location influences the acquisition, extinction, and recovery (following reinstatement) of Pavlovian conditioned threat. Participants (N = 20) completed a differential threat conditioning task in which visual CSs appeared on the same (compatible) or opposite (incompatible) hemispace as the US delivery (aversive shock to one hand), while their skin conductance response served as an index of learning. Results show that initial threat expectations were biased in favor of compatible CSs before conditioning. Nevertheless, this bias was revised during acquisition to reflect current stimulus-outcome contingencies. Computational modeling suggested that this effect occurred through a higher reliance on positive aversive prediction errors for incompatible CSs, thereby facilitating learning of their association with the US. Additionally, the conditioned response to incompatible CSs was associated with initially slower extinction and a greater recovery after threat reinstatement. These findings suggest that spatial information conveyed by stimuli and outcomes can be flexibly used to enact defensive responses to the current source of danger, highlighting the adaptive nature of Pavlovian learning.

Stimulating human prefrontal cortex increases reward learning

Work in computational psychiatry suggests that mood disorders may stem from aberrant reinforcement learning processes. Specifically, it has been proposed that depressed individuals believe that negative events are more informative than positive events, resulting in higher learning rates from negative outcomes (Pulcu and Browning, 2019). In this proof-of-concept study, we investigated whether transcranial direct current stimulation (tDCS) applied to dorsolateral prefrontal cortex, as commonly used in depression treatment trials, might change learning rates for affective outcomes. Healthy adults completed an established reinforcement learning task (Pulcu and Browning, 2017) in which the information content of reward and loss outcomes was manipulated by varying the volatility of stimulus-outcome associations. Learning rates on the tasks were quantified using computational models. Stimulation over dorsolateral prefrontal cortex (DLPFC) but not motor cortex (M1) increased learning rates specifically for reward outcomes. The effects of prefrontal tDCS were cognitive state-dependent: tDCS applied during task performance increased learning rates for wins; tDCS applied before task performance decreased both win and loss learning rates. A replication study confirmed the key finding that tDCS to DLPFC during task performance increased learning rates specifically for rewards. Taken together, these findings demonstrate the potential of tDCS for modulating computational parameters of reinforcement learning that are relevant to mood disorders.

Ambiguity drives higher-order Pavlovian learning.

In the natural world, stimulus-outcome associations are often ambiguous, and most associations are highly complex and situation-dependent. Learning to disambiguate these complex associations to identify which specific outcomes will occur in which situations is critical for survival. Pavlovian occasion setters are stimuli that determine whether other stimuli will result in a specific outcome. Occasion setting is a well-established phenomenon, but very little investigation has been conducted on how occasion setters are disambiguated when they themselves are ambiguous (i.e., when they do not consistently signal whether another stimulus will be reinforced). In two preregistered studies, we investigated the role of higher-order Pavlovian occasion setting in humans. We developed and tested the first computational model predicting direct associative learning, traditional occasion setting (i.e., 1st-order occasion setting), and 2nd-order occasion setting. This model operationalizes stimulus ambiguity as a mechanism to engage in higher-order Pavlovian learning. Both behavioral and computational modeling results suggest that 2nd-order occasion setting was learned, as evidenced by lack and presence of transfer of occasion setting properties when expected and the superior fit of our 2nd-order occasion setting model compared to the 1st-order occasion setting or direct associations models. These results provide a controlled investigation into highly complex associative learning and may ultimately lead to improvements in the treatment of Pavlovian-based mental health disorders (e.g., anxiety disorders, substance use).

Reacting to changing environment: Updating patterns in social anxiety

Social anxiety (SA) was associated with biases in the updating of self-related information. Whether and under which conditions such biases emerge with respect to other-related information remains under-explored. In a pre-registered study, online participants (n = 590) were randomly assigned to one of two structurally identical reversal-learning tasks with social (faces) or non-social (shapes) stimuli. In the initial phase of this task, stimulus-outcome associations were learned by trial and error. Next, in the updating phase of the task, these associations were modified. SA was associated with reduced negative-to-positive updating and enhanced positive-tonegative updating of social, but not non-social, information. The results extend previous studies suggesting that SA is associated not only with biased updating of selfrelated information but also with biased updating of other-related information. This bias is specific to social information and may contribute, along with other information processing biases, to the maintenance of SA.

Hippocampal Contribution to Probabilistic Feedback Learning: Modeling Observation- and Reinforcement-based Processes.

