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A variety of classic psychedelics and MDMA have been shown to enhance fear extinction in rodent models. This has translational significance because a standard treatment for post-traumatic stress disorder (PTSD) is prolonged exposure therapy. However, few studies have investigated psilocybin's potential effect on fear learning paradigms. More specifically, the extents to which dose, timing of administration, and serotonin receptors may influence psilocybin's effect on fear extinction are not understood. In this study, we used a delay fear conditioning paradigm to determine the effects of psilocybin on fear extinction, extinction retention, and fear renewal in male and female mice. Psilocybin robustly enhances fear extinction when given acutely prior to testing for all doses tested. Psilocybin also exerts long-term effects to elevate extinction retention and suppress fear renewal in a novel context, although these changes were sensitive to dose. Analysis of sex differences showed that females may respond to a narrower range of doses than males. Administration of psilocybin prior to fear learning or immediately after extinction yielded no change in behavior, indicating that concurrent extinction experience is necessary for the drug's effects. Cotreatment with a 5-HT2A receptor antagonist blocked psilocybin's effects for extinction, extinction retention, and fear renewal, whereas 5-HT1A receptor antagonism attenuated only the effect on fear renewal. Collectively, these results highlight dose, context, and serotonin receptors as crucial factors in psilocybin's ability to facilitate fear extinction. The study provides preclinical evidence to support investigating psilocybin as a pharmacological adjunct for extinction-based therapy for PTSD.

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Background: Fear responses significantly affect daily life and shape our approach to uncertainty. However, the potential resurgence of fear in unfamiliar situations poses a significant challenge to exposure-based therapies for maladaptive fear responses. Nonetheless, how novel contextual stimuli are associated with the relapse of extinguished fear remains unknown. Methods: Using a context-dependent fear renewal model, the functional circuits and underlying mechanisms of the posterior parietal cortex (PPC) and anterior cingulate cortex (ACC) were investigated using optogenetic, histological, in vivo, and ex vivo electrophysiological and pharmacological techniques. Results: We demonstrated that the PPC-to-ACC pathway governs fear relapse in a novel context. We observed enhanced populational calcium activity in the ACC neurons that received projections from the PPC and increased synaptic activity in the basolateral amygdala-projecting PPC-to-ACC neurons upon renewal in a novel context, where excitatory postsynaptic currents amplitudes increased but inhibitory postsynaptic current amplitudes decreased. In addition, we found that parvalbumin-expressing interneurons controlled novel context-dependent fear renewal, which was blocked by the chronic administration of fluoxetine. Conclusions: Our findings highlight the PPC-to-ACC pathway in mediating the relapse of extinguished fear in novel contexts, thereby contributing significant insights into the intricate neural mechanisms that govern fear renewal.

To improve outcomes for exposure-based therapy, it is vital to understand the renewal of fear after extinction in new environments. Using optogenetics and other techniques, Joo et al. found that a brain circuit connecting the posterior parietal cortex (PPC) to the anterior cingulate cortex (ACC) is crucial for the return of fear memories in mice exposed to a novel context. Certain PPC→ACC neuron types and their connections to the amygdala became more active during fear renewal in a novel context, and inhibiting parvalbumin-expressing interneurons reduced this fear response. This study provides insights into the brain mechanisms underlying the reappearance of fear in unfamiliar situations.

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Hyperactive orbitofrontal cortical activation is commonly seen in patients of obsessive-compulsive disorder (OCD). Previous studies from our laboratory showed that for rats with aberrant activation of the orbitofrontal cortex (OFC) during the extinction phase, they were unable to use contexts as the reference for proper retrieval of fear memory during renewal test. This result supported the phenomenon that many OCD patients show poor regulation of fear-related behavior. Since there are robust anatomical connections of the OFC with the fear-circuit, we aim to further examine whether the OFC is actively engaged in fear regulation under normal circumstances. In this study, the lateral or medial OFC was inactivated during the extinction phase using the ABA fear renewal procedure. We found that these animals showed intact fear renewal during retrieval test with their freezing levels equivalent to the control rats, revealing that the OFC did not have decisive roles in extinction acquisition. Together with our previous study, we suggest that the OFC only interferes with fear regulation when it becomes pathophysiologically hyperactive.

