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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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: 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., Methods: 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., Results: 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)., Limitations: The limited number of studies and the heterogeneous designs of the selected studies made cross-study and cross-species comparison difficult., Conclusions: Our findings shed light on the optimal non-invasive brain stimulation protocols for targeting the neural circuitry of threat extinction in humans., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: 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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

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., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

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., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Rationale: Therapeutic approaches to mitigating traumatic memories have often faced resistance. Exploring safe reconsolidation blockers, drugs capable of reducing the emotional valence of the memory upon brief retrieval and reactivation, emerges as a promising pharmacological strategy. Towards this objective, preclinical investigations should focus on aversive memories resulting in maladaptive outcomes and consider sex-related differences to enhance their translatability., Objectives: After selecting a relatively high training magnitude leading to the formation of a more intense and generalized fear memory in adult female and male rats, we investigated whether two clinically approved drugs disrupting its reconsolidation remain effective., Results: We found resistant reconsolidation impairment by the α 2 -adrenergic receptor agonist clonidine or cannabidiol, a major non-psychotomimetic Cannabis sativa component. However, pre-retrieval administration of D-cycloserine, a partial agonist at the glycine-binding site of the N-methyl-D-aspartate (NMDA) receptor complex, facilitated their impairing effects on reconsolidation. A similar reconsolidation blockade by clonidine or cannabidiol was achieved following exposure to a non-conditioned but generalized context after D-cycloserine administration. This suggests that sufficient memory destabilization can accompany generalized fear expression. Combining clonidine with cannabidiol without potentiating memory destabilization by D-cycloserine was ineffective., Conclusions: These findings highlight the importance of NMDA receptor signaling in memory destabilization and underscore the efficacy of a dual-step pharmacological intervention in attenuating traumatic-like memories, even in a context different from the original learning environment., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: To observe the effects of electroacupuncture (EA) on fear extinction and sleep phase in single prolonged stress (SPS) mice, and explore its mechanism in view of the expression of relevant synaptic proteins., Methods: Thirty-two C57BL/6J male mice were randomly divided into a control group, a model group, an EA group and a paroxetine (PRX) group, with 8 mice in each one. Modified SPS method was used to establish PTSD model in the model group, the EA group and the PRX group. Seven days after modeling completion, in the EA group, the intervention was delivered at "Baihui" (GV 20) and bilateral "Zusanli" (ST 36), with disperse-dense wave, 3 Hz/15 Hz in frequency and 1 mA in current intensity, for 30 min. In the PRX group, paroxetine solution (2.5 g/L) was administered intragastrically (10 mg/kg). The intervention was given once daily and for consecutive 10 days in the above two groups. The fear conditioning task and the elevated plus-maze test were adopted to evaluate the fear extinction and anxiety of the mice in each group. Using Medusa electroencephalogram (EEG) and electromyography (EMG) recording system from rats and mice, the sleep phase was determined in the mice. With Western blot method adopted, the protein expression of the postsynaptic density protein 95 (PSD95), activity-regulated cytoskeleton-associated protein (ARC), brain-derived neurotrophic factor (BDNF), N-methyl-D-aspartic acid receptor 2A (GluN2A), N-methyl-D-aspartic acid receptor 2B (GluN2B) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor 1 (GluA1) in the hippocampus was detected in the mice., Results: Compared with the control group, the freezing time for the fear re-exposure in 3 min to 15 min and the fear extinction in 0 min to 3 min were prolonged ( P <0.05), the fear extinction index decreased ( P <0.05), and the open arm time (OT) of the elevated plus-maze was shortened ( P <0.05) in the model group. When compared with the model group, in the EA group and the PRX group, the freezing time for the fear re-exposure in 3 min to 6 min and 12 min to 15 min, as well as the fear extinction in 0 min to 3 min was shortened ( P <0.05), the fear extinction index increased ( P <0.05); the OT in elevated plus-maze was longer in the mice of the EA group ( P <0.05). The period of wake (Wake) was prolonged ( P <0.05), the non-rapid eye movement period (NREM) and the total sleep time (Sleep) were reduced in the model group ( P <0.05) in comparison with the control group. Compared with the model group, the Wake was declined ( P <0.05), and the NREM and Sleep increased in the EA group and the PRX group ( P <0.05). When compared with the control group, the protein expression of PSD95, ARC, BDNF, GluN2A and GluA1 in the hippocampus decreased ( P <0.05), and that of GluN2B increased ( P <0.05) in the model group. In the EA group and the PRX group, the protein expression of PSD95, ARC, BDNF, GluN2A and GluA1 in the hippocampus was elevated ( P <0.05), and that of GluN2B reduced ( P <0.05) when compared with the model group., Conclusion: Electroacupuncture at "Baihui" (GV 29) and "Zusanli" (ST 36) can ameliorate anxiety-like behavior, fear extinction disorder and abnormal sleep phase in SPS mice, which may be related to the regulation of synaptic transmission and synaptic plasticity expression in the hippocampus.

Objective: Anorexia nervosa (AN) is a pernicious psychiatric disorder which is principally characterized by a fear of weight gain. Notwithstanding the centrality of fear in the psychopathology of AN, controlled assessments of negative valence systems are lacking. Herein we assess fear conditioning in adolescent females with AN., Method: Adolescent girls (M age  = 14.6 years, ±1.57) with DSM-5 diagnoses of AN (N = 25) and age-matched control girls (M age  = 14.8 years, ±1.46) with no DSM-5 diagnoses (N = 25) completed structured clinical interviews and participated in a classical three-phase Pavlovian fear conditioning paradigm. Participants with comorbid anxiety disorders were excluded. Skin conductance response (SCR) was measured, alongside self-reported fear, valence, and fear expectancy ratings., Results: Both groups demonstrated significant differential acquisition across all four measures. Regarding group comparisons, no differences emerged for self-reported fear, valence, and fear expectancy ratings during acquisition, although for SCR, those with AN demonstrated reduced physiological arousal relative to controls. Both groups demonstrated significant differential extinction for unconditioned stimuli (US) expectancy, self-report fear, and self-report valence. No statistically significant group differences were evident during extinction to the conditioned stimuli (CS)+, on any outcome measure. However, controls reported more positive valence to the CS- than those with AN., Conclusions: Contrary to our hypotheses, our preliminary assessment did not find support for elevated fear responding among adolescent girls with AN with regards to fear acquisition or extinction. These data suggest that AN in adolescent girls may not be associated with a heightened propensity to acquire fear, but conversely, may suggest that exposure treatments for AN may be helpful, since extinction learning is intact in AN., Public Significance: AN is characterized by fear-related symptoms, including food and weight-related fear, and behavioral avoidance, yet controlled studies assessing fear learning are limited. Our preliminary assessment of adolescent AN indicates no abnormalities in fear learning among adolescents with AN. These findings may inform existing mechanistic models of AN psychopathology, and the development of exposure-based treatments for AN., (© 2024 Wiley Periodicals LLC.)

