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The mammalian dopamine system exhibits notable diversity, with dopamine neurons forming functionally distinct and nonoverlapping subpopulations based on their projection targets. Dopamine neurons have crucial roles in mediating not only reward processing, but also threat and safety learning. Distinct dopaminergic circuits encode prediction errors for threats as well as absence of threats, which are critical dopamine signals for driving associative threat and safety learning, respectively. Dopamine neurons that encode salience also project to brain regions underlying threat and safety learning, and are likely involved in these forms of learning. Dopamine neurons mediate threat and safety learning through their projections to the amygdala, medial prefrontal cortex, and striatum. These distinct dopaminergic circuits mediate different phases of associative learning and memory for threats and safety. The ability to learn from experience that certain cues and situations are associated with threats or safety is crucial for survival and adaptive behavior. Understanding the neural substrates of threat and safety learning has high clinical significance because deficits in these forms of learning characterize anxiety disorders. Traditionally, dopamine neurons were thought to uniformly support reward learning by signaling reward prediction errors. However, the dopamine system is functionally more diverse than was initially appreciated and is also critical for processing threat and safety. In this review, I highlight recent studies demonstrating that dopamine neurons generate prediction errors for threat and safety, and describe how dopamine projections to the amygdala, medial prefrontal cortex (mPFC), and striatum regulate associative threat and safety learning. [ABSTRACT FROM AUTHOR]

• Female rats show faster and more effective trauma extinction than males. • Shock reminder reactivates fear memory only in male rats. • Ultrasonic vocalizations mirror fear behavior profiles in both sexes. • Study underscores the need for female inclusion in preclinical PTSD research. Post-Traumatic Stress Disorder (PTSD) is a complex psychiatric condition arising from traumatic experiences, marked by abnormal fear memories. Despite women are twice as likely as men to develop PTSD, the biological mechanisms underlying this disparity remain inadequately explored, particularly in preclinical studies involving female subjects. Previous research shows that female rats exhibit active fear responses, while males display passive behaviors. Additionally, sex differences in ultrasonic vocalizations (USVs) during fear conditioning have been observed, indicating varying emotional responses. Here, we validated a traumatic stress model consisting of footshock exposure paired with social isolation − originally developed in male rats − on females for the first time, focusing on sex differences in fear memory expression, retention and extinction. Our findings reveal that only during trauma exposure, males predominantly exhibited passive responses, whereas females demonstrated more active responses, despite both sexes emitting similar numbers of alarm USVs. Females also showed lower levels of freezing and USV emissions throughout extinction sessions and displayed a higher extinction rate compared to males. Notably, only males displayed a conditioned fear response when triggered by a single mild stressor. These findings highlight sex differences in trauma responses and fear memory processes. The study emphasizes the importance of incorporating 22-kHz USV evaluations along with other behavioral metrics for a comprehensive understanding of fear memory. This research contributes to the existing literature on traumatic stress models as well as underscores the necessity of including female subjects in preclinical studies to better inform treatment and prevention strategies tailored to both sexes. [ABSTRACT FROM AUTHOR]

We conducted a meta-analysis and qualitative review on the randomized controlled trials investigating the effects of transcranial direct current stimulation and transcranial magnetic stimulation on fear extinction and the return of fear in non-primate animals and humans. The meta-analysis was conducted by searching PubMed, Web of science, PsycINFO, and Cochrane Library and extracting fear response in the active and sham groups in the randomized controlled trials. The pooled effect size was quantified by Hedges' g using a three-level meta-analytic model in R. We identified 18 articles on the tDCS effect and 5 articles on the TMS effect, with 466 animal subjects and 621 human subjects. Our findings show that tDCS of the prefrontal cortex significantly inhibit fear retrieval in animal models (Hedges' g = -0.50). In human studies, TMS targeting the dorsolateral/ventromedial prefrontal cortex has an inhibiting effect on the return of fear (Hedges' g = -0.24). The limited number of studies and the heterogeneous designs of the selected studies made cross-study and cross-species comparison difficult. Our findings shed light on the optimal non-invasive brain stimulation protocols for targeting the neural circuitry of threat extinction in humans. [ABSTRACT FROM AUTHOR]

Fear extinction is a fundamental component of exposure-based therapies for anxiety-related disorders. The renewal of fear in a different context after extinction highlights the importance of contextual factors. In this study, we aimed to investigate the causal role of the left inferior frontal gyrus (LiFG) in the context-dependency of fear extinction learning via administration of transcranial direct current stimulation (tDCS) over this area. 180 healthy subjects were assigned to 9 groups: 3 tDCS conditions (anodal, cathodal, and sham) × 3 context combinations (AAA, ABA, and ABB). The fear conditioning/extinction task was conducted over three consecutive days: acquisition, extinction learning, and extinction recall. tDCS (2 mA, 10min) was administered during the extinction learning phase over the LiFG via a 4-electrode montage. Skin conductance response (SCR) data and self-report assessments were collected. During the extinction learning phase, groups with excitability-enhancing anodal tDCS showed a significantly higher fear response to the threat cues compared to cathodal and sham stimulation conditions, irrespective of contextual factors. This effect was stable until the extinction recall phase. Additionally, excitability-reducing cathodal tDCS caused a significant decrease of the response difference between the threat and safety cues during the extinction recall phase. The self-report assessments showed no significant differences between the conditions throughout the experiment. Independent of the context, excitability enhancement of the LiFG did impair fear extinction, and led to preservation of fear memory. In contrast, excitability reduction of this area enhanced fear extinction retention. These findings imply that the LiFG plays a role in the fear extinction network, which seems to be however context-independent. • Using multiple contextual conditions and tDCS to assess the role of the left inferior frontal gyrus in fear extinction. • tDCS over the left inferior frontal gyrus affected fear extinction independent of context. • tDCS polarity determined the directionality of effects on extinction, and recall. [ABSTRACT FROM AUTHOR]

Understanding why only a subset of trauma-exposed individuals develop posttraumatic stress disorder is critical for advancing clinical strategies. A few behavioral (deficits in fear extinction) and biological (blunted glucocorticoid levels, small hippocampal size, and rapid-eye-movement sleep [REMS] disturbances) traits have been identified as potential vulnerability factors. However, whether and to what extent these traits are interrelated and whether one of them could causally engender the others are not known. In a genetically selected rat model of reduced corticosterone responsiveness to stress, we explored posttraumatic stress disorder–related biobehavioral traits using ex vivo magnetic resonance imaging, cued fear conditioning, and polysomnographic recordings combined with in vivo photometric measurements. We showed that genetic selection for blunted glucocorticoid responsiveness led to a correlated multitrait response, including impaired fear extinction (observed in males but not in females), small hippocampal volume, and REMS disturbances, supporting their interrelatedness. Fear extinction deficits and concomitant disruptions in REMS could be normalized through postextinction corticosterone administration, causally implicating glucocorticoid deficiency in two core posttraumatic stress disorder–related risk factors and manifestations. Furthermore, reduced REMS was accompanied by higher norepinephrine levels in the hippocampal dentate gyrus that were also reversed by postextinction corticosterone treatment. Our results indicate a predominant role for glucocorticoid deficiency over the contribution of reduced hippocampal volume in engendering both REMS alterations and associated deficits in fear extinction consolidation, and they causally implicate blunted glucocorticoids in sustaining neurophysiological disturbances that lead to fear extinction deficits. [ABSTRACT FROM AUTHOR]

The hippocampus (HPC) plays a pivotal role in fear learning and memory. Our two recent studies suggest that rapid eye movement (REM) sleep via the HPC downregulates fear memory consolidation and promotes fear extinction. However, it is not clear whether and how the dorsal and the ventral HPC regulates fear memory differently; and how the HPC in wake regulates fear memory. By chemogenetic stimulating in the HPC directly and its afferent entorhinal cortex that selectively activated the HPC in REM sleep for 3-6 h post-fear-acquisition, we found that HPC activation in REM sleep consolidated fear extinction memory. In particular, dorsal HPC (dHPC) stimulation in REM sleep virtually eliminated fear memory by enhancing fear extinction and reducing fear memory consolidation. By contrast, chemogenetic stimulating HPC afferent the supramammillary nucleus (SUM) induced 3-hr wake with HPC activation impaired fear extinction. Finally, desipramine (DMI) injection that selectively eliminated REM sleep for >6 h impaired fear extinction. Our results demonstrate that the HPC is critical for fear memory regulation; and wake HPC and REM sleep HPC have an opposite role in fear extinction of respective impairment and consolidation. • HPC activation in REM sleep consolidated fear extinction memory. • The dorsal HPC stimulation in REM sleep eliminated fear memory by enhancing fear extinction and reducing fear memory consolidation. • Wake HPC and REM HPC have an opposite role in fear extinction of respective impairment and consolidation. [ABSTRACT FROM AUTHOR]