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Pavlovian conditioning paradigms model the learned fear associations inherent in posttraumatic stress disorder, including the renewal of inappropriate fear responses following extinction learning. However, very few studies in humans investigate the underlying neural mechanisms involved in fear renewal despite its clinical importance. To address this issue, our lab designed a novel, immersive-reality Pavlovian fear acquisition, extinction, recall, and renewal paradigm. We utilized an ecological threat - a snake striking towards the participant - as the unconditioned stimulus (US). Context and background were dynamic and included both visual and auditory cues that are relevant to everyday life. Using functional magnetic resonance imaging and behavioral measures (US expectancy ratings), we examined the validity of this Novel paradigm in healthy adults (n = 49) and compared it to a Standard, well-validated 2D paradigm (n = 28). The Novel paradigm, compared to the Standard, was associated with greater hippocampal activation throughout the task. Participants who underwent the Standard paradigm, compared to the Novel, also displayed insula activation; however, this was not specific to stimulus or time. During fear renewal, the Novel paradigm was associated with dorsal anterior cingulate cortex activation to CS+ (> CS-). Overall, we found that our Novel, immersive-reality paradigm, which features an ecologically relevant US, elicited greater corticolimbic activation. These results suggest that immersive Pavlovian fear conditioning paradigms paired with innately fearful stimuli may improve translatability of preclinical paradigms to clinical interventions for fear-based disorders.

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Synaptic associativity, a feature of Hebbian plasticity wherein coactivation of two inputs onto the same neuron produces synergistic actions on postsynaptic activity, is a primary cellular correlate of associative learning. However, whether and how synaptic associativity are implemented into context-dependent relapse of extinguished memory (i.e. fear renewal) is unknown. Here, using an auditory fear conditioning paradigm in mice, we show that fear renewal is determined by the associativity between convergent inputs from the auditory cortex (ACx) and ventral hippocampus (vHPC) onto the lateral amygdala (LA) that reactivate ensembles engaged during learning. Fear renewal enhances synaptic strengths of both ACx to LA and the previously unknown vHPC to LA monosynaptic inputs. While inactivating either of the afferents abolishes fear renewal, optogenetic activation of their input associativity in the LA recapitulates fear renewal. Thus, input associativity underlies fear memory renewal.

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Exposure-based therapy is an effective treatment for social anxiety, but some patients relapse. We used a novel virtual reality procedure to examine spontaneous recovery (i.e., a return of fear over time) and fear renewal (i.e., the return of fear after a context switch) in individuals with fear of public speaking. On Day 1, 32 participants received exposure training before a virtual audience. On Day 8, participants completed a spontaneous recovery phase, followed by a fear renewal test, in which they gave a presentation in front of a new (context switch) or the same audience (no context switch). After exposure, participants exhibited a lower heart rate, subjective distress, negative valence, and arousal. One week later, participants showed spontaneous recovery of heart rate, and the context switch group showed renewal of subjective distress, negative valence, and arousal. Future studies can use this procedure to test interventions aimed at improving long-term exposure effects in individuals with public speaking fear.

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Some anxiety-related disorders, such as panic disorder, specific phobia, post-traumatic stress disorder (PTSD), and obsessive-compulsive disorder (OCD), develop because of the poor regulation and inappropriate expression of fear-related behavior at the wrong place and wrong time. In clinical settings, exposure therapy, which consists of repeated presentation of trauma-related stimuli without real threats in the therapeutic context, is commonly used to treat these disorders. However, 30-50 % of patients suffer from the recurrence of anxiety symptoms after they leave the therapeutic context. This behavioral phenomenon is called renewal. In this study, ABA Pavlovian fear renewal paradigm was used to assess the role of the aberrant orbitofrontal cortex (OFC) activation, a symptom of OCD patients, on fear regulation in laboratory settings. The rats were fear conditioned in one context (context A), extinguished to the tones in another context (context B), and then tested in either context A or B. During extinction, rats were subjected to lateral or medial OFC activation. We found that rats that underwent extinction with either lateral or medial OFC activation were unable to use the context to determine whether it was a safe or dangerous context during renewal test. Interestingly, the rats with lateral OFC activation during extinction showed generally high fear, whereas the rats with medial OFC activation during extinction showed generally low fear. In conclusion, our results suggested that aberrant activation of specifically the lateral OFC may have a negative impact during exposure therapy treatments and results in their poor regulation of fear-related behavior.