Simple probabilistic reinforcement learning is recognized as a striatum-based learning system, but in recent years, has also been associated with hippocampal involvement. This study examined whether such involvement may be attributed to observation-based learning (OL) processes, running in parallel to striatum-based reinforcement learning. A computational model of OL, mirroring classic models of reinforcement-based learning (RL), was constructed and applied to the neuroimaging data set of Palombo, Hayes, Reid, and Verfaellie [2019. Hippocampal contributions to value-based learning: Converging evidence from fMRI and amnesia. Cognitive, Affective & Behavioral Neuroscience, 19(3), 523-536]. Results suggested that OL processes may indeed take place concomitantly to reinforcement learning and involve activation of the hippocampus and central orbitofrontal cortex. However, rather than independent mechanisms running in parallel, the brain correlates of the OL and RL prediction errors indicated collaboration between systems, with direct implication of the hippocampus in computations of the discrepancy between the expected and actual reinforcing values of actions. These findings are consistent with previous accounts of a role for the hippocampus in encoding the strength of observed stimulus-outcome associations, with updating of such associations through striatal reinforcement-based computations. In addition, enhanced negative RL prediction error signaling was found in the anterior insula with greater use of OL over RL processes. This result may suggest an additional mode of collaboration between the OL and RL systems, implicating the error monitoring network.

Nucleus Accumbens Core Dopamine D2 Receptor-Expressing Neurons Control Reversal Learning but Not Set-Shifting in Behavioral Flexibility in Male Mice.

The ability to use environmental cues to flexibly guide responses is crucial for adaptive behavior and is thought to be controlled within a series of cortico-basal ganglia-thalamo-cortical loops. Previous evidence has indicated that different prefrontal cortical regions control dissociable aspects of behavioral flexibility, with the medial prefrontal cortex (mPFC) necessary for the ability to shift attention to a novel strategy (set-shifting) and the orbitofrontal cortex (OFC) necessary for shifting attention between learned stimulus-outcome associations (reversal learning). The nucleus accumbens (NAc) is a major downstream target of both the mPFC and the OFC; however, its role in controlling reversal learning and set-shifting abilities is still unclear. Here we investigated the contribution of the two major NAc neuronal populations, medium spiny neurons expressing either dopamine D1 or D2 receptors (D1-/D2-MSNs), in guiding reversal learning and set-shifting in an attentional set-shifting task (ASST). Persistent inhibition of neurotransmitter release from NAc D2-MSNs, but not D1-MSNs, resulted in an impaired ability for reversal learning, but not set-shifting in male mice. These findings suggest that NAc D2-MSNs play a critical role in suppressing responding toward specific learned cues that are now associated with unfavorable outcomes (i.e., in reversal stages), but not in the suppression of more general learned strategies (i.e., in set-shifting). This study provides further evidence for the anatomical separation of reversal learning and set-shifting abilities within cortico-basal ganglia-thalamo-cortical loops.

So what'cha want? The impact of individualised rewards on associative learning in psychopathic offenders

Psychopathic individuals typically present with associative learning impairments under explicit learning conditions. The present study aimed to investigate whether the formation of stimulus-outcome associations, as well as updating of these associations after changed contingencies, could be improved by using rewards with sufficiently high subjective values. To this end, 20 psychopathic offenders, 17 non-psychopathic offenders and 18 healthy controls performed a passive avoidance task with a reversal phase under three motivational conditions, using naturalistic rewards. The subjective values of the rewards were assessed a priori for each individual participant using a visual analogue scale. The correspondence of these values to their internal representation was confirmed by analyses of brain potentials. Analyses using both signal detection theory and classical approaches indicated that psychopathic offenders performed worse compared to the other groups during passive avoidance learning. However, using the signal detection approach, we found this deficiency to be present only when a hypothetical reward was used (‘neutral reward’ condition), whereas psychopathic offenders performed similar to the other groups when naturalistic rewards could be obtained (‘low reward’ and ‘high reward’ conditions). Furthermore, traditional analyses suggested that psychopathic offenders had more hits than the other groups during reversal learning, but the signal detection approach indicated that no effects of group or condition were present. Analysis of win-stay and lose-shift behaviour showed that psychopathic offenders were less likely to stay with a rewarded response during passive avoidance learning in the neutral reward condition. In addition, regardless of experimental phase or condition, psychopathic offenders were less likely to stop responding to a particular stimulus after receiving negative feedback. Although the approaches employed did not lead to unequivocal results, our findings suggest that psychopathic offenders do have the ability to adapt their behaviour to environmental contingencies when positive reinforcers with sufficiently high subjective values are used.

