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

Background and Purpose: Post-traumatic stress disorder (PTSD) is a type of psychotic illness that can occur after traumatic events such as war, childhood abuse, rape, natural disasters like earthquakes, and other unfortunate life events. These stresses can damage different brain areas, leading to behavioral changes associated with these regions. Chronic stress increases the activity of microglial cells, resulting in the loss of dendritic spines in the medial prefrontal cortex and hippocampus. Additionally, memory formation is impaired after stress exposure, leading to the inability to replace new memories with previous disturbing ones. The pathophysiology of PTSD involves changes in specific anatomical regions and circuits of the brain. Damage to the prefrontal cortex (PFC) can hinder the ability to forget inappropriate and disturbing memories. The PFC plays a crucial role in the brain's physiological response, providing the necessary functions to create calm, rational, and flexible responses. Studies have shown that acute stress weakens the prefrontal cortex. Medications for psychotic disorders have side effects, and there is a risk of relapse in some patients. Finding new treatment methods with greater benefits and minimal side effects is essential. Exercise, as an adjunctive treatment, may improve the structural and functional changes caused by stress. Materials and Methods: In this experiment, Wistar male laboratory rats and a single prolonged stress animal model were used as valid models for PTSD induction. Following a 4-week exercise intervention on a treadmill (forced exercise at moderate intensity) — the first two weeks at a speed of 10 m/min for half an hour a day and the second two weeks at a speed of 15 m/min for half an hour a day, 5 days per week — cognitive memory and fear extinction were evaluated using behavioral tests (ORMT and Extinction). The animals were then euthanized under deep anesthesia with ketamine and xylazine. The brains were removed, and the hippocampus was fixed for histological studies using the Golgi staining method. The prefrontal cortex was also frozen at -80°C for BDNF measurement. Results: The results of this study showed that rats suffering from PTSD exhibited a decrease in fear extinction (the ability to forget disturbing memories), an increase in freezing behavior, a reduction in cognitive memory, a decrease in BDNF levels in the prefrontal cortex, and a reduction in dendritic branches. The selected exercise program significantly improved behavioral deficits (cognitive memory and fear extinction) and reduced freezing behavior as a measure of fear. Additionally, BDNF levels in the prefrontal cortex increased, and a relative increase in dendritic branches in the hippocampus was observed after the exercise protocol. Conclusion: A regular 4-week course of moderate-intensity exercise can improve the structural and functional damage caused by stress in an animal model of PTSD, particularly in the hippocampus and prefrontal cortex, as well as ameliorate deficits in cognitive memory and reduce fear responses.

The role of the cerebellum in emotional control has gained increasing interest, with studies showing it is involved in fear learning and memory in both humans and rodents. This review will focus on the contributions of the cerebellum to the extinction of learned fear responses. Extinction of fearful memories is critical for adaptive behaviour, and is clinically relevant to anxiety disorders such as post-traumatic stress disorder, in which deficits in extinction processes are thought to occur. We present evidence that supports cerebellar involvement in fear extinction, from rodent studies that investigate molecular mechanisms and functional connectivity with other brain regions of the known fear extinction network, to fMRI studies in humans. This evidence is considered in relation to the theoretical framework that the cerebellum is involved in the formation and updating of internal models of the inner and outer world by detecting errors between predicted and actual outcomes. In the case of fear conditioning, these internal models are thought to predict the occurrence of an aversive unconditioned stimulus (US), and when the aversive US is unexpectedly omitted during extinction learning the cerebellum uses prediction errors to update the internal model. Differences between human and rodent studies are highlighted to help inform future work. [ABSTRACT FROM AUTHOR]