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Anxiety and trauma-related disorders are highly prevalent worldwide, and are associated with altered associative fear learning. Despite the effectiveness of exposure therapy, which aims to reduce associative fear responses, relapse rates remain high. This is due, in part, to the context specificity of exposure therapy, which is a form of extinction. Many studies show that fear relapses when mice are tested outside the extinction context, and this is known as fear renewal. Using Pavlovian fear conditioning and extinction, we can study the mechanisms underlying extinction and renewal. The aim of the current experiment was to identify the role of presynaptic GABAB receptors in these two processes. Previous work from our lab showed that genetic deletion or pharmacological inhibition of GABAB(1a) receptors that provide presynaptic inhibition on glutamatergic terminals reduces context specificity and leads to generalization. We therefore hypothesized that inactivation of these presynaptic GABAB receptors could be used to reduce the context specificity associated with fear extinction training and suppress renewal when mice are tested outside of the extinction context. Using CGP 36216, an antagonist specific for presynaptic GABAB receptors, we blocked presynaptic GABAB receptors using intracerebroventricular injections during various time points of extinction learning in male and female mice. Results showed that blocking these receptors pre- and post-extinction training led to enhanced extinction learning in male mice only. We also found that post-extinction infusions of CGP reduced renewal rates in male mice when they were tested outside of the extinction context. In an attempt to localize the function of presynaptic GABAB receptors within regions of the extinction circuit, we infused CGP locally within the basolateral amygdala or dorsal hippocampus. We failed to reduce renewal when CGP was infused directly within these regions, suggesting that presynaptic inhibition within these regions per se may not be necessary for driving context specificity during extinction learning. Together, these results show an important sex-dependent role of presynaptic GABAB receptors in extinction and renewal processes and identify a novel receptor target that may be used to design pharmacotherapies to enhance the effectiveness of exposure therapy.

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An inherent property of extinguished fear memories is that the fear may return. A recent study in mice by Li et al. provides novel insights into the mechanisms underlying the relapse of an extinguished memory through converging sensory and contextual cues from the auditory cortex (ACx) and ventral hippocampus (vHPC) to the lateral amygdala (LA).

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As a type of fear relapse, fear renewal compromises the efficacy of fear extinction, which serves as the laboratory analog of exposure therapy (a therapeutic strategy for anxiety disorders). Interventions aiming to prevent fear renewal would thus benefit exposure therapy. To date, it remains unknown whether central adenosine monophosphate (AMP)-activated protein kinase (AMPK) activation could produce inhibitory effects on fear renewal. Here, using pharmacological approach and virus-mediated gene overexpression technique, we demonstrated that activation of AMPK in dorsal hippocampus shortly before fear extinction training completely abolished subsequent fear renewal in male mice without affecting other types of fear relapse, including spontaneous recovery of fear and fear reinstatement. Furthermore, we also found that metformin, a first-line antidiabetic drug, was capable of preventing fear renewal in male mice by stimulating AMPK in dorsal hippocampus. Collectively, our study provides insight into the role of hippocampal AMPK in regulation of fear renewal and indicates that increasing activity of hippocampal AMPK can prevent fear renewal, thus enhancing the potency of exposure therapy.

