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Fear extinction is the basis of exposure therapies for posttraumatic stress disorder (PTSD), but half of patients do not improve. Predicting fear extinction in individuals with PTSD may inform personalized exposure therapy development. The participants were 125 trauma-exposed adults (96 female) with a range of PTSD symptoms. Electromyography, electrocardiogram, and skin conductance were recorded at baseline, during dark-enhanced startle, and during fear conditioning and extinction. Using a cross-validated, hold-out sample prediction approach, three penalized regressions and conventional ordinary least squares were trained to predict fear-potentiated startle during extinction using 50 predictor variables (5 clinical, 24 self-reported, and 21 physiological). The predictors, selected by penalized regression algorithms, were included in multivariable regression analyses, while univariate regressions assessed individual predictors. All the penalized regressions outperformed OLS in prediction accuracy and generalizability, as indexed by the lower mean squared error in the training and holdout subsamples. During early extinction, the consistent predictors across all the modeling approaches included dark-enhanced startle, the depersonalization and derealization subscale of the dissociative experiences scale, and the PTSD hyperarousal symptom score. These findings offer novel insights into the modeling approaches and patient characteristics that may reliably predict fear extinction in PTSD. Penalized regression shows promise for identifying symptom-related variables to enhance the predictive modeling accuracy in clinical research.

Background and purpose: Post-traumatic stress disorder (PTSD) is a mental and physical complication. Fluoxetine (FLX) as a selective serotonin reuptake inhibitor is considered as the first line of treatment for PTSD. Exercise can improve the symptoms of PTSD. The aim of this study was to determine the effects of exercise and FLX on testicular tissue and sex hormones in rats with PTSD. Materials and methods: In this experimental study, 80 adult male rats were divided into two groups: PTSD and healthy. Then, each group was divided into four subgroups: control, exercise, fluoxetine, and fluoxetine + exercise. PTSD was induced by single prolonged stress. Fourteen days after induction of PTSD, moderate forced treadmill exercise was performed for 4 weeks, 5 days/week. Fluoxetine was administered at 10 mg/kg/day dissolved in drinking water for 4 weeks. Four weeks after treatment, the fear extinction test, testicular structure, and testosterone and FSH levels were evaluated. Results: PTSD decreased testosterone level and fear extinction but increased follicle-stimulating hormone. Fluoxetine and exercise had protective effect on testicular damage and also increased testosterone level and extinction index but decreased FSH level. Findings showed that co-administration of exercise and fluoxetine was more effective on these parameters. Combination of exercise and fluoxetine significantly increased fear extinction in PTSD rats (P<0.05). Conclusion: Exercise and fluoxetine had a protective effect on testicular tissue structure and hormonal disorders caused by PTSD and also decreased fear caused by stress, which is one of the symptoms of this disease. [ABSTRACT FROM AUTHOR]

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. [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]

Extinguishing the previously acquired fear is critical for the adaptation of an organism to the ever-changing environment, a process requiring the engagement of GABAA receptors (GABAARs). GABAARs 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 GABAARs [GABAA(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 GABAAR family. First, the fear extinction in individual mice was positively correlated with the level of GABAA(δ)R expression and function in their mPFC. Second, knockdown of GABAA(δ)R in mPFC, specifically in its infralimbic (IL) subregion, sufficed to impair the fear extinction in mice. Third, GABAA(δ)R-deficient mice also showed fear extinction deficits, and re-expressing GABAA(δ)Rs in the IL of these mice rescued the impaired extinction. Further mechanistic studies demonstrated that the permissive effect of GABAA(δ)R was associated with its role in enabling the extinction-evoked plastic regulation of neuronal excitability in IL projection neurons. By contrast, GABAA(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 GABAA receptors in fear extinction through a route relying on nonsynaptic plasticity. [ABSTRACT FROM AUTHOR]

Neurobiological evidence in rodents indicates that threat extinction incorporates reward neurocircuitry. Consequently, incorporating reward associations with an extinction memory may be an effective strategy to persistently attenuate threat responses. Moreover, while there is considerable research on the short-term effects of extinction strategies in humans, the long-term effects of extinction are rarely considered. In a within-subjects fMRI study with both female and male participants, we compared counterconditioning (CC; a form of rewarded-extinction) to standard extinction at recent (24 h) and remote (approximately one month) retrieval tests. Relative to standard extinction, rewarded extinction diminished 24-h relapse of arousal and threat expectancy, and reduced activity in brain regions associated with the appraisal and expression of threat (e.g., thalamus, insula, periaqueductal gray). The retrieval of reward-associated extinction memory was accompanied by functional connectivity between the amygdala and the ventral striatum, whereas the retrieval of standard-extinction memories was associated with connectivity between the amygdala and ventromedial prefrontal cortex (vmPFC). One month later, the retrieval of both standard-extinction and rewarded-extinction was associated with amygdala-vmPFC connectivity. However, only rewarded extinction created a stable memory trace in the vmPFC, identified through overlapping multivariate patterns of fMRI activity from extinction to 24-h and one-month retrieval. These findings provide new evidence that reward may generate a more stable and enduring memory trace of attenuated threat in humans. [ABSTRACT FROM AUTHOR]