Transcranial focused ultrasound (tFUS) neuromodulation emerges as a promising non-invasive approach for improving neurological conditions. Extinction of conditioned fear has served as a prime model for exposure-based therapies for anxiety disorders. We investigated whether tFUS stimulation to a critical brain area, the infralimbic subdivision of the prefrontal cortex (IL), could facilitate fear extinction using rats. In a series of experiments, tFUS was delivered to the IL of a freely-moving rat and compared to sham stimulation (tFUS vs. SHAM). Initially, Fos expression in the IL was measured shortly after the stimulation. The results show that Fos expression was significantly increased in the IL but not in the neighboring regions compared to SHAM. Subsequently, two groups of rats were subjected to fear conditioning, extinction, and retention while receiving stimulation during the extinction. Rats in the tFUS group froze significantly less than SHAM during both extinction and retention tests. Importantly, the reduced freezing in the tFUS group was not attributable to non-specific effect such as auditory noise, as both groups demonstrated a similar level of locomotive activity in an open field regardless of the stimulation condition. Finally, we replicated the procedure with a shortened conditioning-to-extinction interval (15 min) to induce immediate extinction deficit. The tFUS group showed a facilitated reduction in freezing during the extinction, which persisted in the subsequent retention session compared to SHAM. In summary, the current findings suggest that tFUS stimulation in the IL facilitates fear extinction, offering a potential therapeutic regimen for fear-related psychiatric disorders. • tFUS stimulation in the IL facilitates fear extinction. • tFUS stimulation promotes Fos expression in the IL. • tFUS stimulation ameliorates immediate extinction deficit. [ABSTRACT FROM AUTHOR]

The ventromedial prefrontal cortex has been viewed as a locus for storage and recall of extinction memory. However, the synaptic and cellular mechanisms underlying these processes remain elusive. We combined transgenic mice, electrophysiological recording, activity-dependent cell labeling, and chemogenetic manipulation to analyze the role of adaptor protein APPL1 in the ventromedial prefrontal cortex in fear extinction retrieval. We found that both constitutive and conditional APPL1 knockout decreased NMDA receptor (NMDAR) function in the ventromedial prefrontal cortex and impaired fear extinction retrieval. Moreover, APPL1 undergoes nuclear translocation during extinction retrieval. Blocking APPL1 nucleocytoplasmic translocation reduced NMDAR currents and disrupted extinction retrieval. We also identified a prefrontal neuronal ensemble that is both necessary and sufficient for the storage of extinction memory. Inducible APPL1 knockout in this ensemble abolished NMDAR-dependent synaptic potentiation and disrupted extinction retrieval, while chemogenetic activation of this ensemble simultaneously rescued the impaired behaviors. Our results indicate that a prefrontal neuronal ensemble stores extinction memory, and APPL1 signaling supports these neurons in retrieving extinction memory by controlling NMDAR-dependent potentiation. [ABSTRACT FROM AUTHOR]

Mild traumatic brain injury (mTBI) and post-traumatic stress disorder (PTSD) have emerged as the signature injuries of the U.S. veterans who served in Iraq and Afghanistan, and frequently co-occur in both military and civilian populations. To better understand how fear learning and underlying neural systems might be altered after mTBI, we examined the acquisition of cued fear conditioning and its extinction along with brain morphology and dendritic plasticity in a mouse model of mTBI. To induce mTBI in adult male C57BL/6J mice, a lateral fluid percussive injury (LFP 1.7) was produced using a fluid pulse of 1.7 atmosphere force to the right parietal lobe. Behavior in LFP 1.7 mice was compared to behavior in mice from two separate control groups: mice subjected to craniotomy without LFP injury (Sham) and mice that did not undergo surgery (Unoperated). Following behavioral testing, neural endpoints (dendritic structural plasticity and neuronal volume) were assessed in the basolateral nucleus of the amygdala (BLA), which plays a critical sensory role in fear learning, and medial prefrontal cortex (mPFC), responsible for executive functions and inhibition of fear behaviors. No gross motor abnormalities or increased anxiety-like behaviors were observed in LFP or Sham mice after surgery compared to Unoperated mice. We found that all mice acquired fear behavior, assessed as conditioned freezing to auditory cue in a single session of 6 trials, and acquisition was similar across treatment groups. Using a linear mixed effects analysis, we showed that fear behavior decreased overall over 6 days of extinction training with no effect of treatment group across extinction days. However, a significant interaction was demonstrated between the treatment groups during within-session freezing behavior (5 trials per day) during extinction training. Specifically, freezing behavior increased across within-session extinction trials in LFP 1.7 mice, whereas freezing behavior in control groups did not change on extinction test days, reflecting a dissociation between within-trial and between-trial fear extinction. Additionally, LFP mice demonstrated bilateral increases in dendritic spine density in the BLA and decreases in dendritic complexity in the PFC. The translational implications are that individuals with TBI undergoing fear extinction therapy may demonstrate within-session aberrant learning that could be targeted for more effective treatment interventions. • TBI mouse model showed normal between-session fear extinction (FE) vs. controls. • However, within-session freezing for TBI mice was increased during FE vs. controls. • The TBI group had reduced dendritic arborizations in prefrontal cortex (PFC). • The TBI group showed greater basolateral amygdalar (BLA) spine density vs. controls. • TBI produced aberrant FE with reciprocal changes in dendrites in PFC and BLA. [ABSTRACT FROM AUTHOR]

The relationship between structural characteristics and extinction-induced brain activations in anxiety disorders (ANX) remains a space for greater exploration. In this study, we assessed gray matter volume (GMV) and its associated functional activations during fear extinction memory recall in an ANX cohort. We performed voxel-based morphometry analysis to examine GMVs from ANX (n = 92) and controls (n = 73). We further examined the correlation between GMVs and extinction-induced neural activations during recall across groups. In the patients' group, we observed decreased GMV in the anterior hippocampus and increased GMV in the dorsolateral prefrontal cortex (dlPFC). Hippocampal volume was positively correlated with ventromedial prefrontal cortex activation in healthy controls, while it was negatively correlated with dorsal anterior cingulate cortex (dACC) activation in ANX. The dlPFC volume was positively correlated with activations of dACC, pre- and post-central gyrus, and supramarginal gyrus only in healthy controls. Therefore, the link between structural and functional imbalance within the hippocampus and dlPFC might contribute to the pathophysiology of ANX. In the controls, the relationship between structural variance in the hippocampus and dlPFC and extinction-induced neural activations is consistent with a greater ability to regulate fear responding; associations that were absent in the ANX cohort. Furthermore, our findings of structure-function abnormalities within key nodes of emotional homeostasis in ANX point to dlPFC as a potential neural node to target using neuromodulation tools. • Hippocampus and dlPFC structural alterations observed in anxiety disorders. • Structural alterations associated with extinction-induced functional activations. • Distinct associative patterns between structure and function were noted in controls and patients. [ABSTRACT FROM AUTHOR]

Personality traits linked to internalizing disorders influence the way we develop fears, but also how we regain a sense of safety. In the present study, we investigated the effect of intolerance of uncertainty (IU) on defensive responses using a differential fear conditioning protocol with an extinction phase. The conditioned stimulus was associated with an aversive sound (90 dB) in 75 % of the presentations during acquisition. A final sample of 176 participants completed the experiment. We measured self-reports of associative (expectancy of the unconditioned stimulus in acquisition) and evaluative learning (arousal and valence), and both physiological (skin conductance response) and electrocortical responses (steady-state visually evoked potentials, ssVEPs; late positive potentials, LPP) to the conditioned stimuli. Our results show that IU's impact is limited, with no effect in both acquisition and extinction. These findings emphasize the necessity of large samples in research on inter-individual differences and contribute to our understanding of how IU may or may not be involved in fear and safety learning processes considering multiple aspects of fear responding. • Intolerance of Uncertainty (IU) is marked by discomfort or avoidance of uncertain situations. • Multiple ratings and physiological measures recorded. • IU has no impact on fear acquisition responses. • IU shows no effect during or after the uninstructed extinction phase. [ABSTRACT FROM AUTHOR]

[Display omitted] • Anxioescapic behavior is 'active motor responses in anxiogenic situations'. • Female rats show more anxioescapic behavior and show less freezing behavior during fear extinction compared to males. • Female and male rats have similar fear memory and learning of safety as assessed with avoidance extinction. • Female and male rats have similar unconditioned fear responses. Fear memories are important for survival and are implicated in the etiology of fear disorders such as Post Traumatic Stress Disorder (PTSD). Fear memories are well studied pre-clinically and sex differences in rodent fear expression have been reported: females tend to freeze less than males. Whether this is a difference in fear learning or expression is debated. We aimed to differentiate between these possibilities with a task that allowed female rats to express fear memory by moving, rather than freezing. We assessed fear extinction after contextual fear conditioning in the isolated Shock Arm of a Y-maze in female and male rats by either placing them back in the isolated Shock Arm (Fear Extinction in the Shock Context) or allowing them to move freely in the Y-maze during extinction training and enter/avoid the Shock Arm (Avoidance Extinction). We confirmed that female rats freeze less than males during fear extinction in both settings. During Avoidance Extinction, however, both sexes had similar avoidance of the Shock Context, showing comparable fear memory and extinction. Additionally, female rats made more entries into the non-shock arms. Thus, female and male rats have similar fear learning but females express it with an active motor response. Furthermore, female rats also exhibited an active motor response under other anxiogenic conditions (Elevated Plus Maze) and had higher reactivity (Acoustic Startle Response) but not when fear-eliciting stimuli were present: cat hair and foot-shock. In summary, female rats have an active motor response to anxiogenic stimuli which we termed 'Anxioescapic' behavior strategy. [ABSTRACT FROM AUTHOR]