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/&#95;node.html; Study 1: DRKS00010550; Study 2: DRKS00018933)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: 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., Methods: 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., Results: 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., Conclusion: 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., Competing Interests: Declaration of competing interest MA Nitsche is a member of Scientific Advisory Boards of Neuroelectrics and Precisis. None of the remaining authors have potential conflicts of interest to be disclosed., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Fear conditioning evokes a physiologic release of glucocorticoids that assists learning. As a cochaperone in the glucocorticoid receptor complex, FKBP51 modulates stress-induced glucocorticoid signaling and may influence conditioned fear responses. This study combines molecular and behavioral approaches to examine whether locally reducing FKBP51 expression in the ventral hippocampus is sufficient to affect fear-related behaviors. We hypothesized that reducing FKBP51 expression in the VH would increase glucocorticoid signaling to alter auditory fear conditioning. Adult male rats were injected with an adeno-associated virus (AAV) vector expressing short hairpin - RNAs (shRNA) targeting FKBP5 into the ventral hippocampus to reduce FKBP5 levels or a control AAV. Infusion of FKBP5-shRNA into the ventral hippocampus decreased auditory fear acquisition and recall. Although animals injected with FKBP5-shRNA showed less freezing during extinction recall, the difference was due to a reduced fear recall rather than improved extinction. Reducing ventral hippocampus FKBP51 did not affect exploratory behavior in either the open field test or the elevated zero maze test but did increase passive behavior in the forced swim test, suggesting that the reduction in auditory fear recall was not due to more active responses to acute stress. Furthermore, lower ventral hippocampus FKBP51 levels did not alter corticosterone release in response to restraint stress, suggesting that the reduced fear recall was not due to lower corticosterone release. Our findings suggest FKBP51 in the ventral hippocampus plays a selective role in modulating fear-learning processes and passive behavioral responses to acute stress rather than hypothalamic-pituitary-adrenal axis reactivity or exploratory responses.

Background: Fear memory extinction is closely related to insomnia. Repetitive transcranial magnetic stimulation (rTMS) is safe and effective for treating insomnia disorder (ID), and it has been shown to be an efficient method for modulating fear extinction. However, whether rTMS can improve fear extinction memory in ID patients remains to be studied. In this study, we specifically aim to (1) show that 1 Hz rTMS stimulation could improve fear extinction memory in ID patients and (2) examine whether changes in sleep mediate this impact., Methods and Design: We propose a parallel group randomised controlled trial of 62 ID participants who meet the inclusion criteria. Participants will be assigned to a real rTMS group or a sham rTMS group. The allocation ratio will be 1:1, with 31 subjects in each group. Interventions will be administered five times per week over a 4-week period. The assessments will take place at baseline (week 0), post-intervention (week 4), and 8-week follow-up (week 8). The primary outcome measure of this study will be the mean change in the Pittsburgh Sleep Quality Index (PSQI) scores from baseline to post-intervention at week 4. The secondary outcome measures include the mean change in skin conductance response (SCR), fear expectation during fear extinction, Insomnia Severity Index (ISI), Zung Self-Rating Anxiety Scale (SAS), and the Zung Self-Rating Depression Scale (SDS)., Discussion: This study will be the first examination of the impact of rTMS on fear memory extinction in ID patients., Trial Registration: Chinese Clinical Trials Register ChiCTR2300076097. Registered on 25 September 2021., (© 2024. The Author(s).)

Rapid eye movement (REM) sleep is known to facilitate fear extinction and play a protective role against fearful memories. 1 , 2 Using calcium imaging, we found in mice that most IL pyramidal neurons are intensively activated during REM sleep. Optogenetically suppressing the IL specifically during REM sleep within a 4-h window after auditory-cued fear conditioning impaired extinction memory consolidation. In contrast, REM-specific IL inhibition after extinction learning did not affect the extinction memory. Whole-cell patch-clamp recordings demonstrated that inactivating IL neurons during REM sleep depresses their excitability. Together, our findings suggest that REM sleep after fear conditioning facilitates fear extinction by enhancing IL excitability and highlight the importance of REM sleep in the aftermath of traumatic events for protecting against traumatic memories.3 , 4 However, the underlying mechanisms by which REM sleep promotes extinction of aversive memories remain largely unknown. The infralimbic cortex (IL) is a key brain structure for the consolidation of extinction memory. 5 Using calcium imaging, we found in mice that most IL pyramidal neurons are intensively activated during REM sleep. Optogenetically suppressing the IL specifically during REM sleep within a 4-h window after auditory-cued fear conditioning impaired extinction memory consolidation. In contrast, REM-specific IL inhibition after extinction learning did not affect the extinction memory. Whole-cell patch-clamp recordings demonstrated that inactivating IL neurons during REM sleep depresses their excitability. Together, our findings suggest that REM sleep after fear conditioning facilitates fear extinction by enhancing IL excitability and highlight the importance of REM sleep in the aftermath of traumatic events for protecting against traumatic memories., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