Background: 3,4-Methylenedioxymethamphetamine (MDMA) has shown initial promise as an adjunct in psychotherapy to treat posttraumatic stress disorder (PTSD). Its efficacy and safety have been demonstrated across phase I-III studies. However, the mechanism underlying the potential utility of MDMA to treat PTSD in humans has not yet been thoroughly investigated. Preliminary evidence suggests that MDMA may facilitate fear extinction recall, which may be through the release of oxytocin. To test this hypothesis, we examined the efficacy of acute MDMA treatment to enhance fear extinction learning and recall. Methods: We used a two-period, double-blind, randomized, placebo-controlled crossover design in 30 healthy male subjects who received a placebo and a single dose of MDMA (125 mg). Fear extinction was tested using two separate Pavlovian fear conditioning paradigms, one using skin conductance response (SCR), and the other fearpotentiated startle (FPS) to conditioned cues. MDMA treatment occurred after fear conditioning and 2 h before extinction learning. Extinction recall was tested 23 h after MDMA intake. Additional outcome measures included subjective effects, emotion recognition tasks, plasma levels of oxytocin, and pharmacokinetics. Results: Fear conditioning and extinction learning were successful in both fear extinction paradigms (generalized eta-squared [ges] for SCR: 0.08; FPS: 0.07). Compared to placebo treatment, MDMA treatment significantly reduced SCRs to the reinforced conditioned stimulus (CS+) during extinction learning (ges = 0.03) and recall (ges = 0.06). Intensity of the subjective effects of MDMA (good effect, trust, and openness) during extinction learning negatively correlated with the discrimination between CS+ and the safety stimulus (CS-) during recall. MDMA did not influence FPS to conditioned cues. Oxytocin concentration was increased fourfold on average by MDMA during acute effects but was not associated with fear extinction outcomes. Conclusions: MDMA treatment facilitated rapid fear extinction and retention of extinction as measured by SCR to fear cues, in line with animal studies of MDMA facilitation of extinction. However, this effect may be limited to certain forms of learned fear responses, as it was not observed in the extinction model using startle reactivity as the outcome. This study provides further evidence for the facilitation of extinction with MDMA treatment and suggests this may be a component of its efficacy when paired with psychotherapy. [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]

In auditory fear conditioning, experimental subjects learn to associate an auditory conditioned stimulus (CS) with an aversive unconditioned stimulus. With sufficient training, animals fear conditioned to an auditory CS show fear response to the CS, but not to irrelevant auditory stimuli. Although long-term potentiation (LTP) in the lateral amygdala (LA) plays an essential role in auditory fear conditioning, it is unknown whether LTP is induced selectively in the neural pathways conveying specific CS information to the LA in discriminative fear learning. Here, we show that postsynaptically expressed LTP is induced selectively in the CS-specific auditory pathways to the LA in a mouse model of auditory discriminative fear conditioning. Moreover, optogenetically induced depotentiation of the CS-specific auditory pathways to the LA suppressed conditioned fear responses to the CS. Our results suggest that input-specific LTP in the LA contributes to fear memory specificity, enabling adaptive fear responses only to the relevant sensory cue. VIDEO ABSTRACT.

Post-traumatic stress disorder (PTSD) is a debilitating illness characterized by dysfunction in the medial prefrontal cortex (mPFC). Although both pharmacological and cognitive behavioral interventions have shown some promise at alleviating symptoms, high attrition and persistence of treatment-resistant symptoms pose significant challenges that remain unresolved. Specifically, prolonged exposure therapy, a gold standard intervention to treat PTSD, has high dropout rates resulting in many patients receiving less than a fully effective course of treatment. Administering pharmacological treatments together with behavioral psychotherapies like prolonged exposure may offer an important avenue for enhancing therapeutic efficacy sooner, thus reducing the duration of treatment and mitigating the impact of attrition. In this study, using extinction learning as a rat model of exposure therapy, we hypothesized that administering ketamine as an adjunct treatment together with extinction will enhance the efficacy of extinction in reversing stress-induced deficits in set shifting, a measure of cognitive flexibility. Results showed that combining a sub-effective dose of ketamine with a shortened, sub-effective extinction protocol fully reversed stress-induced cognitive set-shifting deficits in both male and female rats. These effects may be due to shared molecular mechanisms between extinction and ketamine, such as increased neuronal plasticity in common circuitry (e.g., hippocampus-mPFC), or increased BDNF signaling. This work suggests that fast-acting drugs, such as ketamine, can be effectively used in combination with behavioral interventions to reduce treatment duration and potentially mitigate the impact of attrition. Future work is needed to delineate other pharmacotherapies that may complement the effects of extinction via shared or independent mechanisms.