[Display omitted] • Stimulus salience evaluation is vital to filter important from unimportant information. • Neuropeptide S (NPS) signaling in the paraventricular thalamus is involved in encoding stimulus salience. • NPS influences encoding of aversive, neutral or reinforcing stimuli. • Stimulus salience perception affects subsequent memory formation. • Absence of NPS signaling impedes extinction learning of low-salience stimuli. Evaluation of stimulus salience is critical for any higher organism, as it allows for prioritizing of vital information, preparation of responses, and formation of valuable memory. The paraventricular nucleus of the thalamus (PVT) has recently been identified as an integrator of stimulus salience but the neurochemical basis and afferent input regarding salience signaling have remained elusive. Here we report that neuropeptide S (NPS) signaling in the PVT is necessary for stimulus salience encoding, including aversive, neutral and reinforcing sensory input. Taking advantage of a striking deficit of both NPS receptor (NPSR1) and NPS precursor knockout mice in fear extinction or novel object memory formation, we demonstrate that intra-PVT injections of NPS can rescue the phenotype in NPS precursor knockout mice by increasing the salience of otherwise low-intensity stimuli, while intra-PVT injections of NPSR1 antagonist in wild type mice partially replicates the knockout phenotype. The PVT appears to provide stimulus salience encoding in a dose- and NPS-dependent manner. PVT NPSR1 neurons recruit the nucleus accumbens shell and structures in the prefrontal cortex and amygdala, which were previously linked to the brain salience network. Overall, these results demonstrate that stimulus salience encoding is critically associated with NPS activity in the PVT. [ABSTRACT FROM AUTHOR]

Intolerance of uncertainty is a transdiagnostic risk factor for fear-related disorders and is associated with higher levels of anxiety in children and adolescents. It is unclear how uncertainty relates to development of psychopathology in children who have experienced trauma in early life. The present study used a fear-potentiated startle paradigm in children to examine associations between uncertainty (assessed as unawareness of a change in reinforcement during fear extinction) and symptoms of anxiety and posttraumatic stress disorder (PTSD), as well as startle potentiation to threat and safety cues. Results showed that unaware children had strong positive associations between trauma exposure and PTSD symptoms, whereas aware children did not. Uncertainty interacted with anxiety in that children who were both unaware and had higher anxiety displayed higher fear-potentiated startle to safety cues and did not show discrimination between threat and safety during fear conditioning. These results suggest that anxious children who persist in associating a threat cue with an aversive event during extinction, after repeated presentations of the no longer reinforced conditioned stimulus, may express psychophysiological phenotypes related to PTSD. • A fear-potentiated startle paradigm examined associations between uncertainty and symptoms of anxiety and PTSD in children • Uncertainty was defined as the lack of contingency awareness of the absence of the aversive stimulus during fear extinction • Children who were both unaware and more anxious had higher fear-potentiated startle to safety cues • Trauma exposure was correlated with PTSD symptoms only children that were unaware of the contingency shift • Intolerance of uncertainty may increase risk for psychopathology in children with trauma exposure [ABSTRACT FROM AUTHOR]

Post-traumatic stress disorder (PTSD) is a trauma-related condition that produces distressing fear memory intrusions, avoidance behaviors, hyperarousal/startle, stress responses and insomnia. This review focuses on the importance of the orexin neural system as a novel mechanism related to the pathophysiology of PTSD. Orexinergic neurons originate in the lateral hypothalamus and project widely to key neurotransmitter systems, autonomic neurons, the hypothalamic-pituitary-adrenal (HPA) axis, and fear-related neural circuits. After trauma or stress, the basolateral amygdala (BLA) transmits sensory information to the central nucleus of the amygdala (CeA) and in turn to the hypothalamus and other subcortical and brainstem regions to promote fear and threat behaviors. Orexin receptors have a prominent role in this circuit as fear conditioned orexin receptor knockout mice show decreased fear expression while dual orexin receptor antagonists (DORAs) inhibit fear acquisition and expression. Orexin activation of an infralimbic-amygdala circuit impedes fear extinction while DORA treatments enhance it. Increased orexin signaling to the amygdalo-cortical-hippocampal circuit promotes avoidance behaviors. Orexin has an important role in activating sympathetic nervous system (SNS) activity and HPA axis stress responses. Blockade of orexin receptors reduces fear-conditioned startle responses. In PTSD models, individuals demonstrate sleep disturbances such as increased sleep latency and more transitions to wakefulness. Increased orexin activity impairs sleep by promoting wakefulness and reducing total sleep time while DORA treatments enhance sleep onset and maintenance. The orexinergic neural system provides important mechanisms for understanding multiple PTSD behaviors and provides new medication targets to treat this often persistent and debilitating illness. [ABSTRACT FROM AUTHOR]

Non-invasive brain stimulation targeting the left ventromedial prefrontal cortex (vmPFC) has shown potential in enhancing fear extinction. However, optimal stimulation parameters for clinical application remain unclear. Methods: This study investigated the effects of intermittent theta burst stimulation (iTBS) on fear extinction using a three-day paradigm. Fifty healthy participants underwent fear acquisition (day 1), extinction learning (day 2), and both a spontaneous recovery and reinstatement test (day 3). Active or sham iTBS was applied before extinction learning to the left posterior PFC (MNI: −56, 2, 40), previously shown to be functionally connected to the vmPFC. Fear responses were measured using skin conductance responses (SCR) during CS+ and CS- presentations, along with arousal, valence, and contingency awareness ratings. Results: A significant time x group interaction was found for iTBS administered before extinction learning, with the active group showing reduced SCR during extinction learning compared to sham. However, no TMS effects were observed during the spontaneous recovery or reinstatement tests. Conclusion: These findings suggest limited therapeutic potential for iTBS targeting the left posterior PFC in enhancing extinction memory consolidation. Further research is needed to determine optimal stimulation parameters for clinical application. • iTBS targeting the left PFC before extinction learning showed a trend toward enhanced fear reduction in healthy subjects. • No additional effects were observed during extinction recall 24 hours later. • Targeting the left PFC with iTBS before extinction shows limited therapeutic potential for anxiety disorders. [ABSTRACT FROM AUTHOR]

According to the behavioral tagging theory, various stages of fear memory, such as contextual fear conditioning, memory retrieval, and fear extinction, can be facilitated by the exploration of a novel open field (OF). A critical time window of efficacy exists for this process. Novel exploration closely adjacent to weak learning may interfere with the setting of the learning tag, leading to a negative effect. In this mouse study, we consistently showed that exposure to a novel or familiar OF immediately prior to the retention test impaired the retrieval of long-term contextual fear memory. However, OF exposure had no effect on the retrieval of recent or remote cued fear memory or short-term contextual fear memory or the reconsolidation of contextual fear memory. In addition, OF exposure impaired spaced but not massed extinction of contextual fear memory. These results suggest that interfering stimulus may result in the transient forgetting of fear memory; however, temporary loss of fear may lead to retention failure of fear extinction. The results of this study are an important complement to the behavioral tagging theory and may provide new guidance for the treatment of post-traumatic stress disorder. • OF exposure had no effect on the retrieval of recent or remote cued fear memory. • OF exposure impaired the retrieval of LTM but not STM of contextual fear. • OF exposure had no effect on the reconsolidation of contextual fear memory. • OF exposure impaired spaced, not massed, extinction of contextual fear memory. [ABSTRACT FROM AUTHOR]

Excessive or inappropriate fear responses can lead to anxiety-related disorders, such as post-traumatic stress disorder (PTSD). Studies have shown that microglial activation occurs after fear conditioning and that microglial inhibition impacts fear memory. However, the role of microglia in fear memory recall remains unclear. In this study, we investigated the activated profiles of microglia after the recall of remote-cued fear memory and the role of activated microglia in the extinction of remote-cued fear in adult male C57BL/6 mice. The results revealed that the expression of the microglia marker Iba1 increased in the medial prefrontal cortex (mPFC) at 10 min and 1 h following remote-cued fear recall, which was accompanied by amoeboid morphology. Inhibiting microglial activation through PLX3397 treatment before remote fear recall did not affect recall, reconsolidation, or regular extinction but facilitated recall-extinction and mitigated spontaneous recovery. Moreover, our results demonstrated reduced co-expression of Iba1 and postsynaptic density protein 95 (PSD95) in the mPFC, along with decreases in the p-PI3K/PI3K ratio, p-Akt/Akt ratio, and KLF4 expression after PLX3397 treatment. Our results suggest that microglial activation after remote fear recall impedes fear extinction through the pruning of synapses in the mPFC, accompanied by alterations in the expression of the PI3K/AKT/KLF4 pathway. This finding can help elucidate the mechanism involved in remote fear extinction, contributing to the theoretical foundation for the intervention and treatment of PTSD. • The expression of the microglia marker Iba1 increased in the mPFC following remote-cued fear recall. • Microglial inhibition before remote fear recall facilitated recall-extinction and mitigated spontaneous recovery. • PLX3397 treatment reduced co-expression of Iba1 and postsynaptic density protein 95 in the mPFC. PLX3397 treatment decreased the p-PI3K/PI3K ratio, p-Akt/Akt ratio and KLF4 expression in the mPFC. [ABSTRACT FROM AUTHOR]

Previous studies showed that glucose has beneficial effects on memory function and can enhance contextual fear learning. To derive potential therapeutic interventions, further research is needed regarding the effects of glucose on fear extinction. In two experimental studies with healthy participants (Study 1: N = 68, 39 females; Study 2: N = 89, 67 females), we investigated the effects of glucose on fear extinction learning and its consolidation. Participants completed a differential fear conditioning paradigm consisting of acquisition, extinction, and return of fear tests: reinstatement, and extinction recall. US-expectancy ratings, skin conductance response (SCR), and fear potentiated startle (FPS) were collected. Participants were pseudorandomized and double-blinded to one of two groups: They received either a drink containing glucose or saccharine 20 min before (Study 1) or immediately after extinction (Study 2). The glucose group showed a significantly stronger decrease in differential FPS during extinction (Study 1) and extinction recall (Study 2). Additionally, the glucose group showed a significantly lower contextual anxiety at test of reinstatement (Study 2). Our findings provide first evidence that glucose supports the process of fear extinction, and in particular the consolidation of fear extinction memory, and thus has potential as a beneficial adjuvant to extinction-based treatments. Registered through the German Clinical Trials Registry (https://www.bfarm.de/EN/BfArM/Tasks/German-Clinical-Trials-Register/%5fnode.html ; Study 1: DRKS00010550; Study 2: DRKS00018933). • Glucose administration before extinction leads to faster extinction learning. • Glucose administration after extinction leads to enhanced extinction consolidation. • Glucose affects non-declarative fear memory processes. [ABSTRACT FROM AUTHOR]