The mediodorsal thalamus supports adaptive responding based on stimulus-outcome associations.

The ability to engage into flexible behaviors is crucial in dynamic environments. We recently showed that in addition to the well described role of the orbitofrontal cortex (OFC), its thalamic input from the submedius thalamic nucleus (Sub) also contributes to adaptive responding during Pavlovian degradation. In the present study, we examined the role of the mediodorsal thalamus (MD) which is the other main thalamic input to the OFC. To this end, we assessed the effect of both pre- and post-training MD lesions in rats performing a Pavlovian contingency degradation task. Pre-training lesions mildly impeded the establishment of stimulus-outcome associations during the initial training of Pavlovian conditioning without interfering with Pavlovian degradation training when the sensory feedback provided by the outcome rewards were available to animals. However, we found that both pre- and post-training MD lesions produced a selective impairment during a test conducted under extinction conditions, during which only current mental representation could guide behavior. Altogether, these data suggest a role for the MD in the successful encoding and representation of Pavlovian associations.

Computational mechanisms of distributed value representations and mixed learning strategies

Learning appropriate representations of the reward environment is challenging in the real world where there are many options, each with multiple attributes or features. Despite existence of alternative solutions for this challenge, neural mechanisms underlying emergence and adoption of value representations and learning strategies remain unknown. To address this, we measure learning and choice during a multi-dimensional probabilistic learning task in humans and trained recurrent neural networks (RNNs) to capture our experimental observations. We find that human participants estimate stimulus-outcome associations by learning and combining estimates of reward probabilities associated with the informative feature followed by those of informative conjunctions. Through analyzing representations, connectivity, and lesioning of the RNNs, we demonstrate this mixed learning strategy relies on a distributed neural code and opponency between excitatory and inhibitory neurons through value-dependent disinhibition. Together, our results suggest computational and neural mechanisms underlying emergence of complex learning strategies in naturalistic settings.

A bidirectional corticoamygdala circuit for the encoding and retrieval of detailed reward memories.

Adaptive reward-related decision making often requires accurate and detailed representation of potential available rewards. Environmental reward-predictive stimuli can facilitate these representations, allowing one to infer which specific rewards might be available and choose accordingly. This process relies on encoded relationships between the cues and the sensory-specific details of the rewards they predict. Here, we interrogated the function of the basolateral amygdala (BLA) and its interaction with the lateral orbitofrontal cortex (lOFC) in the ability to learn such stimulus-outcome associations and use these memories to guide decision making. Using optical recording and inhibition approaches, Pavlovian cue-reward conditioning, and the outcome-selective Pavlovian-to-instrumental transfer (PIT) test in male rats, we found that the BLA is robustly activated at the time of stimulus-outcome learning and that this activity is necessary for sensory-specific stimulus-outcome memories to be encoded, so they can subsequently influence reward choices. Direct input from the lOFC was found to support the BLA in this function. Based on prior work, activity in BLA projections back to the lOFC was known to support the use of stimulus-outcome memories to influence decision making. By multiplexing optogenetic and chemogenetic inhibition we performed a serial circuit disconnection and found that the lOFC→BLA and BLA→lOFC pathways form a functional circuit regulating the encoding (lOFC→BLA) and subsequent use (BLA→lOFC) of the stimulus-dependent, sensory-specific reward memories that are critical for adaptive, appetitive decision making.

Latent cause inference during extinction learning in trauma-exposed individuals with and without PTSD.

Problems in learning that sights, sounds, or situations that were once associated with danger have become safe (extinction learning) may explain why some individuals suffer prolonged psychological distress following traumatic experiences. Although simple learning models have been unable to provide a convincing account of why this learning fails, it has recently been proposed that this may be explained by individual differences in beliefs about the causal structure of the environment. Here, we tested two competing hypotheses as to how differences in causal inference might be related to trauma-related psychopathology, using extinction learning data collected from clinically well-characterised individuals with varying degrees of post-traumatic stress (N = 56). Model parameters describing individual differences in causal inference were related to multiple post-traumatic stress disorder (PTSD) and depression symptom dimensions via network analysis. Individuals with more severe PTSD were more likely to assign observations from conditioning and extinction stages to a single underlying cause. Specifically, greater re-experiencing symptom severity was associated with a lower likelihood of inferring that multiple causes were active in the environment. We interpret these results as providing evidence of a primary deficit in discriminative learning in participants with more severe PTSD. Specifically, a tendency to attribute a greater diversity of stimulus configurations to the same underlying cause resulted in greater uncertainty about stimulus-outcome associations, impeding learning both that certain stimuli were safe, and that certain stimuli were no longer dangerous. In the future, better understanding of the role of causal inference in trauma-related psychopathology may help refine cognitive therapies for these disorders.