Background: 3,4-Methylenedioxymethamphetamine (MDMA) has shown initial promise as an adjunct in psychotherapy to treat posttraumatic stress disorder (PTSD). Its efficacy and safety have been demonstrated across phase I–III studies. However, the mechanism underlying the potential utility of MDMA to treat PTSD in humans has not yet been thoroughly investigated. Preliminary evidence suggests that MDMA may facilitate fear extinction recall, which may be through the release of oxytocin. To test this hypothesis, we examined the efficacy of acute MDMA treatment to enhance fear extinction learning and recall.Methods: We used a two-period, double-blind, randomized, placebo-controlled crossover design in 30 healthy male subjects who received a placebo and a single dose of MDMA (125 mg). Fear extinction was tested using two separate Pavlovian fear conditioning paradigms, one using skin conductance response (SCR), and the other fear-potentiated startle (FPS) to conditioned cues. MDMA treatment occurred after fear conditioning and 2 h before extinction learning. Extinction recall was tested 23 h after MDMA intake. Additional outcome measures included subjective effects, emotion recognition tasks, plasma levels of oxytocin, and pharmacokinetics.Results: Fear conditioning and extinction learning were successful in both fear extinction paradigms (generalized eta–squared [ges] for SCR: 0.08; FPS: 0.07). Compared to placebo treatment, MDMA treatment significantly reduced SCRs to the reinforced conditioned stimulus (CS+) during extinction learning (ges = 0.03) and recall (ges = 0.06). Intensity of the subjective effects of MDMA (good effect, trust, and openness) during extinction learning negatively correlated with the discrimination between CS+ and the safety stimulus (CS−) during recall. MDMA did not influence FPS to conditioned cues. Oxytocin concentration was increased fourfold on average by MDMA during acute effects but was not associated with fear extinction outcomes.Conclusions: MDMA treatment facilitated rapid fear extinction and retention of extinction as measured by SCR to fear cues, in line with animal studies of MDMA facilitation of extinction. However, this effect may be limited to certain forms of learned fear responses, as it was not observed in the extinction model using startle reactivity as the outcome. This study provides further evidence for the facilitation of extinction with MDMA treatment and suggests this may be a component of its efficacy when paired with psychotherapy.Clinical Trial registration:clinicaltrials.gov identifier: NCT03527316

Objective(s): Treatments that reverse deficits in fear extinction are promising for the management of post-traumatic stress disorder (PTSD). 5-Hydroxytryptamine type 3 (5-HT3) receptor is involved in the extinction of fear memories. The present work aims to investigate the role of 5HT3 receptors in the infralimbic part of the medial prefrontal cortex (IL-mPFC) in extinction of conditioned fear in the single prolonged stress (SPS) model of PTSD in rats.Materials and Methods: The effect of SPS administration was evaluated on the freezing behavior in contextual and cued fear conditioning models. After the behavioral tests, levels of 5HT3 transcription in IL-mPFC were also measured in the same animals using the real-time RT-PCR method. To evaluate the possible role of local 5HT3 receptors on fear extinction, conditioned freezing was evaluated in another cohort of animals that received local microinjections of ondansetron (a 5HT3 antagonist) and ondansetron plus a 5HT3 agonist (SR 57227A) after extinction sessions. Results: Our findings showed that exposure to SPS increased the freezing response in both contextual and cued fear models. We also found that SPS is associated with increased expression of 5HT3 receptors in the IL-mPFC region. Ondansetron enhanced the fear of extinction in these animals and the enhancement was blocked by the 5HT3 agonist, SR 57227A.Conclusion: It seems that up-regulation of 5HT3 receptors in IL-mPFC is an important factor in the neurobiology of PTSD and blockade of these receptors could be considered a potential treatment for this condition.

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]

We have previously reported that socially partnered stress sensitive Wistar-Kyoto (WKY) rats exhibited a reduced response to cued fear-conditioning (CFC) compared to their socially isolated counterparts. Given that altered glutamatergic neurotransmission in the limbic and forebrain regions have been implicated in stress-induced psychiatric disorders, the present study investigated the effects of CFC on [3H] MK-801 binding to N-methyl-D-aspartate (NMDA) receptors in socially isolated (CFC-SI) and socially partnered (CFC-SP) WKY rats, in comparison to the stress resilient Wistar (WIS) rats. Binding of [3H] MK-801 to NMDA receptors was measured in the prefrontal cortex (PFC), basolateral amygdala (BLA), central amygdala (CeA), and the CA1/CA2, CA3 and dentate gyrus (DG) of the hippocampus. Extinction of CFC in a socially isolated environment resulted in higher NMDA binding in the PFC in WKY rats but lower binding in the PFC in WIS rats. While extinction of CFC in a socially partnered environment did not alter NMDA binding in WKY rats, higher NMDA binding was seen in the BLA, CA1/CA2 and DG in WIS rats. Our results suggest that NMDA-mediated mechanisms of fear extinction in a socially isolated or socially partnered environment may be different in the two phenotypes and may involve other central mechanisms. [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]

Background: 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. Objective: 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. Methods: 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. Results: 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. Conclusions: Our data provide a rationale to further explore anodal tDCS over the PFC as potential support for trauma-based psychotherapy for PTSD.

Disruption of sleep due to acute or chronic stress can lead to changes in emotional memory processing. Sleep disturbances are highly prevalent in post-traumatic stress disorder (PTSD), but still, the contribution of sleep deprivation on the susceptibility to PTSD has received little attention. To determine whether rapid eye movement sleep deprivation (SD) alters the development of fear expression or fear-associated memory impairment in adolescent rats, we performed animal emotional behavior tests using an SD animal model with the flowerpot technique. SD rats showed an increase in locomotor activity frequency and a decrease in sucrose consumption compared to control rats. An increase in freezing behavior during shock trials was observed in SD rats. Noticeably, it was observed that when applying the SD condition after fear stimuli exposure, fear extinction was delayed more in SD rats than in control rats. Overall, these results indicate that SD in adolescent rats leads to increased locomotor activity and anhedonic behavior, as well as increased fear expression and delayed fear extinction, suggesting that SD would lead to increased severity of PTSD-like phenotype.