Hormone therapy (HT) has failed to improve learning and memory in postmenopausal women according to recent clinical studies; however, the reason for failure of HT in improving cognitive performance is unknown. In our research, we found cognitive flexibility was improved by 17β-Estradiol (E2) in mice 1 week after ovariectomy (OVX ST), but not in mice 3 months after ovariectomy (OVX LT). Isobaric tags for relative and absolute quantitation (iTRAQ) revealed increased cannabinoid receptor interacting protein 1 (CNRIP1) in E2-treated OVX LT mice compared with E2-treated OVX ST mice. Adeno-associated virus 2/9 (AAV2/9) delivery of Cnrip1 short-hairpin small interfering RNA (Cnrip1 -shRNA) rescued the impaired cognitive flexibility in E2 treated OVX LT mice. This effect is dependent on CB1 function, which could be blocked by AM251—a CB1 antagonist. Our results indicated a new method to increasing cognitive flexibility in women receiving HT by disrupting CNRIP1. • Estrogen fails to rescue cognitive flexibility in long-term estrogen-deprived female mice. • CNRIP1 protein is increased in long-term estrogen-deprived female mice compared with short-term group. • Disrupting CNRIP1 rescues cognitive flexibility long-term estrogen-deprived female mice after estrogen treatment. [ABSTRACT FROM AUTHOR]

While effective, exposure therapy can be distressing, which creates problems with treatment acceptance. Can exposure be effectively delivered unconsciously—and thus without causing phobic people to experience distress? No study has tested this hypothesis in a sufficiently rigorous experiment that selected between mechanisms for reducing fear unconsciously. We conducted a psychophysiological experiment of an unconscious exposure intervention to discern its mechanism of therapeutic action. We identified 98 highly spider-phobic participants with a validated fear questionnaire and a Behavioral Avoidance Test in which they gradually approached and exhibited impairment of a live tarantula, which was indicative of a DSM-5 diagnosis of specific phobia. These participants were randomized to viewing unconscious exposure to spiders, visible exposure to spiders, or unconscious exposure to flowers (control). In a novel psychophysiological design, concurrent changes in sympathetic arousal and subjective fear were monitored throughout exposure. Shortly thereafter, phobic participants approached the tarantula again in order to measure exposure-induced changes in real-life avoidance behavior and experienced fear. Unconscious exposure did not induce concurrent changes in sympathetic arousal or subjective fear, and subsequently reduced fear of the tarantula. Visible exposure to the same phobic stimuli, by contrast, induced significant arousal and fear, but did not affect fear of the tarantula. Levels of arousal during exposure moderated effects on fear of the tarantula: lower arousal during unconscious exposure, but not during conscious exposure, predicted greater fear reduction. Unconscious exposure reduces fear by generating new implicit learning of nonaversive, stimulus-response associations that facilitate fear extinction in phobic persons. [ABSTRACT FROM AUTHOR]

• Increasing progesterone is associated with more emotionally negative recall and intrusive memories. • The progesterone effect on intentional recall is enhanced under stress induction. • Estradiol level is positively associated with fear extinction recall. • Future studies should examine progesterone and estradiol concurrently across all menstrual phases and the interaction with stress hormones on emotional memory consolidation. Anxiety and stress-related disorders are more prevalent in women and associated with negative emotional memory consolidation as well as impaired fear extinction recall. Recent research has identified a role of gonadal steroid hormones in influencing emotional memories and fear extinction, however most individual studies have small samples and employed various protocols. A systematic review and meta-analysis were conducted on studies that examined sex hormones (estrogen, progesterone, testosterone, allopregnanolone, dehydroepiandrosterone) on four aspects of memory, namely, intentional recall (k = 13), recognition memory (k = 7), intrusive memories (k = 9), and extinction recall (k = 11). The meta-analysis on natural cycling women revealed that progesterone level was positively associated with negative recall and negative intrusive memories, and this effect on intentional recall was enhanced under stress induction. Estradiol level was positively associated with extinction recall. This study reveals an important role of progesterone and estradiol in influencing emotional memory consolidation. It highlights the need to control for these hormonal effects and examine progesterone and estradiol concurrently across all menstrual phases in future emotional memory paradigms. [ABSTRACT FROM AUTHOR]

Neurocircuitry models of posttraumatic stress disorder (PTSD) suggest specific alterations in brain structures linked with fear conditioning and extinction. Most models assume a unitary pattern of neurocircuitry dysfunction in PTSD and little attention has focused on defining unique profiles of neurocircuitry engagement (i.e., biotypes), despite known clinical heterogeneity in PTSD. Here, we aim to address this gap using a data-driven approach to characterize unique neurocircuitry profiles among women with PTSD. Seventy-six women with PTSD related to assaultive violence exposure competed a task during fMRI that alternated between fear conditioning, where a geometric shape predicted the occurrence of an electric shock, and fear extinction, where the geometric shape no longer predicted electric shock. A multivariate clustering analysis was applied to neurocircuitry patterns constrained within an a priori mask of structures linked with emotion processing. Resulting biotypes were compared on clinical measures of neurocognition, trauma exposure, general mental health symptoms, and PTSD symptoms and on psychophysiological responding during the task. The clustering analysis identified three biotypes (BT), differentiated by patterns of engagement within salience, default mode, and visual processing networks. BT1 was characterized by higher working memory, fewer general mental health symptoms, and low childhood sexual abuse, and lower PTSD symptom severity. BT2 was characterized by lower verbal IQ but better extinction learning as defined by psychophysiology and threat expectancy. BT3 was characterized by low childhood sexual abuse, anxious arousal, and re-experiencing symptoms. Conclusion: This data demonstrates unique profiles of neurocircuitry engagement in PTSD, each associated with different clinical characteristics, and suggests further research defining distinct biotypes of PTSD. Clinicaltrials.gov , https://clinicaltrials.gov/ct2/home , NCT02560389. [ABSTRACT FROM AUTHOR]

• Extinction of auditory-cue fear memory is disrupted in GluN2A TG mice. • NMDAR-dependent LTD at T-LA are reduced in TG mice. • AMPAR internalization are decreased during NMDAR-dependent chem-LTD in TG slices. N-methyl- d -aspartic acid receptor (NMDAR)-dependent synaptic plasticity at the thalamus-lateral amygdala (T-LA) synapses is related to acquisition and extinction of auditory fear memory. However, the roles of the NMDAR GluN2A subunit in acquisition and extinction of auditory fear memory as well as synaptic plasticity at T-LA synapses remain unclear. Here, using electrophysiologic, molecular biological techniques and behavioral methods, we found that the forebrain specific GluN2A overexpression transgenic (TG) mice exhibited normal acquisition but impaired extinction of auditory fear memory. In addition, in vitro electrophysiological data showed normal basal synaptic transmission and NMDAR-dependent long-term potentiation (LTP) at T-LA synapses, but deficit in NMDAR-dependent long-term depression (LTD) at T-LA synapses in GluN2A TG mice. Consistent with the reduced NMDAR-dependent LTD, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) internalization was also weakened during NMDAR-dependent LTD in GluN2A TG mice. Taken together, our findings for the first time indicate that GluN2A overexpression impairs extinction of auditory fear memory and NMDAR-dependent LTD at T-LA synapses, which further confirms the close relationship between NMDAR-dependent LTD and fear extinction. [ABSTRACT FROM AUTHOR]

Cognitive behavioral therapy, rooted in exposure therapy, is currently the primary approach employed in the treatment of anxiety-related conditions, including post-traumatic stress disorder (PTSD). In laboratory settings, fear extinction in animals is a commonly employed technique to investigate exposure therapy; however, the precise mechanisms underlying fear extinction remain elusive. Casein kinase 2 (CK2), which regulates neuroplasticity via phosphorylation of its substrates, has a significant influence in various neurological disorders, such as Alzheimer's disease and Parkinson's disease, as well as in the process of learning and memory. In this study, we adopted a classical Pavlovian fear conditioning model to investigate the involvement of CK2 in remote fear memory extinction and its underlying mechanisms. The results indicated that the activity of CK2 in the medial prefrontal cortex (mPFC) of mice was significantly upregulated after extinction training of remote cued fear memory. Notably, administration of the CK2 inhibitor CX-4945 prior to extinction training facilitated the extinction of remote fear memory. In addition, CX-4945 significantly upregulated the expression of p-ERK1/2 and p-CREB in the mPFC. Our results suggest that CK2 negatively regulates remote fear memory extinction, at least in part, by inhibiting the ERK-CREB pathway. These findings contribute to our understanding of the underlying mechanisms of remote cued fear extinction, thereby offering a theoretical foundation and identifying potential targets for the intervention and treatment of PTSD. • CK2 activity increased in mPFC after extinction training of remote cued fear memory. • CK2 inhibition facilitated the extinction of remote cued fear memory. • Inhibition of CK2 activated the ERK-CREB pathway in the mPFC. [ABSTRACT FROM AUTHOR]