Background and Purpose: Post-traumatic stress disorder (PTSD) is a type of psychotic illness that can occur after traumatic events such as war, childhood abuse, rape, natural disasters like earthquakes, and other unfortunate life events. These stresses can damage different brain areas, leading to behavioral changes associated with these regions. Chronic stress increases the activity of microglial cells, resulting in the loss of dendritic spines in the medial prefrontal cortex and hippocampus. Additionally, memory formation is impaired after stress exposure, leading to the inability to replace new memories with previous disturbing ones. The pathophysiology of PTSD involves changes in specific anatomical regions and circuits of the brain. Damage to the prefrontal cortex (PFC) can hinder the ability to forget inappropriate and disturbing memories. The PFC plays a crucial role in the brain's physiological response, providing the necessary functions to create calm, rational, and flexible responses. Studies have shown that acute stress weakens the prefrontal cortex. Medications for psychotic disorders have side effects, and there is a risk of relapse in some patients. Finding new treatment methods with greater benefits and minimal side effects is essential. Exercise, as an adjunctive treatment, may improve the structural and functional changes caused by stress. Materials and Methods: In this experiment, Wistar male laboratory rats and a single prolonged stress animal model were used as valid models for PTSD induction. Following a 4-week exercise intervention on a treadmill (forced exercise at moderate intensity) — the first two weeks at a speed of 10 m/min for half an hour a day and the second two weeks at a speed of 15 m/min for half an hour a day, 5 days per week — cognitive memory and fear extinction were evaluated using behavioral tests (ORMT and Extinction). The animals were then euthanized under deep anesthesia with ketamine and xylazine. The brains were removed, and the hippocampus was fixed for histological studies using the Golgi staining method. The prefrontal cortex was also frozen at -80°C for BDNF measurement. Results: The results of this study showed that rats suffering from PTSD exhibited a decrease in fear extinction (the ability to forget disturbing memories), an increase in freezing behavior, a reduction in cognitive memory, a decrease in BDNF levels in the prefrontal cortex, and a reduction in dendritic branches. The selected exercise program significantly improved behavioral deficits (cognitive memory and fear extinction) and reduced freezing behavior as a measure of fear. Additionally, BDNF levels in the prefrontal cortex increased, and a relative increase in dendritic branches in the hippocampus was observed after the exercise protocol. Conclusion: A regular 4-week course of moderate-intensity exercise can improve the structural and functional damage caused by stress in an animal model of PTSD, particularly in the hippocampus and prefrontal cortex, as well as ameliorate deficits in cognitive memory and reduce fear responses. [ABSTRACT FROM AUTHOR]

MDMA-assisted psychotherapy has shown potential as an effective treatment for post-traumatic stress disorder (PTSD). Preclinical studies involving rodents have demonstrated that MDMA can facilitate the extinction of fear memories. It has been noted that MDMA impacts oxytocin neurons and pro-inflammatory cytokines. Thus, the aim of this study was to explore the role of oxytocinergic signaling and neuroinflammatory markers in the therapeutic effects of MDMA. To achieve this, male rats were subjected to a model of PTSD involving exposure to shock and situational reminders. MDMA was microinjected into the medial prefrontal cortex (mPFC) before extinction training, followed by behavioral tests assessing activity levels, anxiety, and social function. Our findings indicate that MDMA treatment facilitated fear extinction and mitigated the shock-induced increase in freezing, as well as deficits in social behavior. Shock exposure led to altered expression of the gene coding for OXT-R and neuroinflammation in the mPFC and basolateral amygdala (BLA), which were restored by MDMA treatment. Importantly, the OXT-R antagonist L-368,899 prevented MDMA's therapeutic effects on extinction and freezing behavior. In conclusion, MDMA's therapeutic effects in the PTSD model are associated with alterations in OXT-R expression and neuroinflammation, and MDMA's effects on extinction and anxiety may be mediated by oxytocinergic signaling. [ABSTRACT FROM AUTHOR]

Fear-related disorders, including post-traumatic stress disorder (PTSD), and anxiety disorders are pervasive psychiatric conditions marked by persistent fear, stemming from its dysregulated acquisition and extinction. The primary treatment for these disorders, exposure therapy (ET), relies heavily on fear extinction (FE) principles. Adolescence, a vulnerable period for developing psychiatric disorders, is characterized by neurobiological changes in the fear circuitry, leading to impaired FE and increased susceptibility to relapse following ET. Ketamine, known for relieving anxiety and reducing PTSD symptoms, influences fear-related learning processes and synaptic plasticity across the fear circuitry. Our study aimed to investigate the effects of ketamine (10 mg/kg) on FE in adolescent male C57 BL/6 mice at the behavioral and molecular levels. We analyzed the protein and gene expression of synaptic plasticity markers in the hippocampus (HPC) and prefrontal cortex (PFC) and sought to identify neural correlates associated with ketamine's effects on adolescent extinction learning. Ketamine ameliorated FE in the adolescent males, likely affecting the consolidation and/or recall of extinction memory. Ketamine also increased the Akt and mTOR activity and the GluA1 and GluN2A levels in the HPC and upregulated BDNF exon IV mRNA expression in the HPC and PFC of the fear-extinguished mice. Furthermore, ketamine increased the c-Fos expression in specific brain regions, including the ventral HPC (vHPC) and the left infralimbic ventromedial PFC (IL vmPFC). Providing a comprehensive exploration of ketamine's mechanisms in adolescent FE, our study suggests that ketamine's effects on FE in adolescent males are associated with the activation of hippocampal Akt-mTOR-GluA1 signaling, with the vHPC and the left IL vmPFC as the proposed neural correlates. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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