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., Competing Interests: Conflict of interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Benzodiazepines undermine the success of exposure therapy in humans with anxiety disorders, and impair the long-term memory of fear extinction (the laboratory basis of exposure therapy) in rodents. However, most rodent studies on fear extinction and benzodiazepines have been conducted in male rodents. In female rodents, the estrous cycle influences the consolidation of fear extinction memories and sensitivity to benzodiazepines. In addition, pregnancy leads to long-term changes in the neurobiological, hormonal, and behavioural features of fear extinction, as well as the responsivity to benzodiazepines. Therefore, the present experiments examined the impact of benzodiazepines on fear extinction in female rats with and without reproductive experience. Age-matched nulliparous (no reproductive experience) and primiparous (one prior reproductive experience; tested one-month post-weaning) rats received fear conditioning to a discrete cue. The next day, rats were administered the benzodiazepine diazepam (2 mg/kg, s.c), or vehicle, prior to or immediately after extinction training. Rats were then tested the next day, drug free, for extinction retention. Similar to previous findings in males, diazepam impaired extinction retention in both nulliparous and primiparous rats when administered either pre- or post-extinction training. These findings may have potential clinical implications as they suggest that benzodiazepine use in conjunction with exposure therapy may undermine long-term treatment success in women with and without reproductive experience, although this remains to be tested in human populations. Moreover, these findings are theoretically important when considered in light of previous studies showing dissociable mechanisms of fear extinction in females pre- versus post-pregnancy., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Rationale: Preclinical research suggests that pharmacologically elevating cannabinoid levels may attenuate fear memory expression and enhance fear extinction., Objectives: We studied the effects of cannabidiol (CBD) on fear memory expression and fear re-extinction in 69 patients with panic disorder with agoraphobia or with social anxiety disorder. Moderation by sex, diagnosis, and serotonergic antidepressant (AD) use was explored., Methods: A cued fear conditioning paradigm was applied before the first treatment session with 300 mg CBD/placebo augmented exposure therapy. Study medication was administered orally preceding 8 weekly sessions. Fear acquisition and suboptimal extinction took place prior to the first medication ingestion (T0). After the first medication ingestion (T1), we investigated effects on fear memory expression at retention and fear re-extinction. Subjective fear, shock expectancy, skin conductance, and startle responses to conditioned (CS+) and safety stimulus (CS-) were measured., Results: Across the sample, CBD reduced shock expectancy at retention under low and ambiguous threat of shock, but fear re-extinction at T1 was unaffected by CBD. However, in AD users, re-extinction of subjective fear was impaired in the CBD condition compared to placebo. In female AD users, CBD interfered with safety learning measured with fear-potentiated startle., Conclusions: The current findings provide no evidence for enhanced fear re-extinction by CBD. However, CBD acutely decreased threat expectation at retention, without affecting other indices of fear. More studies are needed to elucidate possible interactions with AD use and sex, as well as potential effects of CBD on threat expectancies., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Laboratory paradigms are widely used to study fear learning in posttraumatic stress disorder (PTSD). Recent basic science models demonstrate that, during fear learning, patterns of activity in large neuronal ensembles for the conditioned stimuli (CS) begin to reinstate neural activity patterns for the unconditioned stimuli (US), suggesting a direct way of quantifying fear memory strength for the CS. Here, we translate this concept to human neuroimaging and test the impact of post-learning dopaminergic neurotransmission on fear memory strength during fear acquisition, extinction, and recall among women with PTSD in a re-analysis of previously reported data., Methods: Participants ( N = 79) completed a context-dependent fear acquisition and extinction task on day 1 and extinction recall tests 24 h later. We decoded activity patterns in large-scale functional networks for the US, then applied this decoder to activity patterns toward the CS on day 1 and day 2., Results: US decoder output for the CS+ increased during acquisition and decreased during extinction in networks traditionally implicated in human fear learning. The strength of US neural reactivation also predicted individuals skin conductance responses. Participants randomized to receive L-DOPA ( n = 43) following extinction on day 1 demonstrated less US neural reactivation on day 2 relative to the placebo group ( n = 28)., Conclusion: These results support neural reactivation as a measure of memory strength between competing memories of threat and safety and further demonstrate the role of dopaminergic neurotransmission in the consolidation of fear extinction memories.

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., Competing Interests: Declaration of competing interest Authors declare none., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

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., Competing Interests: Declaration of competing interest The authors state that there are no existing financial conflicts or personal associations that might seem to have affected the research presented in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Fear extinction is a phenomenon that involves a gradual reduction in conditioned fear responses through repeated exposure to fear-inducing cues. Functional brain connectivity assessments, such as functional magnetic resonance imaging (fMRI), provide valuable insights into how brain regions communicate during these processes. Stress, a ubiquitous aspect of life, influences fear learning and extinction by changing the activity of the amygdala, prefrontal cortex, and hippocampus, leading to enhanced fear responses and/or impaired extinction. Glucocorticoid receptors (GRs) are key to the stress response and show a dual function in fear regulation: while they enhance the consolidation of fear memories, they also facilitate extinction. Accordingly, GR dysregulation is associated with anxiety and mood disorders. Recent advancements in cognitive neuroscience underscore the need for a comprehensive understanding that integrates perspectives from the molecular, cellular, and systems levels. In particular, neuropharmacology provides valuable insights into neurotransmitter and receptor systems, aiding the investigation of mechanisms underlying fear regulation and potential therapeutic targets. A notable player in this context is cortisol, a key stress hormone, which significantly influences both fear memory reconsolidation and extinction processes. Gaining a thorough understanding of these intricate interactions has implications in terms of addressing psychiatric disorders related to stress. This review sheds light on the complex interactions between cognitive processes, emotions, and their neural bases. In this endeavor, our aim is to reshape the comprehension of fear, stress, and their implications for emotional well-being, ultimately aiding in the development of therapeutic interventions.

Fear conditioning paradigms have been studied for over 100 years and are of great interest to the behavioral and clinical sciences given that several safety learning processes (e.g., extinction learning and recall) are thought to be fundamental to the success of exposure-based therapies for anxiety and related disorders. This chapter provides an overview of preclinical and clinical investigations that examined the effects of exercise on initial fear acquisition, fear extinction learning and consolidation, and return of fear outcomes. This chapter highlights the collective body of evidence suggesting that exercise administered after extinction learning enhances the consolidation and subsequent recall of extinction memories to a greater extent than exercise administered prior to extinction learning. This suggests that the addition of exercise after exposure therapy sessions may improve treatment outcomes for people with anxiety and related disorders. Potential mechanisms are discussed in addition to suggestions for future research to improve our understanding of the effects of exercise on fear conditioning and extinction outcomes., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Background: Posttraumatic stress disorder is characterized by deficits in cognitive flexibility related to dysfunction of the medial prefrontal cortex (mPFC). Exposure therapy can effectively reverse these deficits. Fear extinction in rodents bears similarity to exposure therapy. Extinction reverses chronic stress-induced deficits in cognitive flexibility on the attentional set-shifting test (AST), an mPFC-mediated process. This therapeutic effect requires activity of pyramidal neurons and brain derived neurotrophic factor (BDNF) signaling in infralimbic cortex (IL). However, the circuit mechanisms governing BDNF-mediated plasticity initiated by extinction in IL are unknown. The ventral hippocampus (vHipp) plays a role in regulating IL activity during extinction, and plasticity in vHipp is necessary for extinction memory consolidation. Therefore, we investigated the role of vHipp input to IL in the effects of extinction in reversing stress-induced cognitive deficits., Methods: vHipp input to IL was silenced using a Gi-Designer Receptors Exclusively Activated by Designer Drugs (DREADD) via local infusion of clozapine-N-oxide (CNO) into IL before extinction. A day later, rats were tested on AST. In a separate experiment, we tested whether vHipp input to the IL induces BDNF signaling to exert therapeutic effects. We activated the vHipp using a Gq-DREADD, and injected an anti-BDNF neutralizing antibody into IL. Rats were tested on the AST 24 hours later., Results: Silencing the vHipp input to IL prevented the beneficial effects of extinction in reversing stress-induced cognitive deficits. Activating vHipp input to IL in the absence of extinction was sufficient to reverse stress-induced deficits in set-shifting. The beneficial effects were blocked by local infusion of a neutralizing anti-BDNF antibody into IL., Conclusions: vHipp-driven BDNF signaling in IL is critical for extinction to counteract the deleterious cognitive effects of chronic stress., (© The Author(s) 2023. Published by Oxford University Press on behalf of CINP.)