Trauma-based psychotherapy is a first line treatment for post-traumatic stress disorder (PTSD) but not all patients achieve long-term remission. Transcranial direct current stimulation (tDCS) received considerable attention as a neuromodulation method that may improve trauma-based psychotherapy. We explored the effects of repeated anodal tDCS over the prefrontal cortex (PFC) on fear extinction in mice as a preclinical model for trauma-based psychotherapy. We performed auditory fear conditioning with moderate or high shock intensity on C57BL6/J mice. Next, mice received anodal tDCS (0.2 mA, 20 min) or sham stimulation over the PFC twice daily for five consecutive days. Extinction training was performed by repeatedly exposing mice to the auditory cue the day after the last stimulation session. Early and late retention of extinction were evaluated one day and three weeks after extinction training respectively. We observed no significant effect of tDCS on the acquisition or retention of fear extinction in mice subjected to fear conditioning with moderate intensity. However, when the intensity of fear conditioning was high, tDCS significantly lowered freezing during the acquisition of extinction, regardless of the extinction protocol. Moreover, when tDCS was combined with a strong extinction protocol, we also observed a significant improvement of early extinction recall. Finally, we found that tDCS reduced generalized fear induced by contextual cues when the intensity of conditioning is high and extinction training limited. Our data provide a rationale to further explore anodal tDCS over the PFC as potential support for trauma-based psychotherapy for PTSD. • We investigated the effect of repeated anodal tDCS above the PFC on fear extinction. • No significant effect of tDCS on fear extinction after moderate intensity conditioning. • Significant short-term effects of tDCS on fear extinction after high intensity conditioning. • No significant long-term effects of tDCS on retention of fear extinction. • Significant long-term effect of tDCS on contextual fear generalization after high intensity conditioning. [ABSTRACT FROM AUTHOR]

An amorphous formula of curcumin (CUR) has shown to enable an improved bioavailability after ingestion. The aim of this study was to investigate the hypothesis that exogenously administered CUR has an advantage in ameliorating post-traumatic stress disorder at low doses. To this end, Long-Evans rats were dietary exposed to CUR at 0.1% or 0.5% from gestational day 6 to postnatal day (PND) 74 or 77. Offspring exposed to 0.1% CUR revealed facilitation of anti-anxiety-like behavior in the open field test and fear-extinction learning tested during PND 62 to 74, increases in hippocampal granule cells expressing immediate-early gene proteins and a decrease in prelimbic cortical neurons expressing phosphorylated extracellular signal-regulated kinase 1/2 after the last trial of the fear-extinction learning test on PND 74. The constitutive gene expression levels of Gria1, Gria2, Grin2d, Slc17a6, and Slc17a7 were altered in the hippocampal dentate gyrus and amygdala on PND 77. These results suggest alterations in synaptic plasticity to strengthen neural circuits in promoting the behavioral effects by 0.1%-CUR. In contrast, 0.5% CUR revealed a lack of any of the changes in behavioral tests that were observed at 0.1%; however, this dose upregulated oxidative stress and neuroinflammation-related genes in the hippocampal dentate gyrus, and increased neural stem cells and proliferation activity of the subgranular zone in the dentate gyrus. These results suggest a possible preventive use of CUR at low doses in mitigating some stress disorders; however, excessively absorbed doses may prevent behavioral changes by inducing neuroinflammation that affects hippocampal neurogenesis involving neural stem cells. Image, graphical abstract [ABSTRACT FROM AUTHOR]

Altered functional connectivity of the amygdala has been observed in a resting state immediately after fear learning, even one day after aversive exposure. The persistence of increased resting-state functional connectivity (rsFC) of the amygdala has been a critical finding in patients with stress and anxiety disorders. However, longitudinal changes in amygdala rsFC have rarely been explored in healthy participants. To address this issue, we studied the rsFC of the amygdala in two groups of healthy volunteers. The control group participated in three fMRI scanning sessions of their resting state at the first visit, one day, and one week later. The experimental group participated in three fMRI sessions on the first day: a resting state before fear conditioning, a fear extinction session, and a resting state immediately after fear extinction. Furthermore, this group experienced scanning after one day and week. The fear-conditioning paradigm consisted of visual stimuli with a distinct rate of partial reinforcement by electric shock. During the extinction, we presented the same stimuli in another sequence without aversive pairing. In the control group, rsFC maps were statistically similar between sessions for the left and right amygdala. However, in the experimental group, the increased rsFC mainly of the left amygdala was observed after extinction, one day, and one week. The between-group comparison also demonstrated an increase in the left amygdala rsFC in the experimental group. Our results indicate that functional connections of the left amygdala influenced by fear learning may persist for several hours and days in the human brain. • Resting-state amygdala functional connectivity changes after fear extinction. • Altered amygdala connectivity persisted in one week after fear extinction. • The left amygdala exhibited more prominent changes in functional connectivity. [ABSTRACT FROM AUTHOR]

This work describes the characterization of BNC210 (6-[(2,3-dihydro-1 H -inden-2-yl)amino]-1-ethyl-3-(4-morpholinylcarbonyl)-1,8-naphthyridin-4(1 H)-one), a selective, small molecule, negative allosteric modulator (NAM) of α7 nicotinic acetylcholine receptors (α7 nAChR). With the aim to discover a non-sedating, anxiolytic compound, BNC210 was identified during phenotypic screening of a focused medicinal chemistry library using the mouse Light Dark (LD) box to evaluate anxiolytic-like activity and the mouse Open Field (OF) (dark) test to detect sedative and/or motor effects. BNC210 exhibited anxiolytic-like activity with no measurable sedative or motor effects. Electrophysiology showed that BNC210 did not induce α7 nAChR currents by itself but inhibited EC 80 agonist-evoked currents in recombinant GH4C1 cell lines stably expressing the rat or human α7 nAChR. BNC210 was not active when tested on cell lines expressing other members of the cys-loop ligand-gated ion channel family. Screening over 400 other targets did not reveal any activity for BNC210 confirming its selectivity for α7 nAChR. Oral administration of BNC210 to male mice and rats in several tests of behavior related to anxiety- and stress- related disorders, demonstrated significant reduction of these behaviors over a broad therapeutic range up to 500 times the minimum effective dose. Further testing for potential adverse effects in suitable rat and mouse tests showed that BNC210 did not produce sedation, memory and motor impairment or physical dependence, symptoms associated with current anxiolytic therapeutics. These data suggest that allosteric inhibition of α7 nAChR function may represent a differentiated approach to treating anxiety- and stress- related disorders with an improved safety profile compared to current treatments. • BNC210 - an a7 nAChR negative allosteric modulator identified from a focused library built on a GABA A active compound: • Is selective for a7 nAChR and demonstrated anxiolytic-like behavior in rodent tests. • Has antidepressant-like activity in rodent tests. • Enhances fear extinction in mouse model of conditioned fear. • A Phase 2 B PTSD trial with BNC210 has recently reported positive results. [ABSTRACT FROM AUTHOR]

It is assumed that extinction learning is a suitable model for understanding the mechanisms underlying exposure therapy. Furthermore, there is evidence that non-invasive brain stimulation (NIBS) can elevate extinction learning by enhancing frontal brain activity and therefore NIBS can augment symptom reduction during exposure therapy in phobias. But, the underlying processes are still not well established. Open questions arise from NIBS time points and electrode placement, among others. Therefore, we investigated in a 2-day fear conditioning experiment, whether anodal transcranial direct current stimulation (tDCS) of the ventromedial prefrontal cortex (vmPFC) modulates either fear memory consolidation or dampened fear reaction during fear extinction. Sixty-six healthy participants were randomly assigned either to a group that received tDCS after fear acquisition (and before fear memory consolidation), to a group that received tDCS directly before fear extinction, or to a control group that never received active stimulation (sham). Differential skin conductance response (SCR) to CS+ vs. CS- was significantly decreased in both tDCS-groups compared to sham group. Our region of interest, the vmPFC, was stimulated best focally with a lateral anode position and a cathode on the contralateral side. But this comes along with a slightly lateral stimulation of vmPFC depending on whether anode is placed left or right. To avoid unintended effects of stimulated sides the two electrode montages (anode left or right) were mirror-inverted which led to differential effects in SCR and electrocortical (mainly late positive potential [LPP]) data in our exploratory analyses. Results indicated that tDCS-timing is relevant for fear reactions via disturbed fear memory consolidation as well as fear expression, and this depends on whether vmPFC is stimulated with either left- or right-sided anode electrode montage. Electrocortical data can shed more light on the underlying neural correlates and exaggerated LPP seems to be associated with disturbed fear memory consolidation and dampened SCR to CS+ vs. CS-, but solely in the right anode electrode montage. Further open questions addressing where and when to stimulate the prefrontal brain in the course of augmenting fear extinction are raised. [ABSTRACT FROM AUTHOR]

Extinction of conditioned fear is considered a fundamental process in the recovery from posttraumatic stress disorder and anxiety disorders. Sleep, especially rapid-eye-movement (REM) sleep, has been implicated in promoting extinction memory. The orexin system contributes to the regulation of sleep and wakefulness and emotional behaviors. In rodents, administrations of an orexin receptor antagonist following fear extinction training enhanced consolidation of extinction memory. Although orexin antagonists increase sleep, including REM sleep, the possible contribution of sleep to the effects of orexin antagonists on extinction memory has not been examined. Therefore, this study examined the effects of suvorexant, a dual orexin receptor antagonist, on extinction memory and sleep and their associations in mice. C57BL/6 mice underwent sleep recording for 24 h before and after contextual fear conditioning with footshocks and extinction learning during the early light phase or early dark phase. Mice were systemically injected with either 25 mg/kg of suvorexant or vehicle immediately after the extinction session. We found that suvorexant neither altered sleep nor improved extinction memory recall compared with vehicle. The higher percentages of REM sleep during the post-extinction dark phase were associated with lower extinction memory recall and greater freezing responses to the fear context. Results also indicate that animals did not reach complete extinction of fear with the fear extinction training protocol used in this study. These findings suggest that promoting REM sleep may not enhance fear extinction memory when extinction of fear is incomplete. • Suvorexant administered post-extinction training did not enhance extinction memory. • Fear conditioning and extinction during the light phase reduced REM sleep. • Post-extinction suvorexant administration did not alter sleep. • Fear conditioning and extinction during the dark phase increased non-REM sleep. • Higher REM sleep percentages were associated with lower extinction memory recall. [ABSTRACT FROM AUTHOR]