This paper is based upon a panel discussion What I Have Changed My Mind About and Why held on 5 November in New Orleans, Louisiana (USA), as part of the ISTSS 2015 annual meeting Back to Basics: Integrating Clinical and Scientific Knowledge to Advance the Field of Trauma. The panel was chaired by Professor Dr. Rachel Yehuda of the Icahn School of Medicine at Mount Sinai and the James J. Peters Veterans Affairs, and included five clinician-scholars who exchanged thoughts about what they have changed their minds about over the years: Dr. David Spiegel, Dr. Steven Southwick, Dr. Lori Davis, Dr. Thomas Neylan, and Dr. John Krystal. This paper provides a summary of the salient points made by each expert and the questions and discussion that ensured. Major issues raised included the increasingly clear limitations to the fear-based model that has advanced the field. While treatments for PTSD have improved, there are some aspects of trauma exposure that cannot be entirely repaired. Research providing an evidence base to treatment has led to overly specific treatment guidelines that may obscure more general principles of effective treatment. Treatment might be viewed as a way to increase the plasticity of the brain in the context of processing social cues. A variety of novel and integrative therapies include comprehensive holistic care, exercise, returning to competitive work, logotherapy, mindfulness, enhancing well-being and resilience, and medications with novel mechanisms, such as ketamine.

Acid sphingomyelinase (ASM) regulates a variety of physiological processes and plays an important role in emotional behavior. The role of ASM in fear-related behavior has not been investigated so far. Using transgenic mice overexpressing ASM (ASMtg) and ASM deficient mice, we studied whether ASM regulates fear learning and expression of cued and contextual fear in a classical fear conditioning paradigm, a model used to investigate specific attributes of post-traumatic stress disorder (PTSD). We show that ASM does not affect fear learning as both ASMtg and ASM deficient mice display unaltered fear conditioning when compared to wild-type littermates. However, ASM regulates the expression of contextual fear in a sex-specific manner. While ASM overexpression enhances the expression of contextual fear in both male and female mice, ASM deficiency reduces the expression of contextual fear specifically in male mice. The expression of cued fear, however, is not regulated by ASM as ASMtg and ASM deficient mice display similar tone-elicited freezing levels. This study shows that ASM modulates the expression of contextual fear but not of cued fear in a sex-specific manner and adds a novel piece of information regarding the involvement of ASM in hippocampal-dependent aversive memory. [ABSTRACT FROM AUTHOR]

Stress represents a major risk factor for psychiatric disorders, including post-traumatic stress disorder (PTSD). Recently, we dissected the destabilizing effects of acute stress on the excitatory glutamate system in the prefrontal cortex (PFC). Here, we assessed the effects of single subanesthetic administration of ketamine (10 mg/kg) on glutamate transmission and dendritic arborization in the PFC of footshock (FS)-stressed rats, along with changes in depressive, anxious, and fear extinction behaviors. We found that ketamine, while inducing a mild increase of glutamate release in the PFC of naïve rats, blocked the acute stress-induced enhancement of glutamate release when administered 24 or 72 h before or 6 h after FS. Accordingly, the treatment with ketamine 6 h after FS also reduced the stress-dependent increase of spontaneous excitatory postsynaptic current (sEPSC) amplitude in prelimbic (PL)-PFC. At the same time, ketamine injection 6 h after FS was found to rescue apical dendritic retraction of pyramidal neurons induced by acute stress in PL-PFC and facilitated contextual fear extinction. These results show rapid effects of ketamine in animals subjected to acute FS, in line with previous studies suggesting a therapeutic action of the drug in PTSD models. Our data are consistent with a mechanism of ketamine involving re-establishment of synaptic homeostasis, through restoration of glutamate release, and structural remodeling of dendrites. [ABSTRACT FROM AUTHOR]

Background: Fear conditioning and extinction are well-characterized cross-species models of fear-related posttraumatic stress disorder (PTSD) symptoms, and recent animal data suggest that 3,4-methylenedioxymethamphetamine (MDMA) enhances fear extinction retention.Aims: This study investigated the effect of MDMA on fear learning, extinction training, and retention in healthy humans.Methods: The study involved a randomized placebo-controlled, two-group, parallel design trial in a sample of healthy adults, age 21-55 recruited from a major metropolitan area. The experimental paradigm included a fear acquisition session followed by an extinction training session 24 hours later, and 2 hours after study drug administration. Fear extinction retention was measured 48 hours after extinction training. Participants (N = 34; 70.6% male and 29.4% female) were randomly assigned in 1:1 ratio to 100 mg MDMA or placebo. All randomized participants completed the trial and were included in primary analyses. Safety was monitored via adverse events and vital signs. MDMA was well-tolerated with no serious adverse events.Results: Results indicated a significant main effect of session between extinction training and retention with no significant group differences. Significantly more participants in the MDMA group retained extinction learning compared to the placebo group (χ2 = 7.29, p = 0.007).Conclusion: Although we did not observe the hypothesized facilitation of extinction retention, the findings from this initial human trial provide compelling rationale to continue to explore the potential for MDMA to impact extinction retention.Clinical Trials Registry Name and Identifier: Evaluation of MDMA on Startle Response (NCT0318176) https://clinicaltrials.gov/ct2/show/NCT03181763?term = MDMA&draw = 2&rank = 9. [ABSTRACT FROM AUTHOR]