Posttraumatic stress disorder (PTSD) is a widespread fear-related psychiatric affection associated with fear extinction impairments and important avoidance behaviors. Trauma-related exposure therapy is the current first-hand treatment for PTSD, yet it needs to be improved to shorten the time necessary to reach remission and increase responsiveness. Additional studies to decipher the neurobiological bases of extinction and effects on PTSD-like symptoms could therefore be of use. However, a PTSD-like animal model exhibiting pronounced PTSD-related phenotypes even after an extinction training directly linked to the fearful event is necessary. Thus, using a contextual fear conditioning model of PTSD, we increased the severity of stress during conditioning to search for effects on extinction acquisition and on pre- and post-extinction behaviors. During conditioning, mice received either two or four electrical shocks while a control group was constituted of mice only exposed to the context. Stressed mice exhibited important fear generalization, high fear reaction to the context and selective avoidance of a contextual reminder even after the extinction protocol. Increasing the number of footshocks did not induce major changes on these behaviors. [ABSTRACT FROM AUTHOR]

Impaired extinction of fear memory is one of the most common symptoms in post‐traumatic stress disorder (PTSD), with limited therapeutic strategies due to the poor understanding of its underlying neural substrates. In this study, functional screening is performed and identified hyperactivity in the mediodorsal thalamic nucleus (MD) during fear extinction. Furthermore, the encoding patterns of the hyperactivated MD is investigated during persistent fear responses using multiple machine learning algorithms. The anterior cingulate cortex (ACC) is also identified as a functional downstream region of the MD that mediates the extinction of fear memory. The thalamocortical circuit is comprehensively analyzed and found that the MD‐ACC parvalbumin interneurons circuit is preferentially enhanced in PTSD mice, disrupting the local excitatory and inhibitory balance. It is found that decreased phosphorylation of the Kv3.2 channel contributed to the hyperactivated MD, primarily to the malfunctioning thalamocortical circuit. Using a lipid nanoparticle‐based RNA therapy strategy, channelopathy is corrected via a methoxylated siRNA targeting the protein phosphatase 6 catalytic subunit and restored fear memory extinction in PTSD mice. These findings highlight the function of the thalamocortical circuit in PTSD‐related impaired extinction of fear memory and provide therapeutic insights into Kv3.2‐targeted RNA therapy for PTSD. [ABSTRACT FROM AUTHOR]

The consequences of the COVID-19 pandemic have resulted in many disruptions to daily life, including an abrupt increase in social disconnection. As measures were put in place to combat the spread of COVID-19, people across the globe began living in states of limited social contact, fostering feelings of social isolation and loneliness. Previous literature suggests that these increases in social disconnection can have profound effects on both physical and mental health, perhaps especially in the case of fear disorders. The combination of feeling disconnected from others and the high level of daily threat experienced due to COVID-19 created conditions under which dysfunctional and persistent fears were especially likely to develop. Building on current understanding of the harmful effects of social disconnection on well-being in general as well as specific implications for fear, here we present findings from three preliminary investigations that are the first to directly examine the effects of loneliness on how fears are learned and maintained. The Results of this work show that loneliness impairs the process by which fears are extinguished, which is central to both the regulation of fear and treatment of fear disorders, and provide insight into potential avenues to mitigate such effects.