Hormonal contraceptive use can aggravate existing symptoms of anxiety and depression and influence the response to pharmacologic treatment. The impact of hormonal contraceptive use on non-pharmacological treatment efficacy in anxiety disorders is less well explored. Oral contraceptives, which suppress endogenous sex hormone secretion, can alter fear extinction learning. Fear extinction is considered the laboratory proxy of exposure therapy in anxiety disorders. This study set out to examine whether oral contraceptive use is related to exposure-based treatment response in specific phobia. We recruited spider-phobic women (n = 28) using oral contraceptives (OC) and free-cycling women (n =26, No-OC). All participants were subjected to an identical in-vivo exposure. Exposure-based symptom improvement was assessed with several behavioral and subjective indices at pre-treatment, post-treatment and six-weeks follow-up. No–OC women showed higher pre-exposure fear levels on the FSQ and SPQ. OC women showed slightly less pronounced exposure benefit compared to their free-cycling counterparts (No-OC woman) as reflected by lower levels of fear reduction from pre-treatment to follow-up on the subjective level. After correction for multiple testing, OC and No-OC women showed differences in self-report measures (SPQ, FAS and SBQ) from pre- to follow-up treatment but not from pre-to post-treatment. These findings implicate that oral contraceptive use can account for differential exposure-based fear symptom improvement. Our study highlights the importance of monitoring and managing hormonal contraceptives use in the context of non-pharmacological exposure-based interventions. [ABSTRACT FROM AUTHOR]

• Considers methodological comparability of translational research in fear conditioning in rodents and humans. • Equips researchers with practical and methodological considerations across species to foster translational behavioural neuroscience. • Aid designing of future experiments that employ more comparable processes in human participants and laboratory rodents in fear conditioning protocols. • Originates from discussions about fear conditioning protocols used in rodents and humans. Translational neuroscience bridges insights from specific mechanisms in rodents to complex functions in humans and is key to advance our general understanding of central nervous function. A prime example of translational research is the study of cross-species mechanisms that underlie responding to learned threats, by employing Pavlovian fear conditioning protocols in rodents and humans. Hitherto, evidence for (and critique of) these cross-species comparisons in fear conditioning research was based on theoretical viewpoints. Here, we provide a perspective to substantiate these theoretical concepts with empirical considerations of cross-species methodology. This meta-research perspective is expected to foster cross-species comparability and reproducibility to ultimately facilitate successful transfer of results from basic science into clinical applications. [ABSTRACT FROM AUTHOR]

Rodents and humans show an attenuation of fear extinction during adolescence, which coincides with the onset of several psychiatric disorders. Although the ethological relevance and the underlying mechanism are largely unknown, the suppression of fear extinction during adolescence is associated with a diminished plasticity in the glutamatergic neurons of the infralimbic medial prefrontal cortex, a brain region critical for fear extinction. Given the putative effect of synaptic inhibition on glutamatergic neuron activity, we studied whether gamma-aminobutyric acidergic neurons in the infralimbic medial prefrontal cortex are involved in the suppression of fear extinction during adolescence. We assessed membrane and synaptic properties in parvalbumin-positive interneurons (PVINs) and somatostatin-positive interneurons (SSTINs) in male preadolescent, adolescent, and adult mice. The effect of fear conditioning and extinction on PVIN-pyramidal neuron and SSTIN-pyramidal neuron synapses in male preadolescent, adolescent, and adult mice was evaluated using an optogenetic approach. The development of the membrane excitability of PVINs is delayed and reaches maturity only by adulthood, while the SSTIN membrane properties are developed early and remain stable during development from preadolescence to adulthood. Although the synaptic inhibition mediated by PVINs undergoes a protracted development, it does not exhibit a fear behavior–specific plasticity. However, the synaptic inhibition mediated by SSTINs undergoes an adolescence-specific enhancement, and this increased inhibition is suppressed by fear learning but is not restored by extinction training. This altered plasticity during adolescence overlapped with a reduction in calcium-permeable glutamate receptors in SSTINs. The adolescence-specific plasticity in the SSTINs might play a role in fear extinction suppression during adolescence in mice. [ABSTRACT FROM AUTHOR]

Exposure therapy is a first-line treatment for anxiety disorders but remains ineffective in a large proportion of patients. A proposed mechanism of exposure involves inhibitory learning whereby the association between a stimulus and an aversive outcome is suppressed by a new association with an appetitive or neutral outcome. The blood pressure medication losartan augments fear extinction in rodents and may have similar synergistic effects on human exposure therapy, but the exact cognitive mechanisms underlying these effects remain unknown. We used a reinforcement learning paradigm with compound rewards and punishments to test the prediction that losartan augments learning from appetitive relative to aversive outcomes. In a double-blind parallel design, healthy volunteers were randomly assigned to single-dose losartan (50 mg) (n = 28) versus placebo (n = 25). Participants then performed a reinforcement learning task, which simultaneously probes appetitive and aversive learning. Participant choice behavior was analyzed using both a standard reinforcement learning model and analysis of choice switching behavior. Losartan significantly reduced learning rates from aversive events (losses) when participants were first exposed to the novel task environment, while preserving learning from positive outcomes. The same effect was seen in choice switching behavior. This study shows that losartan enhances learning from positive relative to negative events. This effect may represent a computationally defined neurocognitive mechanism by which the drug could enhance the effect of exposure in clinical populations. [ABSTRACT FROM AUTHOR]

• Anterior cingulate and insular cortices are activated by extinction and reappraisal. • Activation in sensory and emotion processing regions is observed in fear extinction. • Cognitive reappraisal recruits the dorsal fronto-parietal network. • Reappraisal differences with extinction partially depend on the regulation strategy. Cognitive reappraisal and fear extinction learning represent two different approaches to emotion regulation. While their respective neural correlates have been widely studied with functional magnetic resonance imaging (fMRI), few direct comparisons between these processes have been conducted. We conducted a meta-analysis of fMRI studies of reappraisal and fear extinction, with the aim of examining both commonalities and differences in their neural correlates. We also conducted independent analyses that focused on specific reappraisal strategies (reinterpretation, distancing). Overall, we observed that the dorsal anterior cingulate cortex (dACC) and the bilateral anterior insular cortex (AIC) were similarly consistently engaged by reappraisal and extinction. Extinction was more consistently linked to activation of sensory and emotion processing regions, whereas reappraisal was more consistently associated with activation of a dorsal fronto-parietal network. Interestingly, the amygdala was preferentially deactivated by distancing. These results suggest that the dACC and the AIC are involved in domain-general regulatory networks. Differences between extinction and reappraisal could be explained by their relative processing demands on visual perceptual versus higher cognitive neural systems. [ABSTRACT FROM AUTHOR]

The prefrontal cortex (PFC) integrates information from multiple inputs to exert top-down control allowing for appropriate responses in a given context. In psychiatric disorders such as posttraumatic stress disorder, PFC hyperactivity is associated with inappropriate fear in safe situations. We previously reported a form of muscarinic acetylcholine receptor (mAChR)–dependent long-term depression in the PFC that we hypothesize is involved in appropriate fear responding and could serve to reduce cortical hyperactivity following stress. However, it is unknown whether this long-term depression occurs at fear-related inputs. Using optogenetics with extracellular and whole-cell electrophysiology, we assessed the effect of mAChR activation on the synaptic strength of specific PFC inputs. We used selective pharmacological tools to assess the involvement of M 1 mAChRs in conditioned fear extinction in control mice and in the stress-enhanced fear-learning model. M 1 mAChR activation induced long-term depression at inputs from the ventral hippocampus and basolateral amygdala but not from the mediodorsal nucleus of the thalamus. We found that systemic M 1 mAChR antagonism impaired contextual fear extinction. Treatment with an M 1 positive allosteric modulator enhanced contextual fear extinction consolidation in stress-enhanced fear learning–conditioned mice. M 1 mAChRs dynamically modulate synaptic transmission at two PFC inputs whose activity is necessary for fear extinction, and M 1 mAChR function is required for proper contextual fear extinction. Furthermore, an M 1 positive allosteric modulator enhanced the consolidation of fear extinction in the stress-enhanced fear-learning model, suggesting that M 1 positive allosteric modulators may provide a novel treatment strategy to facilitate exposure therapy in the clinic for the treatment of posttraumatic stress disorder. [ABSTRACT FROM AUTHOR]

Background and Objectives: In psychoeducation before exposure treatment patients are sometimes provided with information about the (low) probability that the feared outcome would occur. Since it has been proposed in the literature that this might have adverse effects, the current study investigated the effect of providing participants with this type of safety information on return of fear.Method: In an ABA-renewal paradigm, participants in the experimental group were instructed between acquisition and extinction that the probability of US-occurrence would be extremely small in the remainder of the experiment. Participants in the control group did not receive this information.Results: Less return of fear in US-expectancy ratings was observed in participants who received the safety information.Limitations: We failed to find successful acquisition in the skin-conductance data, which prevented us from interpreting the results of this outcome measure.Conclusions: These results suggest that providing safety information is not deleterious for the effects of exposure and can even be beneficial for its effects. However, further clinical research is needed. [ABSTRACT FROM AUTHOR]