Post-traumatic Stress Disorder (PTSD) is a diagnosis of extreme anxiety caused by a traumatic event. Less than 10% of individuals who have experienced severe trauma will develop this disorder. Treatment options include various psychotherapies, but not all patients respond to them. Different pharmacological approaches have been explored as potential adjuvants, including using cannabinoids to target the endocannabinoid system to reduce the symptoms and enhance extinction training over the associated fear memories. This review was aimed to determine the effects of using cannabinoids for treatment of PTSD. For this review, four cohort studies, four randomized clinical trials, one case report, and one case series were obtained from PubMed within the last 10 years. Cannabis extracts, tetrahydrocannabinol (THC) and cannabidiol (CBD), and synthetic cannabinoids were used in the studies to target the cannabinoid receptors 1 and 2. Cannabinoids were shown to improve overall PTSD symptoms, including sleep quality and quantity, hyperarousal, and treatment-resistant nightmares. When participants were undergoing extinction training, cannabinoids given within the same time interval enhanced consolidation and retention. Cannabinoids have been shown to be an effective treatment option for patients with PTSD. Besides aiding to relieve the symptoms and enhance extinction training, they also are relatively well tolerated. Common adverse effects included light-headedness, forgetfulness, dizziness, and headaches. [ABSTRACT FROM AUTHOR]

The present study used auditory fear conditioning to assess the impact of repeated binge-like episodes of alcohol exposure during adolescence on conditioned fear in adulthood. Male and female Long-Evans rats were subjected to adolescent intermittent ethanol (AIE) exposure by vapor inhalation between post-natal day 28 and 44. After aging into adulthood, rats then underwent fear conditioning by exposure to a series of tone-shock pairings. This was followed by cued-tone extinction training, and then testing of fear recovery. In male rats, AIE exposure enhanced conditioned freezing but did not alter the time-course of extinction of cued-tone freezing. During subsequent assessment of fear recovery, AIE exposed rats exhibited less freezing during contextual fear renewal, but greater freezing during extinction recall and spontaneous recovery. Compared to males, female rats exhibited significantly lower levels of freezing during fear conditioning, more rapid extinction of freezing behavior, and significantly lower levels of freezing during the tests of fear recovery. Unlike males that were all classified as high conditioners; female rats could be parsed into either a high or low conditioning group. However, irrespective of their level of conditioned freezing, both the high and low conditioning groups of female rats exhibited rapid extinction of conditioned freezing behavior and comparatively low levels of freezing in tests of fear recovery. Regardless of group classification, AIE had no effect on freezing behavior in female rats during acquisition, extinction, or fear recovery. Lastly, exposure of male rats to the mGlu5 positive allosteric modulator CDPPB prevented AIE-induced alterations in freezing. Taken together, these observations demonstrate sex-specific changes in conditioned fear behaviors that are reversible by pharmacological interventions that target mGlu5 receptor activation. [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]

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). [ABSTRACT FROM AUTHOR]

Abstract Background Posttraumatic stress disorder (PTSD) may stem from the formation of aberrant and enduring aversive memories. Some PTSD patients have recreationally used Cannabis, probably aiming at relieving their symptomatology. However, it is still largely unknown whether and how Cannabis or its psychotomimetic compound Δ9-tetrahydrocannabinol (THC) attenuates the aversive/traumatic memory outcomes. Here, we seek to review and discuss the effects of THC on aversive memory extinction and anxiety in healthy humans and PTSD patients. Methods Medline, PubMed, Cochrane Library, and Central Register for Controlled Trials databases were searched to identify peer-reviewed published studies and randomized controlled trials in humans published in English between 1974 and July 2020, including those using only THC and THC combined with cannabidiol (CBD). The effect size of the experimental intervention under investigation was calculated. Results At low doses, THC can enhance the extinction rate and reduce anxiety responses. Both effects involve the activation of cannabinoid type-1 receptors in discrete components of the corticolimbic circuitry, which could couterbalance the low “endocannabinoid tonus” reported in PTSD patients. The advantage of associating CBD with THC to attenuate anxiety while minimizing the potential psychotic or anxiogenic effect produced by high doses of THC has been reported. The effects of THC either alone or combined with CBD on aversive memory reconsolidation, however, are still unknown. Conclusions Current evidence from healthy humans and PTSD patients supports the THC value to suppress anxiety and aversive memory expression without producing significant adverse effects if used in low doses or when associated with CBD. Future studies are guaranteed to address open questions related to their dose ratios, administration routes, pharmacokinetic interactions, sex-dependent differences, and prolonged efficacy.