Abstract Impaired extinction of fear memory is one of the most common symptoms in post‐traumatic stress disorder (PTSD), with limited therapeutic strategies due to the poor understanding of its underlying neural substrates. In this study, functional screening is performed and identified hyperactivity in the mediodorsal thalamic nucleus (MD) during fear extinction. Furthermore, the encoding patterns of the hyperactivated MD is investigated during persistent fear responses using multiple machine learning algorithms. The anterior cingulate cortex (ACC) is also identified as a functional downstream region of the MD that mediates the extinction of fear memory. The thalamocortical circuit is comprehensively analyzed and found that the MD‐ACC parvalbumin interneurons circuit is preferentially enhanced in PTSD mice, disrupting the local excitatory and inhibitory balance. It is found that decreased phosphorylation of the Kv3.2 channel contributed to the hyperactivated MD, primarily to the malfunctioning thalamocortical circuit. Using a lipid nanoparticle‐based RNA therapy strategy, channelopathy is corrected via a methoxylated siRNA targeting the protein phosphatase 6 catalytic subunit and restored fear memory extinction in PTSD mice. These findings highlight the function of the thalamocortical circuit in PTSD‐related impaired extinction of fear memory and provide therapeutic insights into Kv3.2‐targeted RNA therapy for PTSD.

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Recent research indicates that there is mixed success in using exposure therapies on patients with post-traumatic stress disorder (PTSD). Our study argues that there are two major reasons for this: The first is that there are nonassociative aspects of PTSD, such as hyperactive amygdala activity, that cannot be attenuated using the exposure therapy; The second is that exposure therapy is conceptualized from the theoretical framework of Pavlovian fear extinction, which we know is heavily context dependent. Thus, reducing fear response in a therapist's office does not guarantee reduced response in other situations. This study also discusses work relating to the role of the hippocampus in context encoding, and how these findings can be beneficial for improving exposure therapies.

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

The role of the cerebellum in emotional control has gained increasing interest, with studies showing it is involved in fear learning and memory in both humans and rodents. This review will focus on the contributions of the cerebellum to the extinction of learned fear responses. Extinction of fearful memories is critical for adaptive behaviour, and is clinically relevant to anxiety disorders such as post-traumatic stress disorder, in which deficits in extinction processes are thought to occur. We present evidence that supports cerebellar involvement in fear extinction, from rodent studies that investigate molecular mechanisms and functional connectivity with other brain regions of the known fear extinction network, to fMRI studies in humans. This evidence is considered in relation to the theoretical framework that the cerebellum is involved in the formation and updating of internal models of the inner and outer world by detecting errors between predicted and actual outcomes. In the case of fear conditioning, these internal models are thought to predict the occurrence of an aversive unconditioned stimulus (US), and when the aversive US is unexpectedly omitted during extinction learning the cerebellum uses prediction errors to update the internal model. Differences between human and rodent studies are highlighted to help inform future work. [ABSTRACT FROM AUTHOR]

• Rat microglia express more P2X7Rs and inflammatory cytokines 3 days after SPS. • Serum inflammatory cytokines increase 3 days after SPS exposure. • Auditory fear extinction recall is impaired 7 but not 3 days after SPS. • Microglial and peripheral inflammation precede the onset of impaired fear extinction. • Blocking P2X7Rs prevented SPS from impairing fear extinction recall in both sexes. Clinical evidence has linked increased peripheral pro-inflammatory cytokines with post-traumatic stress disorder (PTSD) symptoms. However, whether inflammation contributes to or is a consequence of PTSD is still unclear. Previous research shows that stress can activate purinergic P2X7 receptors (P2X7Rs) on microglia to induce inflammation and behavioral changes. In this investigation, we examined whether P2X7Rs contribute to the development of PTSD-like behaviors induced by single prolonged stress (SPS) exposure in rats. Consistent with the literature, exposing adult male and female rats to SPS produced a PTSD-like phenotype of impaired fear extinction and extinction of cue-induced center avoidance one week after exposure. Next, we examined if inflammation precedes the behavioral manifestations. Three days after SPS exposure, increased inflammatory cytokines were found in the blood and hippocampal microglia showed increased expression of the P2X7R, IL-1β, and TNF-α, suggesting increased peripheral and central inflammation before the onset of impaired fear extinction. In addition, SPS-exposed animals with impaired fear extinction recall also had more Iba1-positive microglia expressing the P2X7R in the ventral hippocampus. To determine whether P2X7Rs contribute to the PTSD-related behaviors induced by SPS exposure, we gave ICV infusions of the P2X7R antagonist, A-438079, for one week starting the day of SPS exposure. Blocking P2X7Rs prevented the SPS-induced impaired fear extinction and extinction of cue-induced center avoidance in male and female rats, suggesting that SPS activates P2X7Rs which increase inflammation to produce a PTSD-like phenotype. [ABSTRACT FROM AUTHOR]

