Search

Objective: We sought to determine whether acute delta 9‐tetrahyrdrocannabidol (THC) administration would facilitate fear extinction in young occasional cannabis users, given that animal models indicate THC facilitates extinction learning, and recent studies indicate THC administration may also enhance threat memory extinction in humans. Methods: On each of the 2 days, 24+ hour THC‐deprived participants were conditioned to fear visual stimuli in a delay conditioning and extinction paradigm. Both CS+ and CS− were faces of negative emotional valence, with the CS+ paired with mild electric shock. Throughout both conditioning and extinction paradigms, EEG was measured to quantify event‐related potentials for these learning processes. Following conditioning, individuals, in a randomized and counter‐balanced order, smoked either an active THC cigarette (26.25 mg/2.7% THC) or a placebo marijuana cigarette (0.002% THC) on 1 day and the opposite cigarette on the second day. After smoking, CS+ and CS− were presented without shock, resulting in extinction of conditioned fear. Results: Relative to placebo, THC facilitated extinction of the conditioned response to the CS+, as reflected by reductions in late positive potential amplitude during extinction learning. Conclusions: The results indicate that acute THC administration may facilitate extinction of the conditioned fear response in humans. [ABSTRACT FROM AUTHOR]

Circadian rhythms have received increasing attention within the context of mental disorders. Evening chronotype has been associated with enhanced risk to develop anxiety and post-traumatic stress disorder (PTSD). The classical fear conditioning paradigm is a powerful tool to reveal key mechanisms of anxiety and PTSD. We used this paradigm to study the neurocognitive basis of the association between chronotype and fear responses in healthy humans. 20 participants with evening chronotype and 20 controls (i.e., intermediate chronotype) completed a 2-day Pavlovian fear learning and extinction virtual reality task. Participants received fear conditioning, and extinction learning on day 1. Extinction memory recall was tested on day 2. To address interactions between chronotype and time of day of the fear conditioning, and extinction performance, half of the participants were tested in the morning, and the other half in the evening. Skin conductance response (SCR) and subjective fear ratings were measured as primary outcomes. Chronotype was established via the morningness-eveningness questionnaire (MEQ). We found an overall higher SCR for fear acquisition in participants with the evening chronotype profile, compared to controls. Moreover, the higher the MEQ scores -indicative of less eveningness - the lower the SCR was. No effects of chronotype were found for extinction and extinction recall. The higher vulnerability of the evening chronotype for anxiety and related disorders may thus be explained by enhanced fear acquisition of this group. [ABSTRACT FROM AUTHOR]

It is well known that nitric oxide (NO) is involved in forming signal memory for stimulation of different modalities. We studied the involvement of nitric oxide in processes of the reconsolidation (repeated consolidation of a long-term memory on reminding) of conditioned reflex contextual fear memory in rats. After a single training session, animals demonstrated significant increases in freezing on presentation of the conditioned context. Reactivation of this memory on the background of blockade of de novo protein synthesis with cycloheximide led to a significant decrease in freezing time in the conditioned context in rats. Administration of the selective neuronal NO synthase blocker 3-bromo-7-indazole in conditions of memory reactivation on the background of protein synthesis blockade prevented weakening of conditioned reflex freezing reactions, as demonstrated by subsequent testing of animals in the conditioned context. In addition, administration of 3-bromo-7-indazole without reactivation did not elicit significant changes in measures of conditioned reflex freezing in rats. These results suggest that nitric oxide is involved in the labilization of conditioned reflex contextual fear memory on reminding, and is thus a necessary component of the triggering of the reconsolidation process. [ABSTRACT FROM AUTHOR]

The long-lasting nature of fear memories is essential for survival, but the neural circuitry for retrieval of these associations changes with the passage of time. We previously reported a time-dependent shift from prefrontal-amygdalar circuits to prefrontal-thalamic circuits for the retrieval of auditory fear conditioning. However, little is known about the time-dependent changes in the originating site, the prefrontal cortex. Here we monitored the responses of prelimbic (PL) prefrontal neurons to conditioned tones at early (2 h) vs. late (4 days) timepoints following training. Using c-Fos, we find that PL neurons projecting to the amygdala are activated early after learning, but not later, whereas PL neurons projecting to the paraventricular thalamus (PVT) show the opposite pattern. Using unit recording, we find that PL neurons in layer V (the origin of projections to amygdala) showed cue-induced excitation at earlier but not later timepoints, whereas PL neurons in Layer VI (the origin of projections to PVT) showed cue-induced inhibition at later, but not earlier, timepoints, along with an increase in spontaneous firing rate. Thus, soon after conditioning, there are conditioned excitatory responses in PL layer V which influence the amygdala. With the passage of time, however, retrieval of fear memories shifts to inhibitory responses in PL layer VI which influence the midline thalamus. [ABSTRACT FROM AUTHOR]