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The return of fear following extinction therapy is an important issue associated with the treatment of many fear-related disorders. Fear renewal is a suitable model, with which context-dependent modulation of the fear response can be examined. In this model, any context outside of an extinction context (e.g., novel or familiar contexts) could evoke relapse of the fear response. However, brain regions associated with context-dependent modulation are not fully understood. The posterior parietal cortex (PPC) is considered a center for integrating multisensory information and making decisions. To study its role in the contextual modulation of fear relapse, we reversibly inactivated the PPC in mice before they were exposed to various contexts after extinction training. When muscimol was infused into the PPC, fear renewal was impaired in a novel context, but not in a familiar context. Fear relapses were blocked during optogenetic inhibition of the PPC, only when animals were placed in a novel context. We propose that the neural activity of the PPC is necessary for the relapse of a precise response to an extinguished conditioned stimulus in a novel context.

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Fear renewal is defined as return of the conditioned fear responses after extinction when a conditioned stimulus (CS) is given outside of the extinction context. Previously, we have suggested that extinction induces S-nitrosylation of GluA1 in the lateral amygdala (LA), and that the extinction-induced S-nitrosylation of GluA1 lowers the threshold of GluA1 phosphorylation (at Ser 831) which is required for fear renewal. This fits nicely with the fact that fear renewal is induced by weak stimuli. However, it has not been tested whether S-nitrosylation of GluA1 in the LA is indeed required for fear renewal. In the present study, we used three different chemicals to impede protein S-nitrosylation via distinct mechanisms. Fear renewal was inhibited by microinjection of 7-Nitroindazole (nNOS inhibitor), and ZL006 (a blocker of PSD-95-nNOS interaction) before fear renewal. Furthermore, fear renewal was also attenuated by microinjection of a strong antioxidant (N-acetyl cysteine), which scavenges reactive oxygen including nitric oxide, into the LA before each extinction training. These findings suggest that protein S-nitrosylation is required for fear renewal.

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BACKGROUND: Fear renewal, the context-specific relapse of a conditioned fear after extinction, is a widely pursued model of post-traumatic stress disorder and phobias. However, its cellular and molecular mechanisms remain poorly understood. The dentate gyrus (DG) has emerged as a critical locus of plasticity with relevance to memory, anxiety disorders, and depression, and it contributes to fear memory retrieval. Here, we have identified the role of the DG in fear renewal and its molecular mechanism. MATERIALS AND METHODS: Muscimol (MUS), activator of cyclic adenosine monophosphate (cAMP) forskolin (FSK), inhibitor of protein kinase A (PKA), Rip-cAMP, and a phosphodiesterase inhibitor rolipram were infused into DG of standard deviation rats before renewal testing. cAMP levels after fear renewal was measured by enzyme-linked immunosorbent assay. The protein levels of phosphodiesterase 4 (PDE4) isoforms were tested by western blot. At last, the roles of cAMP signaling were also tested in the acquisition of fear conditioning, fear retrieval, and extinction. RESULTS: Intra-DG treatment of MUS and Rp-cAMP impaired fear renewal. FSK and rolipram exhibited the opposite effect, which also occurred in the retrieval of original fear memory. This change in fear renewal was regulated by PDE4 isoforms PDE4A, PDE4A5, and PDE4D. In addition, FSK and rolipram facilitated the acquisition of fear conditioning in long-term memory, but not short-term memory, while Rp-cAMP impaired long-term memory. For extinction, FSK and rolipram inhibited extinction process, while Rp-cAMP facilitated fear extinction. CONCLUSION: These findings demonstrated that fear renewal activated cAMP signaling in the DG through decreased PDE4 activity. Because of the role of cAMP signaling in the acquisition or retrieval of fear conditioning and encoding of extinction, it is speculated that initial learning and extinction may have similarities in molecular mechanism, especially fear retrieval and fear renewal may share cAMP signaling pathway in the DG.