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

Insomnia confers a 2.5-to-3-fold risk of developing posttraumatic stress disorder (PTSD) after a traumatic event. The mechanism underlying this increased risk, however, remains unknown. We postulate insomnia may contribute to PTSD by disrupting rapid eye movement (REM) sleep, as REM sleep disruption has been shown to impair fear inhibitory processes, which are central to the natural recovery from trauma. To test this hypothesis, the following protocol aims to: (1) examine the relationship between REM sleep and fear inhibition in insomnia, and (2) examine whether reducing REM fragmentation by treating insomnia, in turn, improves fear inhibition. Ninety-two adults with Insomnia Disorder will be block randomized (1:1; stratified by sex) to an active treatment (7 weekly sessions of Cognitive Behavioral Therapy for Insomnia (CBT-I) via telehealth) or waitlist control condition. REM sleep (latent variable derived from REM %, REM efficiency, and REM latency) and fear inhibition (i.e. safety signal and extinction recall) will be assessed pre- and post-treatment in a 4 night/3 day testing protocol via at-home polysomnography and the fear-potentiated startle paradigm, respectively. Fear extinction recall will serve as the primary outcome, while safety signal recall will serve as the secondary outcome. In summary, this study aims to test an underlying mechanism potentially explaining why insomnia greatly increases PTSD risk, while demonstrating an existing clinical intervention (CBT-I) can be used to improve this mechanism. Findings will have potential clinical implications for novel approaches in the prevention, early intervention, and treatment of PTSD. [ABSTRACT FROM AUTHOR]

Post-traumatic stress disorder (PTSD) is a devastating psychiatric disorder afflictingmillions of people around the world. Characterized by severe anxiety, intrusive thoughts, pervasive nightmares, an assortment of somatic symptoms, associations with severe long-term health problems, and an elevated risk of suicide, as much as 40-70% of patients suffer from refractory disease. 3,4-Methylenedioxy-methamphetamine (MDMA), like classic psychedelics such as psilocybin, have been used to enhance the efficacy of psychotherapy almost since their discovery, but due to their perceived potential for abuse and inclusion on USFDA (United States Food and Drug Administration) schedule 1, research into the mechanism by which they produce improvements in PTSD symptomology has been limited. Nevertheless, several compelling rationales have been explored, with the pro-social effects of MDMA thought to enhance therapeutic alliance and thus facilitate therapist-assisted trauma processing. This may be insufficient to fully explain the efficacy of MDMA in the treatment of psychiatric illness. Molecular mechanisms such as the MDMA mediated increase of brain-derived neurotrophic factor (BDNF) availability in the fear memory learning pathways combined with MDMA's pro-social effects may provide a more nuanced explanation for the therapeutic actions of MDMA. [ABSTRACT FROM AUTHOR]

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]

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]

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]

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]

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]

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]

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]

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]

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. [ABSTRACT FROM AUTHOR]

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

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 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract Introduction Post‐traumatic stress disorder (PTSD) is an anxiety disorder induced by psychologically traumatic events. Using a rat model, this study aimed to determine whether psychological trauma alters relative expression between pro‐inflammatory and anti‐inflammatory markers in microglia. To meet this goal, expression of genes encoding i‐NOS, arginase, TNF‐α, interleukin‐10, CD74, and Mannose Receptor C was analyzed on multiple days following trauma exposure. Methods Single‐prolonged stress (SPS) was used to model PTSD in male Sprague‐Dawley rats. Twenty‐four rats (12 Controls and 12 SPS‐exposed) were sacrificed on Days 1, 3, and 7 post‐SPS. Twenty‐four (12 Controls and 12 SPS‐exposed) additional rats were exposed to classical fear conditioning on Day 7, and fear extinction on Days 8, 9, 10, 15, 16, and 17. Freezing behavior was measured to assess fear resolution. Microglial isolates were collected from the frontal cortex, and RNA was extracted. Changes in relative expression of target genes were quantified via RT‐PCR. Results SPS rats showed significant decreases in IL‐10 and TNF‐α expression and increases in the i‐NOS:Arginase and TNF‐α:IL‐10 ratios compared to Controls on Day 1, but not on Day 3 or Day 7 for any of the dependent variables. Day 17 SPS rats showed a significant decrease in IL‐10 expression and an increase in the TNF‐α:IL‐10 ratio, further characterized by a significant inverse relationship between IL‐10 expression and fear persistence. Conclusion Psychological trauma impacts the immunological phenotype of microglia of the frontal cortex. Consequently, future studies should further evaluate the mechanistic role of microglia in PTSD pathology.