Fear extinction is pivotal for inhibiting fear responding to former threat-predictive stimuli. In rodents, short intervals between fear acquisition and extinction impair extinction recall compared to long intervals. This is called Immediate Extinction Deficit (IED). Importantly, human studies of the IED are sparse and its neurophysiological correlates have not been examined in humans. We, therefore, investigated the IED by recording electroencephalography (EEG), skin conductance responses (SCRs), an electrocardiogram (ECG), and subjective ratings of valence and arousal. Forty male participants were randomly assigned to extinction learning either 10 min after fear acquisition (immediate extinction) or 24 h afterward (delayed extinction). Fear and extinction recall were assessed 24 h after extinction learning. We observed evidence for an IED in SCR responses, but not in the ECG, subjective ratings, or in any assessed neurophysiological marker of fear expression. Irrespective of extinction timing (immediate vs. delayed), fear conditioning caused a tilt of the non-oscillatory background spectrum with decreased low-frequency power (<30 Hz) for threat-predictive stimuli. When controlling for this tilt, we observed a suppression of theta and alpha oscillations to threat-predictive stimuli, especially pronounced during fear acquisition. In sum, our data show that delayed extinction might be partially advantageous over immediate extinction in reducing sympathetic arousal (as assessed via SCR) to former threat-predictive stimuli. However, this effect was limited to SCR responses since all other fear measures were not affected by extinction timing. Additionally, we demonstrate that oscillatory and non-oscillatory activity is sensitive to fear conditioning, which has important implications for fear conditioning studies examining neural oscillations., (© 2023 The Authors. Psychophysiology published by Wiley Periodicals LLC on behalf of Society for Psychophysiological Research.)

Background: 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., Methods: 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., Results: 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., Conclusions: 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., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

The ability to store, retrieve, and extinguish memories of adverse experiences is an essential skill for animals' survival. The cellular and molecular factors that underlie such processes are only partially known. Using chondroitinase ABC treatment targeting chondroitin sulfate proteoglycans (CSPGs), previous studies showed that the maturation of the extracellular matrix makes fear memory resistant to deletion. Mice lacking the cartilage link protein Crtl1 (Crtl1-KO mice) display normal CSPG levels but impaired CSPG condensation in perineuronal nets (PNNs). Thus, we asked whether the presence of PNNs in the adult brain is responsible for the appearance of persistent fear memories by investigating fear extinction in Crtl1-KO mice. We found that mutant mice displayed fear memory erasure after an extinction protocol as revealed by analysis of freezing and pupil dynamics. Fear memory erasure did not depend on passive loss of retention; moreover, we demonstrated that, after extinction training, conditioned Crtl1-KO mice display no neural activation in the amygdala (Zif268 staining) in comparison to control animals. Taken together, our findings suggest that the aggregation of CSPGs into PNNs regulates the boundaries of the critical period for fear extinction., (© 2023. The Author(s).)

Stress has profound effects on fear extinction, a form of learning that is essential to behavioral therapies for trauma-related and stressor-related disorders. Recent work reveals that acute footshock stress reduces medial prefrontal cortex (mPFC) activity that is critical for extinction learning. Reductions in mPFC activity may be mediated by parvalbumin (PV)-containing interneurons via feedforward inhibition imposed by amygdala afferents. To test this hypothesis, footshock stress-induced Fos expression was characterized in PV + and PV - neurons in the prelimbic (PL) and infralimbic (IL) cortices. Footshock stress increased the proportion of PV + cells expressing Fos in both male and female rats; this effect was more pronounced in IL compared with PL. To determine whether PV + interneurons in the mPFC mediate stress-induced extinction impairments, we chemogenetically silenced these neurons before an immediate extinction procedure in PV-Cre rats. Clozapine- N -oxide (CNO) did not affect conditioned freezing during the extinction procedure. However, CNO exacerbated extinction retrieval in both male and female rats with relatively high PL expression of designer receptors exclusively activated by designer drugs (DREADD). In contrast, in rats with relatively high IL DREADD expression, CNO produced a modest facilitation of extinction in the earliest retrieval trials, but in male rats only. Conversely, excitation of IL PV interneurons was sufficient to impair delayed extinction in both male and female rats. Finally, chemogenetic inhibition of IL-projecting amygdala neurons reduced the immediate extinction deficit in male, but not female rats. These results reveal that PV interneurons regulate extinction learning under stress in a sex-dependent manner, and this effect is mediated by amygdaloprefrontal projections. SIGNIFICANCE STATEMENT Stress significantly impairs the memory of fear extinction, a type of learning that is central to behavioral therapies for trauma-based and anxiety-based disorders (e.g., post-traumatic stress disorder). Here we show that acute footshock stress recruits parvalbumin (PV) interneurons in the medial prefrontal cortex (mPFC) of male and female rats. Silencing mPFC PV interneurons or mPFC-projecting amygdala neurons during immediate extinction influenced extinction retrieval in a sex-dependent manner. This work highlights the role for PV-containing mPFC interneurons in stress-induced impairments in extinction learning., (Copyright © 2023 Binette et al.)

Home cage condition influences the central nervous system of experimental animals. However, little is known about the effect of home cage size and bedding material on fear-related behaviors. Thus, in this study, the effects of home cage size (large or small) and/or bedding material (paper or wood) on acquisition, retrieval, extinction, and spontaneous recovery of contextual fear memory were investigated in both male and female mice. The present study demonstrated that males housed in small cages with wood bedding showed a low fear response during fear extinction when compared to males housed in small or large cages with paper bedding. In females, mice housed in small cages with wood bedding showed low fear response during fear conditioning and extinction when compared to mice housed in large cages with paper bedding. Moreover, small cages with wood bedding, but not small or large cages with paper bedding, prevented the spontaneous recovery of fear memory in females. Thus, home cage conditions, and particularly bedding material, influence contextual fear extinction and spontaneous recovery. This finding may help to obtain reproducibility of results by researchers and explain discrepancies of results among research groups., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Exposure therapy is the most effective approach of behavioral therapy for anxiety and post-traumatic stress disorder (PTSD). But fear is easy to reappear even after successful extinction. So, identifying novel strategies for augmenting exposure therapy is rather important. It was reported that exercise had beneficial effects on cognitive and memory deficits. However, whether exercise could affect fear memory, especially for fear extinction remained elusive. Here, our results showed that exposure to acute mild exercise 1 or 2 h before extinction training can augment recent fear extinction retention and 2 h for the remote fear extinction retention. These beneficial effects could be attributed to increased YTHDF1 expression in medial prefrontal cortex (mPFC). Furthermore, by using an AAV-shRNA-based approach to silence YTHDF1 expression via stereotactic injection in prelimbic cortex (PL) or infralimbic cortex (IL), respectively, we demonstrated that silence YTHDF1 in IL, but not in PL, blunted augmentation of exposure therapy induced by acute mild exercise and accompanied with decreased NR2B and GluR1 expression. Moreover, YTHDF1 modulated dendritic spines remodeling of pyramidal neuron in IL. Collectively, our findings suggested that acute mild exercise acted as an effective strategy in augmenting exposure therapy with possible implications for understanding new treatment underlying PTSD., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Anxiety disorders are highly prevalent with an early age of onset. Understanding the aetiology of disorder emergence and recovery is important for establishing preventative measures and optimising treatment. Experimental approaches can serve as a useful model for disorder and recovery relevant processes. One such model is fear conditioning. We conducted a remote fear conditioning paradigm in monozygotic and dizygotic twins to determine the degree and extent of overlap between genetic and environmental influences on fear acquisition and extinction., Methods: In total, 1937 twins aged 22-25 years, including 538 complete pairs from the Twins Early Development Study took part in a fear conditioning experiment delivered remotely via the Fear Learning and Anxiety Response (FLARe) smartphone app. In the fear acquisition phase, participants were exposed to two neutral shape stimuli, one of which was repeatedly paired with a loud aversive noise, while the other was never paired with anything aversive. In the extinction phase, the shapes were repeatedly presented again, this time without the aversive noise. Outcomes were participant ratings of how much they expected the aversive noise to occur when they saw either shape, throughout each phase., Results: Twin analyses indicated a significant contribution of genetic effects to the initial acquisition and consolidation of fear, and the extinction of fear (15, 30 and 15%, respectively) with the remainder of variance due to the non-shared environment. Multivariate analyses revealed that the development of fear and fear extinction show moderate genetic overlap (genetic correlations 0.4-0.5)., Conclusions: Fear acquisition and extinction are heritable, and share some, but not all of the same genetic influences.