Objective To explore the role of transient receptor potential canonical 6 (TRPC6) on conditioning and extinction in contextual fear memory. Methods A total of 32 male C57BL/6J mice (6~8 weeks old) were randomized into fear conditioning (Cond group, n=16) and fear extinction (Ext group, n=16). Both groups were further divided into sh-TRPC6 subgroup (n=8) and GFP subgroup (n=8). Stereotaxic injection of adeno-associated virus (AAV)-TRPC6 or AAV-green fluorescent protein (AAV-GFP) was performed into the hippocampus of the corresponding mice bilaterally for intervention of fear. Immunofluorescence assay and Western blotting were used to detect the expression of TRPC6 in hippocampus of each sub-group in 20 d after stereotaxic injection. On day 21, fear conditioning was established though inescapable foot shock (footshock of 0.7 mA for 2 s and intertrial interval for 58 s, totally 5 cycles), and fear test was carried out on day 22. For the mice from the Ext group, fear conditioning begun in 4 d after stereotaxic injection, fear extinction training started on day 21, and fear test was also carried out on day 22. Results At 20 d after injection, massive GFP-positive cells were observed in the pyramidal layer of hippocampal CA1 region, and Western blotting showed AAV-TRPC6 injection significantly reduced the hippocampal TRPC6 expression in the sh-TRPC6 subgroup than the GFP subgroup (P < 0.01). In the experiment of fear conditioning, the upward trend of the Freezing% levels in sh-TRPC6 subgroup was obviously slower (P < 0.05), and its Freezing% levels were notably lower in fear test when compared with the GFP subgroup (P < 0.05). In the experiment of fear extinction, the downward trend of the Freezing% levels in sh-TRPC6 subgroup was significantly slower (P < 0.05) and its Freezing% levels were significantly higher in fear test when compared with the GFP subgroup (P < 0.05). Conclusion Hippocampal TRPC6 participates in the conditioning and extinction in contextual fear memory, and suppression of its expression can destroy the processes.

The present study used auditory fear conditioning to assess the impact of repeated binge-like episodes of alcohol exposure during adolescence on conditioned fear in adulthood. Male and female Long-Evans rats were subjected to adolescent intermittent ethanol (AIE) exposure by vapor inhalation between post-natal day 28 and 44. After aging into adulthood, rats then underwent fear conditioning by exposure to a series of tone-shock pairings. This was followed by cued-tone extinction training, and then testing of fear recovery. In male rats, AIE exposure enhanced conditioned freezing but did not alter the time-course of extinction of cued-tone freezing. During subsequent assessment of fear recovery, AIE exposed rats exhibited less freezing during contextual fear renewal, but greater freezing during extinction recall and spontaneous recovery. Compared to males, female rats exhibited significantly lower levels of freezing during fear conditioning, more rapid extinction of freezing behavior, and significantly lower levels of freezing during the tests of fear recovery. Unlike males that were all classified as high conditioners; female rats could be parsed into either a high or low conditioning group. However, irrespective of their level of conditioned freezing, both the high and low conditioning groups of female rats exhibited rapid extinction of conditioned freezing behavior and comparatively low levels of freezing in tests of fear recovery. Regardless of group classification, AIE had no effect on freezing behavior in female rats during acquisition, extinction, or fear recovery. Lastly, exposure of male rats to the mGlu5 positive allosteric modulator CDPPB prevented AIE-induced alterations in freezing. Taken together, these observations demonstrate sex-specific changes in conditioned fear behaviors that are reversible by pharmacological interventions that target mGlu5 receptor activation.

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.

This brief review article will describe treatment approaches for posttraumatic stress disorder (PTSD) based on findings from basic research. The focus of this review will be fear conditioning and extinction models, which provide a translational model of PTSD that can help translate basic research in nonhuman animals through well-controlled trials confirming the efficacy of treatment approaches in humans with PTSD such as prolonged exposure therapy. Specific cognitive aspects of fear extinction processes, including consolidation and reconsolidation, are reviewed along with behavioral and pharmacological treatment strategies based on basic research in these areas including attempts to prevent the development of PTSD as well as the treatment of chronic PTSD. Pharmacological, behavioral, and device-based augmentation strategies of PTSD treatment based in basic science findings are reviewed, including those that disrupt noradrenergic receptor processes, medications that act on NMDA receptors, physical exercise, cannabinoids, estradiol, dexamethasone, yohimbine, losartan, dopamine, and MDMA, along with the evidence for their efficacy in human clinical samples. While fear extinction provides an exciting translational opportunity to improve PTSD based on basic science findings, we review limitations and challenges of the extant literature as well as future directions., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

The ability to extinguish aversive memories when they are no longer associated with danger is critical for balancing survival with competing adaptive demands. Previous studies demonstrated that the infralimbic cortex (IL) is essential for extinction of learned fear, while neural activity in the prelimbic cortex (PL) facilitates fear responding and is negatively correlated with the strength of extinction memories. Though these adjacent regions in the prefrontal cortex maintain mutual synaptic connectivity, it has been unclear whether PL and IL interact functionally with each other during fear extinction learning. Here we addressed this question by recording local field potentials (LFPs) simultaneously from PL and IL of awake behaving rats during extinction of auditory fear memories. We found that LFP power in the fast gamma frequency (100–200 Hz) in both PL and IL regions increased during extinction learning. In addition, coherency analysis showed that synchronization between PL and IL in the fast gamma frequency was enhanced over the course of extinction. These findings support the hypothesis that interregional interactions between PL and IL increase as animals extinguish aversive memories. [ABSTRACT FROM AUTHOR]