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Extinction-based exposure therapy is the most common behavioral therapy for anxiety and trauma-related disorders, but fear tends to resurface even after successful extinction. Identification of novel strategies to enhance fear extinction and reduce fear relapse is of paramount importance to mental health. Exercise can enhance cognitive function, but it is not yet well understood whether exercise can be an effective augmentation strategy for fear extinction. In the current review, we present the current state of knowledge on the effects of exercise on fear extinction. Effects of exercise duration, explanations for conflicting results, and potential mechanisms, focusing on a hypothesized role for dopamine, are all discussed. We also provide new data suggesting that the timing in which acute exercise occurs relative to fear extinction, is a crucial variable in determining whether exercise can enhance fear extinction. Clinical implications and ideas to guide future research endeavors in this area are provided.

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Memories about sensory experiences are tightly linked to the context in which they were formed. Memory contextualization is fundamental for the selection of appropriate behavioral reactions needed for survival, yet the underlying neuronal circuits are poorly understood. By combining trans-synaptic viral tracing and optogenetic manipulation, we found that the ventral hippocampus (vHC) and the amygdala, two key brain structures encoding context and emotional experiences, interact via multiple parallel pathways. A projection from the vHC to the basal amygdala mediates fear behavior elicited by a conditioned context, whereas a parallel projection from a distinct subset of vHC neurons onto midbrain-projecting neurons in the central amygdala is necessary for context-dependent retrieval of cued fear memories. Our findings demonstrate that two fundamentally distinct roles of context in fear memory retrieval are processed by distinct vHC output pathways, thereby allowing for the formation of robust contextual fear memories while preserving context-dependent behavioral flexibility.

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Relapse of previously extinguished fear presents a significant, pervasive obstacle to the successful long-term treatment of anxiety and trauma-related disorders. Thus, identification of a novel means to enhance fear extinction to stand the passage of time and generalize across contexts is of the utmost importance. Acute bouts of exercise can be used as inexpensive, noninvasive treatment strategies to reduce anxiety, and have been shown to enhance memory for extinction when performed in close temporal proximity to the extinction session. However, it is unclear whether acute exercise can be used to prevent relapse of fear, and the neural mechanisms underlying this potential effect are unknown. The current study therefore examined whether acute exercise during extinction of auditory fear can protect against the later relapse of fear. Male F344 rats lacking an extended history of wheel running were conditioned to fear a tone CS and subsequently extinguished within either a freely mobile running wheel, a locked wheel, or a control context lacking a wheel. Rats exposed to fear extinction within a freely mobile wheel ran during fear extinction, and demonstrated reduced fear as well as attenuated corticosterone levels during re-exposure to the extinguished CS during the relapse test in a novel context 1week later. Examination of cfos mRNA patterns elicited by re-exposure to the extinguished CS during the relapse test revealed that acute exercise during extinction decreased activation of brain circuits classically involved in driving fear expression and interestingly, increased activity within neurons of the direct striatal pathway involved in reward signaling. These data suggest that exercise during extinction reduces relapse through a mechanism involving the direct pathway of the striatum. It is suggested that a positive affective state could become associated with the CS during exercise during extinction, thus resulting in a relapse-resistant extinction memory.

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Several studies have shown that an isolated retrieval trial before the extinction session (retrieval-extinction) prevents the return of fear memory by inhibition of reconsolidation. Other studies have reported that retrieval-extinction did not prevent the return of the fear. To date, it is still unclear whether retrieval-extinction prevents the return of the original fear memory. A previous study revealed that reconsolidation of conditioned fear memory was not induced by the brevity of the retrieval session. Thus, we examined whether the number of retrievals in the retrieval-extinction paradigm was involved in the prevention of return of fear (Experiment 1). Furthermore, studies with different-age experimental subjects have shown conflicting results. We investigated the potential impact of age on the inhibitory effect of retrieval-extinction on the return of fear (Experiment 2). Our major findings were as follows: (1) Retrieval-extinction procedure did not prevent the return of fear, regardless of the intensity (number of presentations) of the stimulus inducing retrieval of fear memory. (2) The mice in both juvenile and adult age groups (4 and 8 weeks old) retrieved fear memory after retrieval-extinction. These results suggest the possibility that extinction after retrieval does not inhibit reconsolidation of previously consolidated fear memory.