The cholinergic system is a critical regulator of Pavlovian fear learning and extinction. As such, we have begun investigating the cholinergic system's involvement in individual differences in cued fear extinction using a transgenic ChAT::Cre rat model. The current study extends behavioral phenotyping of a transgenic ChAT::Cre rat line by examining both freezing behavior and ultrasonic vocalizations (USVs) during a Pavlovian cued fear learning and extinction paradigm. Freezing, 22 kHz USVs, and 50 kHz USVs were compared between male and female transgenic ChAT::Cre+ rats and their wildtype (Cre-) littermates during fear learning, contextual and cue-conditioned fear recall, cued fear extinction, and generalization to a novel tone. During contextual and cued fear recall ChAT::Cre+ rats froze slightly more than their Cre- littermates, and displayed significant sex differences in contextual and cue-conditioned freezing, 22 kHz USVs, and 50 kHz USVs. Females showed more freezing than males in fear recall trials, but fewer 22 kHz distress calls during fear learning and recall. Females also produced more 50 kHz USVs during exposure to the testing chambers prior to tone (or shock) presentation compared with males, but this effect was blunted in ChAT::Cre+ females. Corroborating previous studies, ChAT::Cre+ transgenic rats overexpressed vesicular acetylcholine transporter immunolabeling in basal forebrain, striatum, basolateral amygdala, and hippocampus, but had similar levels of acetylcholinesterase and numbers of ChAT+ neurons as Cre- rats. This study suggests that variance in behavior between ChAT::Cre+ and wildtype rats is sex dependent and advances theories that distinct neural circuits and processes regulate sexually divergent fear responses., (© 2023 The Authors. Genes, Brain and Behavior published by International Behavioural and Neural Genetics Society and John Wiley & Sons Ltd.)

Background: The present study assessed the influence of recurrent social isolation stress on the aversive memory extinction and dopamine D 2 receptors (D 2 R) expression in the amygdala and the hippocampus subnuclei. We also analyzed the expression of epigenetic factors potentially associated with fear extinction: miRNA-128 and miRNA-142 in the amygdala., Methods: Male adult fear-conditioned rats had three episodes of 48 h social isolation stress before each fear extinction session in weeks intervals. Ninety minutes after the last extinction session, the D 2 R expression in the nuclei of the amygdala and the hippocampus (immunocytochemical technique), and mRNA levels for D 2 R in the amygdala were assessed (PCR). Moreover, we evaluated the levels of miRNA-128 and miRNA-142 in the amygdala., Results: It was found that recurrent social isolation stress decreased the fear extinction rate. The extinguished isolated rats were characterized by higher expression of D 2 R in the CA1 area of the hippocampus compared to the extinguished and the control rats. In turn, the isolated group presented higher D 2 R immunoreactivity in the CA1 area compared to the extinguished, the control, and the extinguished isolated animals. Moreover, the extinguished animals had higher expression of D 2 R in the central amygdala than the control and the extinguished isolated rats. These changes were accompanied by the increase in miRNA-128 level in the amygdala in the extinguished isolated rats compared to the control, the extinguished, and the isolated rats. Moreover, the extinguished rats had lower expression of miRNA-128 compared to the control and the isolated animals., Conclusions: Our results suggest that social isolation stress impairs aversive memory extinction and coexists with changes in the D 2 R expression in the amygdala and hippocampus and increased expression of miRNA-128 in the amygdala., (© 2022. The Author(s).)

In the hippocampus, environmental changes elicit rearrangement of active neuronal ensembles or remapping of place cells. However, it remains elusive how the brain ensures a consistent representation of a certain environment itself despite salient events occurring there. Here, we longitudinally tracked calcium dynamics of dorsal hippocampal CA1 neurons in mice subjected to contextual fear conditioning and extinction training. Overall population activities were significantly changed by fear conditioning and were responsive to footshocks and freezing. However, a small subset of neurons, termed environment cells, were consistently active in a specific environment irrespective of experiences. A decoder modeling study showed that these cells, but not place cells, were able to predict the environment to which the mouse was exposed. Environment cells might underlie the constancy of cognition for distinct environments across time and events. Additionally, our study highlights the functional heterogeneity of cells in the hippocampus., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Fear extinction memories are strongly modulated by sex and hormonal status, but the exact mechanisms are still being discovered. In humans, there are some basal and task-related features in which male and female individuals differ in fear conditioning paradigms. However, analyses considering the effects of sex hormones demonstrate a role for estradiol in fear extinction memory consolidation. Translational studies are taking advantage of the convergent findings between species to understand the brain structures implicated. Nevertheless, the human brain is complex and the transfer of these findings into the clinics remains a challenge. The promising advances in the field together with the standardization of fear extinction methodologies in humans will benefit the design of new personalized therapies., (© 2023. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

In the current study, we test for the specificity of deficits in fear acquisition and extinction for the anxiety disorders spectrum. We compared fear acquisition and fear extinction learning between a group of patients with either an anxiety disorder (n = 93) or depression (n = 103) attending for treatment in our outpatient center and a sample of healthy control participants (n = 60). To assess the specificity of the predictive validity of extinction learning and safety learning for the outcome of exposure-based treatments, patients additionally underwent disorder-specific cognitive behavior therapy (CBT). We found only very little evidence for differences in safety or extinction learning between healthy controls and patients with anxiety-disorders or depression using both a group-based categorical analytic approach, as well as a trans-diagnostic, dimensional analytic approach. On the contrary, for anxiety patients only, more favorable extinction learning and more favorable safety learning was associated with more favorable treatment outcome. In sum, this specific prediction of treatment outcome in anxiety patients confirms and extends current theoretical models of exposure-based treatments for anxiety disorders, but does not support the notion of general extinction learning deficits in the anxiety disorders spectrum., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