In contrast to easily formed fear memories, fear extinction requires prolonged training. The prelimbic cortex (PL), which integrates signals from brain structures involved in fear conditioning and extinction such as the ventral hippocampus (vHIP) and the basolateral amygdala (BL), is necessary for fear memory retrieval. Little is known, however, about how the vHIP and BL inputs to the PL regulate the display of fear after fear extinction. Using functional anatomy tracing in male rats, we found two distinct subpopulations of neurons in the PL activated by either the successful extinction or the relapse of fear. During the retrieval of fear extinction memory, the dominant input to active neurons in the PL was from the vHIP, whereas the retrieval of fear memory, regardless of the age of a memory and testing context, was associated with greater BL input. Optogenetic stimulation of the vHIP-PL pathway after one session of fear extinction increased conditioned fear, whereas stimulation of the vHIP inputs after several sessions of extinction decreased the conditioned fear response. This latter effect was, however, transient, as stimulation of this pathway 28 d after extinction increased conditioned fear response again. The results show that repeated fear extinction training gradually changes vHIP-PL connectivity, making fear suppression possible, whereas in the absence of fear suppression from the vHIP, signals from the BL can play a dominant role, resulting in high levels of fear. [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]

Background Enhancement of N-methyl-D-aspartate (NMDA) receptor function using glycine-site agonist D-cycloserine is known to facilitate fear extinction, providing a means to augment cognitive behavioral therapy in anxiety disorders. A novel class of glycine-site agonists has recently been identified, and we have found that the prototype, AICP, is more effective than D-cycloserine in modulating neuronal function. Methods Using novel glycine-site agonist AICP, local infusion studies, and genetic models, we elucidated the role of GluN2C-containing receptors in fear extinction. Results We tested the effect of intracerebroventricular injection of AICP on fear extinction and found a robust facilitation of fear extinction. This effect was dependent on GluN2C subunit, consistent with superagonist action of AICP at GluN2C-containing receptors. Local infusion studies in wild-type and GluN2C knockout mice suggested that AICP produces its effect via GluN2C-containing receptors in the basolateral amygdala (BLA). Furthermore, consistent with astrocytic expression of GluN2C subunit in the amygdala, we found that AICP did not facilitate fear extinction in mice with conditional deletion of obligatory GluN1 subunit from astrocytes. Importantly, chemogenetic activation of astrocytes in the basolateral amygdala facilitated fear extinction. Acutely, AICP was found to facilitate excitatory neurotransmission in the BLA via presynaptic GluN2C-dependent mechanism. Immunohistochemical studies suggest that AICP-mediated facilitation of fear extinction involves synaptic insertion of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor GluA1 subunit. Conclusion These results identify a unique role of astrocytic NMDA receptors composed of GluN2C subunit in extinction of conditioned fear memory and demonstrate that further development of recently identified superagonists of GluN2C-containing receptors may have utility for anxiety disorders. [ABSTRACT FROM AUTHOR]

Background: The endocannabinoid system is gaining increasing attention as a favorable target for improving posttraumatic stress disorder (PTSD) treatments. Exposure therapy is the gold‐standard treatment for PTSD, and fear extinction learning is a key concept underlying successful exposure. Methods: This study examined the role of genetic endocannabinoid polymorphisms in a fear extinction paradigm with PTSD compared to healthy participants (N = 220). Participants provided saliva for genotyping, completed a fear conditioning and extinction task, with blood samples taken before and after the task (n = 57). Skin conductance was the outcome and was analyzed using mixed models. Results: Results for cannabinoid receptor type 1 polymorphisms suggested that minor alleles of rs2180619 and rs1049353 were associated with poorer extinction learning in PTSD participants. The minor allele of the fatty acid amide hydrolase (FAAH) polymorphism rs324420 was associated with worse extinction in PTSD participants. Subanalysis of healthy participants (n = 57) showed the FAAH rs324420 genotype effect was dependent on plasma arachidonoyl ethanolamide (AEA) level, but not oleoylethanolamide or 2‐arachidonoyl glycerol. Specifically, higher but not lower AEA levels in conjunction with the minor allele of FAAH rs324420 were associated with better extinction learning. Conclusions: These findings provide translational evidence that cannabinoid receptor 1 and AEA are involved in extinction learning in humans. FAAH rs324420's effect on fear extinction is moderated by AEA plasma level in healthy controls. These findings imply that FAAH inhibitors may be effective for targeting anxiety in PTSD, but this effect needs to be explored further in clinical populations. [ABSTRACT FROM AUTHOR]