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After treatment of anxiety disorders, fear often returns. Analogue studies show that outside the extinction context the conditional stimulus (CS) activates the acquisition memory (CS predicts unconditional stimulus; UCS), rather than the extinction memory (CS does not predict UCS). Conditioning theory postulates that fear also diminishes after a reduction in the subjective cost of the UCS, which can occur in absence of any changes in the CS-UCS association. We hypothesized that fear reduction via "UCS deflation" generalizes across context. Healthy students underwent acquisition in context A with neutral CSs and 100dB white noise as UCS. One group received post-conditioning UCS exposure, in which UCS intensity decreased over time ("ABAdefl"). Another group received UCS presentations at equal intensity ("ABActrl"). Two groups did a filler task ("ABB"; "ABA"). Then, all groups underwent extinction in context B and were retested in context A (ABA-groups) or B (ABB-group). During each CS participants rated UCS expectancy and UCS cost. Results showed the typical increase in UCS expectancy following the context switch from extinction to test phase. In contrast, UCS deflation caused a reduction in cost ratings that was maintained after the context change. Findings suggest that UCS deflation techniques may reduce fear renewal.

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Previous research suggests the prelimbic (PL) cortex is involved in expression of conditioned fear (Burgos-Robles, Vidal-Gonzalez, & Quirk, 2009; Corcoran & Quirk, 2007). However, there is a long history of research in the appetitive domain which implicates this region in using higher-order cues to modulate a behavioural response (Birrell & Brown, 2000; Floresco, Block, & Tse, 2008; Marquis, Killcross, & Haddon, 2007; Sharpe & Killcross, 2014). For example, the PL cortex is necessary to allow animals to use contextual cues to disambiguate response conflict in ambiguous circumstances (Marquis et al., 2007). Using an ABA fear renewal procedure, we assessed the role of the PL cortex in using contextual cues to modulate a response towards a conditioned stimulus (CS) in an aversive setting. We found that pre-training lesions of the PL cortex did not impact on the expression or extinction of conditioned fear. Rather, they selectively abolished renewal. Functional inactivation of the PL cortex during extinction did not disrupt the subsequent renewal of conditioned fear or the ability of animals to exhibit fear towards a CS during the extinction session. However, PL inactivation during the renewal test session disrupted the ability of animals to demonstrate a reinstatement of responding in the renewal context. An analysis of orienting responses showed that renewal deficits were accompanied by a lack of change in attentional responding towards the CS. These data suggest the PL cortex uses contextual cues to modulate both a behavioural and an attentional response during aversive procedures. We argue that the role of the PL cortex in the expression of conditioned fear is to use higher-order information to modulate responding towards predictive cues in ambiguous circumstance.

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Avoidance is considered as a central hallmark of all anxiety disorders. The acquisition and expression of avoidance, which leads to the maintenance and exacerbation of pathological fear is closely linked to Pavlovian and operant conditioning processes. Changes in conditionability might represent a key feature of all anxiety disorders but the exact nature of these alterations might vary across different disorders. To date, no information is available on specific changes in conditionability for disorder-irrelevant stimuli in specific phobia (SP). The first aim of this study was to investigate changes in fear acquisition and extinction in spider-fearful individuals as compared to non-fearful participants by using the de novo fear conditioning paradigm. Secondly, we aimed to determine whether differences in the magnitude of context-dependent fear retrieval exist between spider-fearful and non-fearful individuals. Our findings point to an enhanced fear discrimination in spider-fearful individuals as compared to non-fearful individuals at both the physiological and subjective level. The enhanced fear discrimination in spider-fearful individuals was neither mediated by increased state anxiety, depression, nor stress tension. Spider-fearful individuals displayed no changes in extinction learning and/or fear retrieval. Surprisingly, we found no evidence for context-dependent modulation of fear retrieval in either group. Here, we provide first evidence that spider-fearful individuals show an enhanced discriminative fear learning of phobia-irrelevant (de novo) stimuli. Our findings provide novel insights into the role of fear acquisition and expression for the development and maintenance of maladaptive responses in the course of SP.