This chapter reviews the literature on the impact of stress and exercise on fear extinction. Given that key brain regions of the fear circuitry (e.g., hippocampus, amygdala and frontal cortex) can be modulated by stress hormones, it is important to investigate how stress influences this process. Laboratory-based studies performed in healthy adults have yielded mixed results, which are most likely attributable to various methodological factors. Among these factors, inter-individual differences modulating the stress response and timing of stressor administration with respect to the task may contribute to this heterogeneity. Given that fear is a core manifestation of various psychopathologies and that exposure-based therapy relies on fear extinction principles, several studies have attempted to assess the role of stress hormones on exposure-based therapy in patients suffering from post-traumatic stress disorder or anxiety disorders. These studies tend to suggest a beneficial impact of stress hormones (through either natural endogenous variations or synthetic administration) on exposure-based therapy as assessed mostly by subjective fear measures. Similar to stress, exercise can have an impact on many physiological and biological systems in humans. Of note, exercise modulates biomarkers such as brain-derived neurotrophic factor (BDNF) and anandamide (EAE) that act on brain regions implicated in the fear circuitry, supporting the importance of studying the impact of exercise on fear extinction. Overall, the results converge and indicate that fear extinction (tested in the laboratory or via exposure-based therapy in clinical populations) can be enhanced with exercise. Further research is needed to understand the mechanisms by which stress and exercise modulate fear learning and extinction processes, as well as to maximize the applicability to clinical contexts., (© 2023. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Prolonged exposure (PE) therapy aiming to promote fear extinction is a useful treatment for post-traumatic stress disorder (PTSD). However, the mechanisms underlying fear extinction and effective methods used to promote fear extinction in PTSD are still lacking. In this study, we displayed dysfunctions of cyclic adenosine 3,5-monophosphate (cAMP)-protein kinase A (PKA), protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and calcium signaling in peripheral serum of PTSD patients using bioinformatics analysis. Later, we confirmed the dysfunctions of cAMP-PKA, AKT/mTOR and calcium signaling in the hippocampus of PTSD mice. Moreover, the reduction of calpain1 in the hippocampus enhanced fear memory acquisition. Single activation of PKA by systemic application of rolipram (ROL) or meglumine cyclic adenylate (M-cAMP) before re-exposure promoted fear extinction and improved anxiety-like behavior in PTSD mice. Moreover, systemic application of ROL before re-exposure improved hippocampal brain-derived neurotrophic factor (BDNF)/tyrosine kinase receptor B (TrkB) signaling and calpain1/AKT/mTOR signaling. Interestingly, the effects of activation of PKA could be partially blocked by TrkB antagonist, ANA-12 and mTOR inhibitor, RAPA. Finally, intranasal administration of ROL could also adjust the abnormality of fear memory and improve anxiety-like behaviors in PTSD mice. Collectively, activation of PKA could promote fear extinction, which correlated with the reduction of anxiety-like behavior. The mechanisms were related to the BDNF/TrkB and calpain1/AKT/mTOR signaling pathways. PKA activation might be a useful complementary therapy for PE in the symptom elimination of PTSD., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest associated with the manuscript., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Purpose of Review: Exposure therapy is an effective treatment for anxiety-related disorders, but many individuals do not achieve full symptom relief, and return of fear is a common occurrence. Understanding how exposure therapy works enables further development of strategies to improve its effectiveness., Recent Findings: Recent studies have examined mechanisms of exposure-based interventions across multiple levels of analysis, from cognitive and behavioral changes that occur during treatment to the neurobiological mechanisms underlying fear extinction. Belief change and reductions in safety behaviors and avoidance mediate symptom improvements during exposure therapy, suggesting plausible cognitive and behavioral mechanisms. On the neural level, increased activation of prefrontal regions during extinction learning is a likely mechanism of exposure. Improved understanding of the biological mechanisms of exposure have led to exciting developments in clinical research, including pharmacological augmentation, though clinical translation of basic research has produced mixed results. Though still in development, such translational research is a promising future direction for exposure-based interventions., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Exposure therapy is a central component of the first-line treatment for anxiety disorders, a common mental health condition that is twice as prevalent in women relative to men. A key underlying mechanism of exposure therapy is fear extinction, which is an active learning process supported by a neural circuitry that is highly regulated by ovarian hormones. This review synthesises research examining the impact of hormonal contraceptives on laboratory fear extinction tasks in female rats and women, and on exposure therapy in women with anxiety disorders. The evidence indicates that hormonal contraceptives have a detrimental impact on fear extinction and exposure therapy that is consistent across species, and from laboratory to clinical settings. Candidate pathways by which hormonal contraceptives impede fear extinction and exposure therapy include suppression of endogenous ovarian hormones and glucocorticoids, and downregulation of signalling pathways that support extinction learning. Key areas of focus for future research are discussed., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Fear extinction is a learning mechanism that is pivotal for the inhibition of fear responses towards cues or contexts that no longer predict the occurrence of a threat. Failure of fear extinction leads to fear expression under safe conditions and is regarded to be a cardinal characteristic of many anxiety-related disorders and posttraumatic stress disorder. Importantly, the neurotransmitter noradrenaline was shown to be a potent modulator of fear extinction. Rodent studies demonstrated that excessive noradrenaline transmission after acute stress opens a time window of vulnerability, in which fear extinction learning results in attenuated long-term extinction success. In contrast, when excessive noradrenergic transmission subsides, well-coordinated noradrenaline transmission is necessary for the formation of a long-lasting extinction memory. In addition, emerging evidence suggests that the neuropeptide corticotropin releasing hormone (CRF), which strongly regulates noradrenaline transmission under conditions of acute stress, also impedes long-term extinction success. Recent rodent work - using sophisticated methods - provides evidence for a hypothetical mechanistic framework of how noradrenaline and CRF dynamically orchestrate the neural fear and extinction circuitry to attenuate or to improve fear extinction and extinction recall. Accordingly, we review the evidence from rodent studies linking noradrenaline and CRF to fear extinction learning and recall and derive the hypothetical mechanistic framework of how different levels of noradrenaline and CRF may create a time window of vulnerability which impedes successful long-term fear extinction. We also address evidence from human studies linking noradrenaline and fear extinction success. Moreover, we accumulate emerging approaches to non-invasively measure and manipulate the noradrenergic system in healthy humans. Finally, we emphasize the importance of future studies to account for sex (hormone) differences when examining the interaction between fear extinction, noradrenaline, and CRF. To conclude, NA's effects on fear extinction recall strongly depend on the arousal levels at the onset of fear extinction learning. Our review aimed at compiling the available (mainly rodent) data in a neurobiological framework, suited to derive testable hypotheses for future work in humans., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Inappropriate fear expression and failure of fear extinction are commonly seen in patients with post-traumatic stress disorder (PTSD) and obsessive-compulsive disorder (OCD). Among the patients, aberrant and asymmetric activation of the lateral orbitofrontal cortex (lOFC) is reported in some clinical cases. In this study, we aimed to examine the role of lOFC activation in extinction acquisition and explore the potential functional lateralization of lOFC on extinction. We bilaterally or unilaterally activated the lOFC with N-methyl- D -aspartate (NMDA) before fear extinction acquisition in rats. Our data suggested that both left and bilateral lOFC activation interfered with the in-session expression of conditioned fear, whereas activation of the right lOFC did not. In addition, pre-extinction unilateral or bilateral activation of the lOFC, regardless of the side, impaired the acquisition of fear extinction. We also quantified the neuronal activities during the late phase of extinction with immunohistochemical approach. Our data showed that activation of the lOFC increased the neuronal activities on the injection side(s) in the medial prefrontal cortex (mPFC), the lateral amygdala (LA), the basolateral amygdala (BLA; preferentially the non-GABAergic neurons), and the medial intercalated cells (mITC; preferentially the right side). To conclude, aberrant activation of the lOFC during extinction disturbed the excitatory/inhibitory balance of neuronal activities in fear-related brain regions, which interfered with the expression of conditioned fear and impaired the acquisition of fear extinction., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 IBRO. Published by Elsevier Ltd. All rights reserved.)