Background: The ability to modulate undesirable emotions is essential for maintaining mental health. Negative emotions can arise both while experiencing and remembering an unpleasant event, which presents a persistent emotion regulation challenge because emotional memories tend to be particularly vivid and enduring. Despite the central role that memories play in our affective lives, little is known about the memory processes supporting successful regulation of emotions associated with long-term memories, which we refer to as retrospective emotion regulation. Methods: In this paper, we review the literature on the mechanisms of memory modification, which may contribute to the success of retrospective emotion regulation. In particular, we review rodent and human studies that examine the modification of conditioned fear associations and emotional episodic memories. Conclusions: Based on this literature, we conclude that memory reactivation plays a crucial role in memory modification. We discuss further the potential role of memory reactivation in mediating the success of cognitive reappraisal, which may be considered a special case of memory modification. We propose that the completeness, or strength, of reactivation during retrospective emotion regulation will be related to the likelihood of updating an episodic memory, reducing its emotional impact upon later recall. Understanding the role of memory processes in emotion regulation can help to inform research on memory-based treatments for affective disorders. [ABSTRACT FROM AUTHOR]

Fear conditioning and extinction, which are adaptive processes to learn and avoid potential threats, have essential roles in the pathophysiology of anxiety disorders. Experimental fear conditioning and extinction have been used to identify the mechanism of fear and anxiety in humans. However, the brain-based mechanisms of fear conditioning and extinction are yet to be established. In the current review, we summarized the results of neuroimaging studies that examined the brain changes—functional activity and structures—regarding fear conditioning or extinction in healthy individuals. The functional activity of the amygdala, insula, anterior cingulate gyrus, ventromedial prefrontal cortex, and hippocampus changed dynamically with both fear conditioning and extinction. This review may provide an up-to-date summary that may broaden our understanding of pathophysiological mechanisms of anxiety disorder. In addition, the brain regions that are involved in the fear conditioning and extinction may be considered as potential treatment targets in the future studies. [ABSTRACT FROM AUTHOR]

Reproductive experience leads to long-lasting changes in anxiety-like behaviour and fear extinction, the laboratory model of exposure therapy for anxiety disorders. For example, fear extinction is influenced by estrous cycle in nulliparous (no reproductive experience) female rats, but this effect is abolished in primiparous (one reproductive experience) females. It is unclear whether such changes are driven by pregnancy, maternal experience of caring for offspring during the postpartum period, or a combination of both experiences. The present study sought to determine the influence of maternal experience (i.e., exposure to pups and mother-pup interactions) on fear extinction in primiparous rats. In Experiment 1, we tested whether pup exposure is necessary to mitigate estrous effects on fear extinction in primiparous rats. Age-matched nulliparous rats, primiparous rats, and primiparous rats who experienced pregnancy but not pup exposure, underwent fear conditioning on day 1 (2 months post-parturition), extinction training during proestrus (high sex hormones) or metestrus (low sex hormones) on day 2, and extinction recall on day 3. Replicating past research, nulliparous rats showed impaired extinction recall when they were extinguished during metestrus compared to proestrus. In contrast, primiparous rats with and without pup exposure showed comparable extinction recall irrespective of estrous phase. In Experiment 2, we assessed whether naturally-occurring variation in mother-pup interactions predict future fear extinction performance and anxiety-like behaviour. During the first week of lactation, primiparous rats were measured for maternal behaviours toward pups. Primiparous rats were then tested on the light-dark box and elevated plus maze to measure anxiety-like behaviour and underwent a fear extinction protocol 1 month post-weaning. We found no significant correlations between maternal behaviour and fear extinction outcomes or anxiety-like behaviour. Our findings suggest that pregnancy, not maternal experience, mitigates the impact of estrous cycle on fear extinction. In addition, natural variation in maternal experience does not appear to contribute to variability in future fear extinction outcomes or anxiety-like behaviour in primiparous rats.

The inability to extinguish a traumatic memory is a key aspect of post-traumatic stress disorder (PTSD). While PTSD affects 10–20% of individuals who experience a trauma, women are particularly susceptible to developing the disorder. Despite this notable female vulnerability, few studies have investigated this particular resistance to fear extinction observed in females. Similar to humans, rodent models of Pavlovian fear learning and extinction show a wide range of individual differences in fear learning and extinction, although female rodents are considerably understudied. Therefore, the present study examined individual differences in fear responses, including freezing behavior and ultrasonic vocalizations (USVs), of female Long–Evans rats during acquisition of fear conditioning and cued fear extinction. Similar to prior studies in males, female rats displayed individual variation in freezing during cued fear extinction and were divided into extinction competent (EC) and extinction resistant (ER) phenotypes. Differences in freezing between ER and EC females were accompanied by shifts in rearing during extinction, but no darting was seen in any trial. Freezing behavior during fear learning did not differ between the EC and ER females. Vocalizations emitted in the 22 and 50 kHz ranges during fear learning and extinction were also examined. Unlike vocalizations seen in previous studies in males, very few 22 kHz distress vocalizations were emitted by female rats during fear acquisition and extinction, with no difference between ER and EC groups. Interestingly, all female rats produced significant levels of 50 kHz USVs, and EC females emitted significantly more 50 kHz USVs than ER rats. This difference in 50 kHz USVs was most apparent during initial exposure to the testing environment. These results suggest that like males, female rodents show individual differences in both freezing and USVs during fear extinction, although females appear to vocalize more in the 50 kHz range, especially during initial periods of exposure to the testing environment, and emit very few of the 22 kHz distress calls that are typically observed in males during fear learning or extinction paradigms. Overall, these findings show that female rodents display fear behavior repertoires divergent from males.

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]