• About two thirds of youth with OCD treated with CBT were responders. • Treatment responders and non-responders habituated and acquired conditioned fear in a similar manner. • CBT responders were better able to discriminate in extinction trials between conditioned and control/safety stimuli. • Non-responders showed poorer discrimination between conditioned and control/safety stimuli during early and late extinction. While cognitive behavior therapy (CBT) is an effective treatment for many children and adolescents with Obsessive Compulsive Disorder (OCD), therapeutic response is variable. Fear conditioning and extinction are central constructs underlying exposure-based CBT. Fear extinction learning assessed prior to CBT may be a useful predictor of CBT response for guiding treatment decisions. Sixty-four youth who participated in a randomized placebo-controlled trial of CBT with and without d-cycloserine (DCS) completed a fear conditioning task. Skin conductance response (SCR) scores were used to measure fear acquisition and extinction to determine whether extinction learning could predict CBT response. CBT responders and non-responders appeared to acquire conditioned fear SCRs in a similar manner. However, differences between treatment responders and non-responders emerged during the extinction phase. A responder (responder, non-responder) by conditioned stimulus type (CS+, CS−) interaction showed that CBT responders differentiated the stimulus paired with (CS+) and without (CS−) the unconditioned stimulus correctly during early and late extinction, whereas the CBT non-responders did not (p =.004). While the small sample size makes conclusions tentative, this study supports an emerging literature that differential fear extinction may be an important factor underlying clinical correlates of pediatric OCD, including CBT response. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • AGIQ enhanced fear extinction learning at the 3rd extinction trial. • AGIQ upregulated neuronal plasticity-related gene products in brain regions. • AGIQ upregulated Kif21b , encoding a memory-rewriting molecule in the hippocampus. • AGIQ exposure may mitigate some stress disorders. Abstract This study investigated the effect of exogenously administered polyphenolic antioxidant, α-glycosyl isoquercitrin (AGIQ), on neural function in rats following dietary exposure at 0.5% from gestational day 6 to postnatal day 77, in comparison with nonpolyphenolic α-lipoic acid (ALA) at 0.2%. AGIQ-exposed offspring revealed enhanced fear extinction learning at the 3rd trial and transcript upregulation of Fos and Kif21b in the hippocampal dentate gyrus and Grin2d in the amygdala. AGIQ also increased the number of FOS-immunoreactive (+) hippocampal granule cells. While ALA showed fear extinction learning-related transcript expression changes, it changed neither fear extinction learning nor FOS+ cell numbers. The increases of FOS+ cells and Grin2d transcripts by AGIQ suggested an association with increase of synaptic plasticity, leading to enhancement of fear extinction learning. AGIQ may also upregulate KIF21B, a recently identified memory-rewriting molecule. The present study findings suggest a possible therapeutic use of AGIQ in mitigating some stress disorders. [ABSTRACT FROM AUTHOR]

In chronic pain, pain-related fear seems to overgeneralize to safe stimuli, thus contributing to excessive fear and avoidance behavior. Evidence shows that pain-related fear can be acquired and generalized based on conceptual knowledge. Using a fear conditioning paradigm, we investigated whether this concept-based pain-related fear could also be extinguished. During acquisition, exemplars of 1 action category (conditioned stimuli [CSs]; eg, opening boxes) were followed by pain (CS+), whereas exemplars of another action category were not (CS-; eg, closing boxes). Participants reported more pain-related fear and expectancy toward exemplars of the CS+ category compared with those of the CS- category. During generalization, fear and expectancy spread to novel exemplars (generalization stimuli [GSs]) of the CS+ category (GS+), but not to those of the CS- category (GS-). During extinction, exemplars of both categories were presented in the absence of pain. At the end of extinction, participants no longer reported elevated fear or expectancy toward CS+ exemplars compared to CS- exemplars. These findings were not replicated in either the eye-blink startle or skin conductance measures. This is the first study to demonstrate extinction of concept-based pain-related fear, thus providing evidence for the potential of extinction-based techniques in the treatment of conceptual pain-related fear. PERSPECTIVE: This study demonstrates the acquisition, generalization, and extinction of concept-based pain-related fear in healthy participants. These are the first results to show that concept-based pain-related fear can be extinguished, suggesting that conceptual relationships between fear-inducing stimuli may also be important to consider in clinical practice. [ABSTRACT FROM AUTHOR]

Can mental imagery rather than external stimulation reactivate an aversive conditioned memory for the purposes of attenuating fear with subsequent extinction training? To answer this question participant underwent a three-day protocol: Day 1 entailed fear acquisition training in which two conditioned stimuli were paired with mild shock (US), while a CS- never was; day 2 included imagery-based reactivation of only one of the two CS+ followed by standard extinction training within the reconsolidation ten minutes later; day 3 included reinstatement by the unsignaled presentation of the US followed by a re-extinction phase. We observed no evidence of fear recovery on the first trial of re-extinction for the reminded, mentally imaged, CS+, whereas fear returned for the non-reminded CS+. Thus, mental imagery was sufficient to reactivate a fear memory thereby opening the reconsolidation window and facilitating fear suppression via extinction training. The clinical implications of this are potentially far-reaching as it allows for in vivo reconsolidation procedures in exposure therapy. [ABSTRACT FROM AUTHOR]

Abstract Clinical trials have demonstrated that 3,4-methylenedioxymethamphetamine (MDMA) paired with psychotherapy is more effective at reducing symptoms of post-traumatic stress disorder (PTSD) than psychotherapy or pharmacotherapy, alone or in combination. The processes through which MDMA acts to enhance psychotherapy are not well understood. Given that fear memories contribute to PTSD symptomology, MDMA could augment psychotherapy by targeting fear memories. The current studies investigated the effects of a single administration of MDMA on extinction and reconsolidation of cued and contextual fear memory in adult, male Long-Evans rats. Rats were exposed to contextual or auditory fear conditioning followed by systemic administration of saline or varying doses of MDMA (between 1 and 10 mg/kg) either 30 min before fear extinction training or immediately after brief fear memory retrieval (i.e. during the reconsolidation phase). MDMA administered prior to fear extinction training failed to enhance fear extinction memory, and in fact impaired drug-free cued fear extinction recall without impacting later fear relapse. MDMA administered during the reconsolidation phase, but not outside of the reconsolidation phase, produced a delayed and persistent reduction in conditioned fear. These findings are consistent with a general memory-disrupting effect of MDMA and suggest that MDMA could augment psychotherapy by modifying fear memories during reconsolidation without necessarily enhancing their extinction. Highlights • MDMA impairs cued fear extinction recall without impacting relapse. • Post-retrieval MDMA interferes with reconsolidation of fear memories. • The effects of MDMA on reconsolidation are delayed and persistent. • Clinical efficacy of MDMA could be attributed to modification of fear memory during reconsolidation. [ABSTRACT FROM AUTHOR]

Abstract Fear extinction studies in youth have yielded mixed results due to developmental processes and variations in design, methodology and dependent measures. This systematic review focused on studies with healthy youth between 2 and 17 years of age to identify experimental parameters of studies documenting extinction effects. Thirty-five studies met inclusion criteria and the following themes emerged (a) some studies employed parameters and task demands that are complex and require active participant involvement whereas others involved simple stimulus configurations and passive participant involvement, and (b) variation exists among dependent measures in units of measurement, timing and type of measurement. The review identified that studies using geometric shape conditioned stimuli (CS) paired with a tone unconditioned stimulus (US) (e.g., metal scraping on slate), as well as face CSs with a scream US produced the most reliable extinction effects, although the latter combination may be associated with higher drop-out than shape CSs and a tone US. The most commonly used and effective dependent measures for revealing extinction effects were skin conductance responses (SCR) and subjective ratings (SR) of CS valence, fearfulness and arousal. Fear potentiated startle (FPS) blink reflexes were also an effective but less commonly used measure. It is recommended that future studies use shape CSs and the metal scraping on slate US in studies involving children and either shape CSs and the metal scraping on slate US or face CSs paired with a scream US with adolescents. It is also recommended that US expectancy ratings and CS evaluations are assessed trial-by-trial and between-phase, and that startle-eliciting stimuli to measure startle blink reflexes are delivered on every second trial per CS so that SCR and FPS can be examined. However, further research is required to determine whether increased participant involvement due to providing trial-by-trial and between-phase ratings of the CSs and US differentially influences responding, particularly in children relative to adolescents and adults. Highlights • 35 studies met inclusion criteria of healthy youth in differential fear conditioning studies. • The following themes emerged: o Some have complex tasks requiring active others passive involvement. o Variations exist among dependent measures in units of measurement, timing and type. o Both shape CSs with tone USs and face CSs with a scream US are effective. o Most common dependent measures were SCR and subjective ratings of CS valence. o Fear potentiated startle was also a valid but less commonly used measure. • Multiple measures are recommended for use during testing. • Developed a novel quality assessment instrument for differential fear conditioning and extinction experiments. [ABSTRACT FROM AUTHOR]