Background: The BDNF Val66Met single nucleotide polymorphism has been implicated in stress sensitivity and Post-Traumatic Stress Disorder (PTSD) risk. We previously reported that chronic young-adult stress hormone treatment enhanced fear memory in adult BDNF Val66Met mice with the Met/Met genotype. This study aimed to extend this work to fear extinction learning, spontaneous recovery of fear, and neurobiological correlates in the amygdala., Methods: Male and female Val/Val and Met/Met mice received corticosterone in their drinking water during late adolescence to model chronic stress. Following a 2-week recovery period, the mice underwent fear conditioning and extinction training. Immunofluorescent labelling was used to assess density of three interneuron subtypes; somatostatin, parvalbumin and calretinin, within distinct amygdala nuclei., Results: No significant effects of genotype, treatment or sex were found for fear learning. However, adolescent CORT treatment selectively abolished fear extinction of female Met/Met mice. No effect of genotype, sex, or treatment was observed for spontaneous recovery of fear. Significant main effects of genotype and CORT emerged for somatostatin and calretinin cell density, again in females only, further supporting sex-specific effects of the Met/Met genotype and chronic CORT exposure., Conclusion: BDNF Val66Met genotype interacts with chronic adolescent stress hormone exposure to abolish fear extinction in female Met/Met mice in adulthood. This effect was associated with female-specific interneuron dysfunction induced by either genotype or stress hormone exposure, depending on the interneuron subtype. These data provide biological insight into the role of BDNF in sex differences in sensitivity to stress and vulnerability to stress-related disorders in adulthood., Competing Interests: Declaration of competing interest None., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Extinguishing the previously acquired fear is critical for the adaptation of an organism to the ever-changing environment, a process requiring the engagement of GABA A receptors (GABA A Rs). GABA A Rs consist of tens of structurally, pharmacologically, and functionally heterogeneous subtypes. However, the specific roles of these subtypes in fear extinction remain largely unexplored. Here, we observed that in the medial prefrontal cortex (mPFC), a core region for mood regulation, the extrasynaptically situated, δ-subunit-containing GABA A Rs [GABA A (δ)Rs], had a permissive role in tuning fear extinction in male mice, an effect sharply contrasting to the established but suppressive role by the whole GABA A R family. First, the fear extinction in individual mice was positively correlated with the level of GABA A (δ)R expression and function in their mPFC. Second, knockdown of GABA A (δ)R in mPFC, specifically in its infralimbic (IL) subregion, sufficed to impair the fear extinction in mice. Third, GABA A (δ)R-deficient mice also showed fear extinction deficits, and re-expressing GABA A (δ)Rs in the IL of these mice rescued the impaired extinction. Further mechanistic studies demonstrated that the permissive effect of GABA A (δ)R was associated with its role in enabling the extinction-evoked plastic regulation of neuronal excitability in IL projection neurons. By contrast, GABA A (δ)R had little influence on the extinction-evoked plasticity of glutamatergic transmission in these cells. Altogether, our findings revealed an unconventional and permissive role of extrasynaptic GABA A receptors in fear extinction through a route relying on nonsynaptic plasticity. SIGNIFICANCE STATEMENT The medial prefrontal cortex (mPFC) is one of the kernel brain regions engaged in fear extinction. Previous studies have repetitively shown that the GABA A receptor (GABA A R) family in this region act to suppress fear extinction. However, the roles of specific GABA A R subtypes in mPFC are largely unknown. We observed that the GABA A R-containing δ-subunit [GABA A (δ)R], a subtype of GABA A Rs exclusively situated in the extrasynaptic membrane and mediating the tonic neuronal inhibition, works oppositely to the whole GABA A R family and promotes (but does not suppress) fear extinction. More interestingly, in striking contrast to the synaptic GABA A Rs that suppress fear extinction by breaking the extinction-evoked plasticity of glutamatergic transmission, the GABA A (δ)R promotes fear extinction through enabling the plastic regulation of neuronal excitability in the infralimbic subregion of mPFC. Our findings thus reveal an unconventional role of GABA A (δ)R in promoting fear extinction through a route relying on nonsynaptic plasticity., (Copyright © 2022 the authors.)

Fear-based disorders such as post-traumatic stress disorder (PTSD) steepen age-related cognitive decline and double the risk for developing Alzheimer's disease (AD). Because of the seemingly hyperactive properties of fear memories, PTSD symptoms can worsen with age. Perturbations in the synaptic circuitry supporting fear memory extinction are key neural substrates of PTSD. The basolateral amygdala (BLA) is a medial temporal lobe structure that is critical in the encoding, consolidation, and retrieval of fear memories. As little is known about fear extinction memory and BLA synaptic dysfunction within the context of aging and AD, the goal of this study was to investigate how fear extinction memory deficits and basal amygdaloid nucleus (BA) synaptic dysfunction differentially associate in nonpathologic aging and AD in the TgF344AD (TgAD) rat model of AD. Young, middle-aged, and older-aged WT and TgAD rats were trained on a delay fear conditioning and extinction procedure before ex vivo extracellular field potential recording experiments in the BA. Relative to young WT rats, long-term extinction memory was impaired, and in general, was associated with a hyperexcitable BA and impaired LTP in TgAD rats at all ages. In contrast, long-term extinction memory was impaired in aged WT rats and was associated with impaired LTP but not BA hyperexcitability. Interestingly, the middle-aged TgAD rats showed intact short-term extinction and BA LTP, which is suggestive of a compensatory mechanism, whereas differential neural recruitment in older-aged WT rats may have facilitated short-term extinction. As such, associations between fear extinction memory and amygdala deficits in nonpathologic aging and AD are dissociable., (Copyright © 2022 Hernandez et al.)