Introduction: Post‐traumatic stress disorder (PTSD) is an anxiety disorder induced by psychologically traumatic events. Using a rat model, this study aimed to determine whether psychological trauma alters relative expression between pro‐inflammatory and anti‐inflammatory markers in microglia. To meet this goal, expression of genes encoding i‐NOS, arginase, TNF‐α, interleukin‐10, CD74, and Mannose Receptor C was analyzed on multiple days following trauma exposure. Methods: Single‐prolonged stress (SPS) was used to model PTSD in male Sprague‐Dawley rats. Twenty‐four rats (12 Controls and 12 SPS‐exposed) were sacrificed on Days 1, 3, and 7 post‐SPS. Twenty‐four (12 Controls and 12 SPS‐exposed) additional rats were exposed to classical fear conditioning on Day 7, and fear extinction on Days 8, 9, 10, 15, 16, and 17. Freezing behavior was measured to assess fear resolution. Microglial isolates were collected from the frontal cortex, and RNA was extracted. Changes in relative expression of target genes were quantified via RT‐PCR. Results: SPS rats showed significant decreases in IL‐10 and TNF‐α expression and increases in the i‐NOS:Arginase and TNF‐α:IL‐10 ratios compared to Controls on Day 1, but not on Day 3 or Day 7 for any of the dependent variables. Day 17 SPS rats showed a significant decrease in IL‐10 expression and an increase in the TNF‐α:IL‐10 ratio, further characterized by a significant inverse relationship between IL‐10 expression and fear persistence. Conclusion: Psychological trauma impacts the immunological phenotype of microglia of the frontal cortex. Consequently, future studies should further evaluate the mechanistic role of microglia in PTSD pathology. [ABSTRACT FROM AUTHOR]

Background and Purpose: Women are twice as likely as men to develop post‐traumatic stress disorder (PTSD) making the search for biological mechanisms underlying these gender disparities especially crucial. One of the hallmark symptoms of PTSD is an alteration in the ability to extinguish fear responses to trauma‐associated cues. In male rodents, the endocannabinoid system can modulate fear extinction and has been suggested as a therapeutic target for PTSD. However, whether and how the endocannabinoid system may modulate fear expression and extinction in females remains unknown. Experimental Approach To answer this question, we pharmacologically manipulated endocannabinoid signalling in male and female rats prior to extinction of auditory conditioned fear and measured both passive (freezing) and active (darting) conditioned responses. Key Results: Surprisingly, we found that acute systemic inhibition of the endocannabinoid anandamide (AEA) or 2‐arachidonoyl glycerol (2‐AG) hydrolysis did not significantly alter fear expression or extinction in males. However, the same manipulations in females produced diverging effects. Increased AEA signalling at vanilloid TRPV1 receptors impaired fear memory extinction. In contrast, inhibition of 2‐AG hydrolysis promoted active over passive fear responses acutely via activation of cannabinoid1 (CB1) receptors. Measurement of AEA and 2‐AG levels after extinction training revealed sex‐ and brain region‐specific changes. Conclusion and Implications: We provide the first evidence that AEA and 2‐AG signalling affect fear expression and extinction in females in opposite directions. These findings are relevant to future research on sex differences in mechanisms of fear extinction and may help develop sex‐specific therapeutics to treat trauma‐related disorders. [ABSTRACT FROM AUTHOR]