Background: Fear extinction alone does not erase the original fear memory. Interventions that enhance extinction can be beneficial for the treatment of fear-related disorders. Repetitive transcranial magnetic stimulation has been shown to improve memory performance. The present study examined the effects of intermittent theta-burst stimulation (iTBS) on fear extinction and the return of fear memory in humans. Methods: Ninety-one young healthy volunteers underwent 3 experiments using a randomized controlled experimental design. Participants first acquired fear conditioning, after which they received 30 Hz iTBS before and after extinction training. The iTBS was applied to 1 of 2 targets: the left dorsolateral prefrontal cortex (dlPFC) and the vertex (control). Fear responses were measured 24 hours later and 1 month later. Results: During the spontaneous recovery and reinstatement tests, iTBS of the left dlPFC before and after extinction significantly reduced fear response, whereas iTBS of the vertex had no effect on fear memory performance. This combined approach had a relatively long-lasting effect (i.e., at least 1 month). Limitations: We did not explore the effect of iTBS of the dlPFC on the expression of fear without extinction training. The neural mechanisms of iTBS with fear extinction to inhibit the fear response are unclear. Our results are preliminary and should be interpreted with caution. Conclusion: The present results showed that 30 Hz iTBS of the left dlPFC enhanced retention of fear extinction. Our study introduces a new intervention for fear memory and suggests that the left dlPFC may be a treatment target for fear-related disorders. [ABSTRACT FROM AUTHOR]

Fear conditioning and extinction (FCE) are vital processes in adaptive emotion regulation and disrupted in anxiety disorders. Despite substantial comorbidity between alcohol dependence (ALC) and anxiety disorders and reports of altered negative emotion processing in ALC, neural correlates of FCE in this clinical population remain unknown. Here, we used a 2-day fear learning paradigm in 43 healthy participants and 43 individuals with ALC at the National Institutes of Health. Main outcomes of this multimodal study included structural and functional brain magnetic resonance imaging, clinical measures, as well as skin conductance responses (SCRs) to confirm differential conditioning. Successful FCE was demonstrated across participants by differential SCRs in the conditioning phase and no difference in SCRs to the conditioned stimuli in the extinction phase. The ALC group showed significantly reduced blood oxygenation level-dependent responses in the right amygdala during conditioning (Cohen's d = .89, P(FWE) = .037) and in the left amygdala during fear renewal (Cohen's d = .68, P(FWE) = .039). Right amygdala activation during conditioning was significantly correlated with ALC severity (r = .39, P(Bonferroni) = .009), depressive symptoms (r = .37, P(Bonferroni) = .015), trait anxiety (r = .41, P(Bonferroni) = .006), and perceived stress (r = .45, P(Bonferroni) = .002). Our data suggest that individuals with ALC have dysregulated fear learning, in particular, dysregulated neural activation patterns, in the amygdala. Furthermore, amygdala activation during fear conditioning was associated with ALC-related clinical measures. The FCE paradigm may be a promising tool to investigate structures involved in negative affect regulation, which might inform the development of novel treatment approaches for ALC. [ABSTRACT FROM AUTHOR]

Background: Depression in elderly patients is common and characterized by anxiety symptoms and cognitive impairment. To our knowledge, no studies have yet investigated the process of fear extinction in these patients. We investigated fear extinction with a paradigm consisting of habituation, acquisition and extinction.Methods: We included three age matched (mean age: 75.7 years) groups: Late Life Depression (LLD, n = 33), Mild Cognitive Impairment (MCI, n = 39), healthy controls (HC, n = 39). All participants were diagnosed with a standardized procedure including clinical examination, CERAD cognitive test battery, as well as magnetic resonance imaging. Participants underwent a fear conditioning paradigm consisting of habituation, acquisition, and extinction. During acquisition, a neutral face (conditioned stimulus, CS+) was paired with an electrical unconditioned stimulus, whereas another face (safety stimulus, CS-) was unpaired. Conditioned responses were measured by US-expectancy and valence ratings.Results: Compared to HC, both patient groups showed a significantly lower, differential (CS+ vs. CS-) fear acquisition across all measurements. Patients with cognitive impairment showed a significantly slower extinction, which is characterized by higher US-expectancy and reduced positive valence for CS+. Fear extinction was significantly less differential (CS+ vs. CS-) in patients with LLD.Limitations: Due to the cross-sectional design we cannot distinguish whether the observed differences in fear extinction are state or trait markers in the LLD patients.Conclusions: In this study, we demonstrate that fear extinction is impaired in elderly patients with depression. These results can have influence on treatment strategies. [ABSTRACT FROM AUTHOR]