Highlights • Studied the effects of post-exposure cortisol administration on exposure therapy outcome. • Employed contextual changes to examine cortisol effects on fear renewal. • Post-exposure cortisol administration did not promote exposure therapy outcome. • Post-exposure cortisol administration led to a stronger fear renewal at long-term. Abstract Cortisol administration prior to treatment can promote the efficacy of exposure-based treatments in specific phobia: cortisol has been proposed to reduce fear retrieval at the beginning of exposure and to enhance the acquisition and consolidation of corrective information learned during exposure. Whether cortisol exerts a beneficial therapeutic effect when given after exposure, e.g., by targeting the consolidation of new corrective information, has not been addressed so far to date. Here, we examined whether post-exposure cortisol administration promotes fear reduction and reduces return of fear following contextual change in specific phobia. Furthermore, the effect of cortisol on return of fear following contextual change (i.e., contextual renewal) was assessed. Patients with spider phobia (N = 43) were treated with a single session of in-vivo exposure, followed by cortisol administration (20 mg hydrocortisone) in a double-blind, placebo-controlled study design. Return of fear was assessed with behavioral approach tests (BATs) in the familiar therapy context (versus a novel unfamiliar context) at one-month and seven-month follow-up assessment. Exposure was effective in reducing fear from pre-treatment to post-treatment (i.e., 24 h after exposure) on fear-related behavioral (approach behavior during the BAT), psychophysiological (heart rate during the BAT) and subjective (fear during the BAT, spider-fear related questionnaires) measures of therapeutic outcome, with no add-on benefit of cortisol administration. Cortisol had no effect on contextual renewal at one-month follow-up. However, in a subsample (N = 21) that returned to the seven-month follow-up, an adverse effect of cortisol on fear renewal was found, with cortisol-treated patients showing an increase in subjective fear at the final approach distance of the BAT from post-treatment to seven-month follow-up. These and previous findings underline the importance of considering the exact timing of cortisol application when used as an add-on treatment for extinction-based psychotherapy: post-exposure cortisol administration does not seem to be effective, but might promote fear renewal at the subjective level. [ABSTRACT FROM AUTHOR]

Abstract Δ9-tetrahydrocannabinol (THC) consumption during adolescence is reported to be a risk factor for the appearance of psychiatric disorders later in life. The interaction between genetic or environmental events and cannabinoid exposure in the adolescent period can also contribute to exacerbate behavioural deficits in adulthood. Here we investigate the effects of THC treatment as well as the consequences of concomitant THC and stress exposure during adolescence in the extinction of fear memory in adult mice. Adolescent mice treated with THC and exposed to stress exhibit impaired cued fear extinction in adulthood. However, no effect was observed in animals exposed to these two factors separately. Notably, resistance to fear extinction was associated with decreased neuronal activity in the basolateral amygdala (BLA) and the infralimbic prefrontal cortex, suggesting a long-term dysregulation of the fear circuit. These changes in neuronal activation were paralleled with structural plasticity alterations. Indeed, an increase of immature dendritic spines in pyramidal neurons of the BLA was revealed in mice simultaneously exposed to THC and stress. Corticosterone levels were also enhanced after the cued fear conditioning session in the same experimental group. These results show that an interaction between cannabis exposure and stress during adolescence may lead to long-term anxiety disorders characterized by the presence of pathological fear. Highlights • Concomitant THC and stress adolescent exposure impairs fear extinction in adulthood. • Concomitant THC and stress adult exposure does not alter fear extinction. • IL and BLA activity is reduced due to simultaneous THC/stress adolescent exposure. • Concomitant THC/stress adolescent exposure alters BLA structural plasticity. [ABSTRACT FROM AUTHOR]

Highlights • Women with varying estradiol levels underwent an impromptu speech task. • Skin conductance was measured in addition to subjective anxiety and affect. • Estradiol was negatively associated with skin conductance but not subjective responses. • Social anxiety was positively associated with subjective responses but not skin conductance. • Measuring avoidance may help clarify the link between estradiol and fear regulation. Abstract Low estradiol is associated with impaired extinction of conditioned physiological fear responses (e.g. skin conductance) in females. As fear extinction is the laboratory basis of exposure therapy for anxiety disorders, it has been speculated that estradiol may be related to the effectiveness of treatment for anxiety. The present study extended past research by examining whether estradiol is related to physiological and subjective fear responses during the impromptu speech task, where participants perform a surprise speech to camera. This task elicits psychosocial fear, and thus has relevance for social anxiety disorder (SAD). We used a quasi-experimental design with two groups of women: 39 naturally cycling women, and 19 women taking hormonal contraceptives. Based on the measured serum levels, naturally cycling women were further divided into women with higher- vs. lower estradiol levels. Compared to those with higher estradiol, women with lower estradiol, and those using hormonal contraceptives (chronically suppressed estradiol) displayed higher speech-elicited skin conductance yet reported no differences in subjective anxiety or affect. Conversely, irrespective of estradiol status, compared to those with low self-reported social anxiety, participants with higher social anxiety exhibited greater subjective anxiety and affect, yet no differences in skin conductance. These results demonstrate that the relationship between estradiol and physiological fear responses extends to psychosocial tasks. However, the dissociations between physiological and subjective measures highlight the need to consider the relevance of different response outputs so that the potential impact of estradiol on the treatment of anxiety disorders can be better understood. [ABSTRACT FROM AUTHOR]

Abstract Posttraumatic stress disorder is characterized by contextually inappropriate, dys-regulated and generalized fear expression and often resistant to therapy. The hippocampus integrates contextual information into spatial and emotional memories, but how diverse modulatory neurotransmitters are shaping this process is not known. Neuropeptide Y is a peptide-neurotransmitter, which modulates hippocampal excitability by activating several G-protein-coupled receptors. Postsynaptic Y1 receptors create strong anxiolytic and fear-suppressing behavior, while pre-synaptic Y2 receptors (Y2R) are mainly anxiogenic. The role of Y2Rs in spatial compared to emotional learning is, however, still controversial. Here we show that deletion of Y2Rs increased recall, but delayed extinction of contextual fear. Interestingly, spatial memory in the Barnes maze was enhanced during early and late testing, suggesting that Y2Rs suppress learning by hippocampal and extra-hippocampal mechanisms. To demonstrate sufficiency of hippocampal Y2Rs we performed viral vector-mediated, locally restricted re-expression of Y2Rs in the hippocampus of Y2KO mice. This treatment reduced spatial memory to the level of wildtype mice only during early, but not late recall. Furthermore, contextual fear was reduced, while induction of fear extinction appeared earlier. Our results suggest that hippocampal Y2R signaling inhibits learning in a time- and content-specific way, resulting in an early reduction of spatial memory and in a specific suppression of fear, by reducing fear recall and promoting fear extinction. We thus propose that reduction of hippocampal excitability through pre-synaptic Y2Rs may control the integration of contextual information into developing memories. Highlights • NPY and Y2 receptors are expressed by complementary neuronal populations of the dorsal hippocampus. • Deletion of Y2 receptors increases contextual fear memory, while improving working memory and spatial memory. • Re-expression of Y2 receptors in the dorsal hippocampus of Y2KO mice reduces contextual fear but decreases spatial memory. • NPY may suppress contextual fear via Y2 receptors by inhibiting hippocampal memory processing. [ABSTRACT FROM AUTHOR]

Highlights • One-week adult isolation rearing increased contextual fear memory in female mice. • The isolation rearing did not affect contextual fear memory in males. • The isolation rearing did not affect contextual fear extinction in either sex. Abstract Fear conditioning and extinction is a useful tool for understanding the pathogenesis of fear-related disorders including post-traumatic stress disorder (PTSD) and for developing treatments for them. To investigate the role of sub-brain regions or molecular mechanisms in fear conditioning and extinction, neuroscientists have been employing an optogenetic or in vivo recording technique, in which placement of an optical fiber or an electrode into the brain region of a free-moving mouse is essential. These methods require isolation rearing (at least one week) from the brain surgery to the behavioral test. Although such short-term adult rearing has been shown not to influence fear memory and extinction in males, the effect in females remains unclear. In the present study, we investigated the effect on fear memory and fear extinction of adult isolation rearing during the one week before contextual fear conditioning in both male and female mice. This short-term adult isolation rearing increased fear responses in the contextual fear memory test in females but not in males. On the other hand, the rearing showed no effect on fear responses during fear extinction or the recall test in either sex. In summary, adult short-term isolation rearing enhanced only fear memory, and only in females. [ABSTRACT FROM AUTHOR]

Abstract Fear reinstatement is one of several paradigms designed to measure fear return following extinction, as a laboratory model for the relapse of Posttraumatic Stress Disorder (PTSD) symptoms. Sleep is a key factor in emotional memory consolidation, and here we examined the relationship between sleep quality and fear reinstatement in PTSD, relative to trauma-exposed and non-exposed controls. The Pittsburgh Sleep Quality Index (PSQI) was used as a subjective measure of sleep quality, and skin conductance responses (SCR) and unconditioned stimulus (US)-expectancy ratings were used to index threat responses during a differential fear conditioning, extinction, and reinstatement paradigm. There were no significant between-group differences in the reinstatement of conditioned responding. Sleep disturbance and sleep onset latency were significant moderators between reinstatement of fear and PTSD symptom severity, such that there was a positive relationship between PTSD symptoms and fear reinstatement for higher levels – but not lower levels – of sleep disturbance and sleep onset latency. To our knowledge, this is the first study to investigate PTSD-specific reinstatement patterns and sleep as a boundary condition of reinstatement. Future research using polysomnographic measures of sleep-wave architecture may further clarify the relationship between fear reinstatement and sleep quality in clinical samples with PTSD relative to controls. Highlights • Sleep quality is a key factor in PTSD and fear extinction recall. • Fear reinstatement has not been investigated in PTSD. • PTSD was not associated with impaired fear reinstatement in isolation. • Sleep disturbance and sleep onset latency moderated reinstatement in PTSD. [ABSTRACT FROM AUTHOR]