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

Fear extinction remains an unresolved challenge for behavioral exposure therapy in patients with post-traumatic stress disorder (PTSD). Previous reports have suggested that social support from either familiar or unfamiliar same-sex partners is beneficial to attenuating fear responses during fear extinction and renewal. Despite that, few studies have examined the effects of social support in advance on fear extinction and/or retrieval. It is also not clear whether social company by a receptive mating partner in advance facilitates fear extinction. In the present study, we address these questions by introducing a co-housing method, where fear-conditioned male mice are co-housed with or without a receptive mating partner prior to fear extinction. We found that while co-housing with an ovariectomized female mouse showed little effect on fear extinction or retrieval, social company by a receptive mating partner in advance dramatically facilitates fear extinction. In addition, the number of cFos-positive neurons in the basolateral amygdala (BLA) were also found to be reduced in male mice accompanied with receptive mating partner in response to fear extinction and retrieval, indicating diminished neuronal activation. Electrophysiological studies further showed that the excitability of excitatory neurons in BLA was decreased, which is probably due to the attenuated basal level of excitatory synaptic transmission. Together, our observations demonstrate an effect of social company by a receptive mating partner can facilitate fear extinction and afford a possible cellular mechanism.

Conditioning, extinction, and reinstatement are fundamental learning processes of animal adaptation, also strongly involved in human pathologies such as post-traumatic stress disorder, anxiety, depression, and dependencies. Cued fear conditioning, extinction, restatement, and systematic manipulations of the underlying brain amygdala and medial prefrontal cortex, represent key experimental paradigms to study such processes. Numerous empirical studies have revealed several aspects and the neural systems and plasticity underlying them, but at the moment we lack a comprehensive view. Here we propose a computational model based on firing rate leaky units that contributes to such integration by accounting for 25 different experiments on fear conditioning, extinction, and restatement, on the basis of a single neural architecture having a structure and plasticity grounded in known brain biology. This allows the model to furnish three novel contributions to understand these open issues: (a) the functioning of the central and lateral amygdala system supporting conditioning; (b) the role played by the endocannabinoids system in within- and between-session extinction; (c) the formation of three important types of neurons underlying fear processing, namely fear, extinction, and persistent neurons. The model integration of the results on fear conditioning goes substantially beyond what was done in previous models. [ABSTRACT FROM AUTHOR]

Biological psychiatry scholarship on posttraumatic stress disorder (PTSD) is making strides with new omics technologies. In this context, there is growing recognition that noncoding RNAs are vital for the regulation of gene and protein expression. Long noncoding RNAs (lncRNAs) can modulate splicing, influence RNA editing, messenger RNA (mRNA) stability, translation activation, and microRNA–mRNA interactions, are highly abundant in the brain, and have been implicated in neurodevelopmental disorders. The largest subclass of lncRNAs is long intergenic noncoding RNAs (lincRNAs). We report on lincRNAs and their predicted mRNA targets associated with fear extinction induced by co-administration of D-cycloserine and behavioral fear extinction in a PTSD animal model. Forty-three differentially expressed lincRNAs and 190 differentially expressed mRNAs were found to be associated with fear extinction. Eight lincRNAs were predicted to interact with and regulate 108 of these mRNAs, while seven lincRNAs were predicted to interact with 22 of their pre-mRNA transcripts. Based on the functions of their target mRNAs, we inferred that these lincRNAs bind to nucleotides, ribonucleotides, and proteins; subsequently influence nervous system development, morphology, and immune system functioning; and could be associated with nervous system and mental health disorders. We found the quantitative trait loci that overlapped with fear extinction-related lincRNAs included traits such as serum corticosterone level, neuroinflammation, anxiety, stress, and despair-related responses. To the best of our knowledge, this is the first study to identify lincRNAs and their RNA targets with a putative role in transcriptional regulation during fear extinction in the context of an animal model of PTSD. [ABSTRACT FROM AUTHOR]

Post‐traumatic stress disorder (PTSD) is a long‐lasting mental disorder and accompanied by worse fear extinction. Enhanced fear memory or poor fear extinction are typical features of PTSD. Dysfunction of the serotonergic neurotransmitter system is involved in numerous mental and behavioral disorders. Monoamine oxidase A (MAOA) is important in the metabolism of serotonin and play an important role in behavious. The aim of this study was to explore the change of MAOA and effect of MAOA on fear memory in PTSD. We used single prolonged stress (SPS) to create animal model of PTSD. A startle/fear box and elevated plus maze were used to observe fear memory and anxiety level, respectively. We examined the expression of MAOA and synaptic marker protein, as well as the immunological activity of MAOA in the infralimbic cortex (IL) area, which is a critical brain region involved in emotions, especially fear regulation. We found increased anxiety‐like behavior, dysfunction in fear extinction, and increased MAOA in SPS rats. After treatment with moclobemide (a selective inhibitor of MAOA), SPS rats showed significantly improved fear memory and decreased anxiety‐like behavior, which indicated that moclobemide could reverse fear extinction deficit and attenuate abnormally increased levels of anxiety caused by SPS in short term. On the contrary, decreased PSD‐95 and SYN1 expression in the IL region were also reversed by moclobemide. These results suggest that increased MAOA play a negative role in fear extinction and levels of anxiety in PTSD, which may be involved in change in PSD‐95 and SYN1. [ABSTRACT FROM AUTHOR]