Anxiety and stress disorders are often characterized by an inability to extinguish learned fear responses. Orexins/hypocretins are involved in the modulation of aversive memories, and dysregulation of this system may contribute to the aetiology of anxiety disorders characterized by pathological fear. The mechanisms by which orexins regulate fear are unknown. Here we investigated the role of the endogenous cannabinoid system in the impaired fear extinction induced by orexin-A (OXA) in male mice. The selective inhibitor of 2-arachidonoylglycerol (2-AG) biosynthesis O7460 abolished the fear extinction deficits induced by OXA. Accordingly, increased 2-AG levels were observed in the amygdala and hippocampus of mice treated with OXA that do not extinguish fear, suggesting that high levels of this endocannabinoid are related to poor extinction. Impairment of fear extinction induced by OXA was associated with increased expression of CB2 cannabinoid receptor (CB2R) in microglial cells of the basolateral amygdala. Consistently, the intra-amygdala infusion of the CB2R antagonist AM630 completely blocked the impaired extinction promoted by OXA. Microglial and CB2R expression depletion in the amygdala with PLX5622 chow also prevented these extinction deficits. These results show that overactivation of the orexin system leads to impaired fear extinction through 2-AG and amygdalar CB2R. This novel mechanism could be of relevance for the development of novel potential approaches to treat diseases associated with inappropriate retention of fear, such as post-traumatic stress disorder, panic anxiety and phobias., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

The prevalence of post-traumatic stress disorder (PTSD) is higher in women than in men. Among both humans and mice, females exhibit higher resistance to fear extinction than males, suggesting that differences between sexes in fear-extinction processes are involved in the pathophysiology of such fear-related diseases. Sex differences in molecular mechanisms underlying fear memory and extinction are unclear. The cannabinoid (CB) system is well known to be involved in fear memory and extinction, but this involvement is based mainly on experiments using male rodents. It is not known whether there are sex differences in the role of the CB system in fear memory and extinction. To explore this possibility, we investigated the effects of pharmacological manipulations of the CB system on the retrieval and extinction of contextual fear memory in male and female mice. WIN55,212-2, a CB receptor (CBR) agonist, augmented the retrieval of fear memory in both sexes, but SR141716 (a CB1R antagonist) did not affect it in either sex. An enhancement of 2-arachidonylglycerol (2-AG, one of the two major endocannabinoids) via JZL184 (an inhibitor of the 2-AG hydrolase monoacylglycerol lipase [MAGL]), augmented the retrieval of fear memory through the activation of CB1R but not CB2R in female mice. In contrast, the enhancement of N-arachidonylethanolamine (AEA, the other major endocannabinoid) via URB597, an inhibitor of an AEA hydrolase (fatty acid amide hydrolase-1) did not show any effects on the retrieval of fear memory in either sex. WIN55,212-2, SR141716, and JZL184 inhibited fear extinction irrespective of sex. URB enhanced fear extinction in females that were in diestrus phase at the first extinction session, but not in males. These results suggest that although the role of CB1R in the retrieval and extinction of contextual fear memory is common among males and females, the effects of an increase in endocannabinoid levels on the retrieval or extinction of contextual fear memory differ between the sexes., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Here, we used RNA capture-seq to identify a large population of lncRNAs that are expressed in the infralimbic prefrontal cortex of adult male mice in response to fear-related learning. Combining these data with cell-type-specific ATAC-seq on neurons that had been selectively activated by fear extinction learning, we find inducible 434 lncRNAs that are derived from enhancer regions in the vicinity of protein-coding genes. In particular, we discover an experience-induced lncRNA we call ADRAM (activity-dependent lncRNA associated with memory) that acts as both a scaffold and a combinatorial guide to recruit the brain-enriched chaperone protein 14-3-3 to the promoter of the memory-associated immediate-early gene Nr4a2 and is required fear extinction memory. This study expands the lexicon of experience-dependent lncRNA activity in the brain and highlights enhancer-derived RNAs (eRNAs) as key players in the epigenomic regulation of gene expression associated with the formation of fear extinction memory., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Learning theories of posttraumatic stress disorder (PTSD) purport that fear-learning processes, such as those that support fear acquisition and extinction, are impaired. Computational models designed to capture specific processes involved in fear learning have primarily assessed model-free, or trial-and-error, reinforcement learning (RL). Although previous studies indicated that aspects of model-free RL are disrupted among individuals with PTSD, research has yet to identify whether model-based RL, which is inferential and contextually driven, is impaired. Given empirical evidence of aberrant contextual modulation of fear in PTSD, the present study sought to identify whether model-based RL processes are altered during fear conditioning among women with interpersonal violence (IPV)-related PTSD (n = 85) using computational modeling. Model-free, hybrid, and model-based RL models were applied to skin conductance responses (SCR) collected during fear acquisition and extinction, and the model-based RL model was found to provide the best fit to the SCR data. Parameters from the model-based RL model were carried forward to neuroimaging analyses (voxel-wise and independent component analysis). Results revealed that reduced activity within visual processing regions during model-based updating uniquely predicted higher PTSD symptoms. Additionally, after controlling for model-based updating, greater value estimation encoding within the left frontoparietal network during fear acquisition and reduced value estimation encoding within the dorsomedial prefrontal cortex during fear extinction predicted greater PTSD symptoms. Results provide evidence of disrupted RL processes in women with assault-related PTSD, which may contribute to impaired fear and safety learning, and, furthermore, may relate to treatment response (e.g., poorer response to exposure therapy)., (© 2021. The Psychonomic Society, Inc.)

Individual differences in the development of uncontrollable fear in response to traumatic stressors have been observed in clinic, but the underlying mechanisms remain unknown. In the present study we first conducted a meta-analysis of published clinical data and found that malondialdehyde, an oxidative stress biomarker, was significantly elevated in the blood of patients with fear-related anxiety disorders. We then carried out experimental study in rats subjected to fear conditioning. We showed that reestablishing redox homeostasis in basolateral amygdale (BLA) after exposure to fear stressors determined the capacity of learned fear inhibition. Intra-BLA infusion of buthionine sulfoximine (BSO) to deplete the most important endogenous antioxidant glutathione (GSH) blocked fear extinction, whereas intra-BLA infusion of dithiothreitol or N-acetylcysteine (a precursor of GSH) facilitated extinction. In electrophysiological studies conducted on transverse slices, we showed that fear stressors induced redox-dependent inhibition of NMDAR-mediated synaptic function, which was rescued by extinction learning or reducing agents. Our results reveal a novel pharmacological strategy for reversing impaired fear inhibition and highlight the role of GSH in the treatment of psychiatric disorders., (© 2021. The Author(s), under exclusive licence to CPS and SIMM.)