Targeted Stimulation of an Orbitofrontal Network Disrupts Decisions Based on Inferred, Not Experienced Outcomes.

When direct experience is unavailable, animals and humans can imagine or infer the future to guide decisions. Behavior based on direct experience versus inference may recruit partially distinct brain circuits. In rodents, the orbitofrontal cortex (OFC) contains neural signatures of inferred outcomes, and OFC is necessary for behavior that requires inference but not for responding driven by direct experience. In humans, OFC activity is also correlated with inferred outcomes, but it is unclear whether OFC activity is required for inference-based behavior. To test this, we used noninvasive network-based continuous theta burst stimulation (cTBS) in human subjects (male and female) to target lateral OFC networks in the context of a sensory preconditioning task that was designed to isolate inference-based behavior from responding that can be based on direct experience alone. We show that, relative to sham, cTBS targeting this network impairs reward-related behavior in conditions in which outcome expectations have to be mentally inferred. In contrast, OFC-targeted stimulation does not impair behavior that can be based on previously experienced stimulus–outcome associations. These findings suggest that activity in the targeted OFC network supports decision-making when outcomes have to be mentally simulated, providing converging cross-species evidence for a critical role of OFC in model-based but not model-free control of behavior.SIGNIFICANCE STATEMENT It is widely accepted that the orbitofrontal cortex (OFC) is important for decision-making. However, it is less clear how exactly this region contributes to behavior. Here we test the hypothesis that the human OFC is only required for decision-making when future outcomes have to be mentally simulated, but not when direct experience with stimulus–outcome associations is available. We show that targeting OFC network activity in humans using network-based continuous theta burst stimulation selectively impairs behavior that requires inference but does not affect responding that can be based solely on direct experience. These results are in line with previous findings in animals and suggest a critical role for human OFC in model-based but not model-free behavior.

Revaluing the Role of vmPFC in the Acquisition of Pavlovian Threat Conditioning in Humans.

The role of the ventromedial prefrontal cortex (vmPFC) in human pavlovian threat conditioning has been relegated largely to the extinction or reversal of previously acquired stimulus-outcome associations. However, recent neuroimaging evidence questions this view by also showing activity in the vmPFC during threat acquisition. Here we investigate the casual role of vmPFC in the acquisition of pavlovian threat conditioning by assessing skin conductance response (SCR) and declarative memory of stimulus-outcome contingencies during a differential pavlovian threat-conditioning paradigm in eight patients with a bilateral vmPFC lesion, 10 with a lesion outside PFC and 10 healthy participants (each group included both females and males). Results showed that patients with vmPFC lesion failed to produce a conditioned SCR during threat acquisition, despite no evidence of compromised SCR to unconditioned stimulus or compromised declarative memory for stimulus-outcome contingencies. These results suggest that the vmPFC plays a causal role in the acquisition of new learning and not just in the extinction or reversal of previously acquired learning, as previously thought. Given the role of the vmPFC in schema-related processing and latent structure learning, the vmPFC may be required to construct a detailed representation of the task, which is needed to produce a sustained conditioned physiological response in anticipation of the unconditioned stimulus during threat acquisition.SIGNIFICANCE STATEMENT Pavlovian threat conditioning is an adaptive mechanism through which organisms learn to avoid potential threats, thus increasing their chances of survival. Understanding what brain regions contribute to such a process is crucial to understand the mechanisms underlying adaptive as well as maladaptive learning, and has the potential to inform the treatment of anxiety disorders. Importantly, the role of the ventromedial prefrontal cortex (vmPFC) in the acquisition of pavlovian threat conditioning has been relegated largely to the inhibition of previously acquired learning. Here, we show that the vmPFC actually plays a causal role in the acquisition of pavlovian threat conditioning.