Comorbidity between drug abuse and post-traumatic stress disorder (PTSD), a stress-related dysregulation of fear responses, is very high. While some drugs are known to increase fear and anxiety, there are only few data regarding interactions between voluntary drug consumption and fear memory. The spontaneous chronic consumption of either alcohol or cocaine under a 3-week free-choice progressive paradigm of alcohol (3/6/10%) or cocaine (0.2/0.4/0.6 mg/ml), was assessed in VGV transgenic mice, having full 5-HT2C receptor editing and displaying PTSD-like behaviors. The consequences of these drug consumptions on the potentiated contextual and cued fear conditioning responses of VGV mice were assessed. The effects of drugs on hippocampal brain-derived neurotrophic factor (Bdnf) mRNA were measured as its expression was previously found to be decreased in VGV mice. Chronic alcohol consumption was similar in WT and VGV mice. In the alcohol condition, fear acquisition was not different at the end of the learning session and cue-fear extinction was facilitated. Regarding cocaine, in contrast to WT mice, VGV mice did not increase their drug consumption along with increasing doses, an effect that might be related with enhanced drug stimuli discrimination via increased 5-HT2C receptors. Cocaine-intake VGV mice did not display the contextual fear generalization usually observed in control VGV mice. In addition, Bdnf expression was upregulated after either chronic alcohol or cocaine intake. Altogether, these results suggest that both chronic alcohol and cocaine voluntary oral consumptions can exert some therapeutic-like effects in a mutant model of PTSD predisposition. [ABSTRACT FROM AUTHOR]

We review findings and propose a model explaining why women's adaptation to traumatic stress might be different than men's, including the role of cycling hormones and sleep differences in the development of post-traumatic stress and other stress-related disorders. Women are diagnosed with stress-related mental health disorders at a higher frequency than men. Most mental health disorders involve sleep disturbances, which may contribute to these disorders. The mechanisms by which sleep contributes to the development of mental health disorders in women have not been addressed in basic research. Sleep features such as spindle density and rapid eye movement (REM) sleep theta power are important for the role of sleep in emotion and cognition. The effect of hormonal cycles on these and other critical sleep features is only beginning to be understood. We explore what sleep factors could confer resilience to mental health disorders and how they might be altered by hormonal cycles in women. We target a specific system at the nexus of arousal control, stress response, and memory consolidation processes that has not been explored at all in women or across the hormonal cycle in animal studies: the locus coeruleus noradrenergic (LC-NE) system. [ABSTRACT FROM AUTHOR]

Fear extinction remains an unresolved challenge for behavioral exposure therapy in patients with post-traumatic stress disorder (PTSD). Previous reports have suggested that social support from either familiar or unfamiliar same-sex partners is beneficial to attenuating fear responses during fear extinction and renewal. Despite that, few studies have examined the effects of social support in advance on fear extinction and/or retrieval. It is also not clear whether social company by a receptive mating partner in advance facilitates fear extinction. In the present study, we address these questions by introducing a co-housing method, where fear-conditioned male mice are co-housed with or without a receptive mating partner prior to fear extinction. We found that while co-housing with an ovariectomized female mouse showed little effect on fear extinction or retrieval, social company by a receptive mating partner in advance dramatically facilitates fear extinction. In addition, the number of cFos-positive neurons in the basolateral amygdala (BLA) were also found to be reduced in male mice accompanied with receptive mating partner in response to fear extinction and retrieval, indicating diminished neuronal activation. Electrophysiological studies further showed that the excitability of excitatory neurons in BLA was decreased, which is probably due to the attenuated basal level of excitatory synaptic transmission. Together, our observations demonstrate an effect of social company by a receptive mating partner can facilitate fear extinction and afford a possible cellular mechanism. [ABSTRACT FROM AUTHOR]

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