Background: Establishing neurobiological markers of posttraumatic stress disorder (PTSD) is essential to aid in diagnosis and treatment development. Fear processing deficits are central to PTSD, and their neural signatures may be used as such markers. Methods: Here, we conducted a meta-analysis of seven Pavlovian fear conditioning fMRI studies comparing 156 patients with PTSD and 148 trauma-exposed healthy controls (TEHC) using seed-based d-mapping, to contrast neural correlates of experimental phases, namely conditioning, extinction learning, and extinction recall. Results: Patients with PTSD, as compared to TEHCs, exhibited increased activation in the anterior hippocampus (extending to the amygdala) and medial prefrontal cortex during conditioning; in the anterior hippocampus-amygdala regions during extinction learning; and in the anterior hippocampus-amygdala and medial prefrontal areas during extinction recall. Yet, patients with PTSD have shown an overall decreased activation in the thalamus during all phases in this meta-analysis. Conclusion: Findings from this metanalysis suggest that PTSD is characterized by increased activation in areas related to salience and threat, and lower activation in the thalamus, a key relay hub between subcortical areas. If replicated, these fear network alterations may serve as objective diagnostic markers for PTSD, and potential targets for novel treatment development, including pharmacological and brain stimulation interventions. Future longitudinal studies are needed to examine whether these observed network alteration in PTSD are the cause or the consequence of PTSD. [ABSTRACT FROM AUTHOR]

Importance: The Research Domain Criteria project of the National Institute of Mental Health aims to guide neuropsychiatry toward precision medicine. Its inception was partly in response to the overlap of clinical manifestations between different DSM-IV diagnoses within a category. For example, anxiety disorders comprise a DSM-IV category that includes diagnoses that differ from each other but are all characterized by dysregulated fear levels. Whether DSM-IV-based and Research Domain Criteria-based analytic approaches provide distinct or similar information with regard to the fear circuitry of individuals with anxiety disorders has not been directly tested.Objective: To use a threat conditioning and extinction protocol to conduct categorical (DSM-IV-based) and dimensional (Research Domain Criteria-based) assessments of psychophysiological, neural, and psychometric responses in individuals with and without anxiety disorders.Design, Setting, and Participants: This cross-sectional study was conducted at the Athinoula A. Martinos Center for Biomedical Imaging at Massachusetts General Hospital in Boston between March 2013 and May 2015. Functional magnetic resonance imaging was used to assess psychophysiological, neural, and psychometric responses among adults aged 18 to 65 years with specific phobia, generalized anxiety disorder, social anxiety disorder, and panic disorder as well as a control group of adults without anxiety disorders. Data were analyzed between May 2018 and April 2019.Exposures: A 2-day threat conditioning and extinction protocol.Main Outcomes and Measures: Skin conductance responses and blood oxygenated level-dependent responses were measured during the threat and extinction protocol. The categorical analysis was performed by grouping participants based on their primary DSM-IV diagnosis. The dimensional analysis was performed by regrouping participants, irrespective of their diagnoses, based on their skin conductance responses to shock delivery during threat conditioning.Results: This cross-sectional study of 114 adults aged 18 to 65 years included 93 participants (34 men and 59 women; mean [SD] age, 29.7 [11.1] years) with at least 1 anxiety disorder (specific phobia, generalized anxiety disorder, social anxiety disorder, or panic disorder) and 21 participants (11 men and 10 women) without an anxiety disorder. The categorical DSM-IV-based approach indicated that all anxiety disorder groups exhibited hypoactivation in the ventromedial prefrontal cortex during extinction recall (ηp2 = 0.15; P = .004). The Research Domain Criteria-based approach revealed that higher arousal to the unconditioned stimulus was associated with higher threat responses during extinction recall (for skin conductance responses, ηp2 = 0.21; P = .01 and in functional magnetic resonance imaging results, ηp2 = 0.12; P = .02). The direct comparison of DSM-IV-based vs Research Domain Criteria-based results did not yield significant findings (ηp2 values ranged from 0.02 to 0.078; P values ranged from .09 to .98), suggesting no overlap between the approaches.Conclusions and Relevance: The data obtained from both approaches indicated complementary yet distinct findings. The findings highlight the validity and importance of using both categorical and dimensional approaches to optimize understanding of the etiology and treatment of anxiety symptoms. [ABSTRACT FROM AUTHOR]

Several studies have revealed that fear recovery is prevented when extinction training is conducted after retrieval of a fear memory. Postretrieval extinction training is related to modification of memory during reconsolidation. Providing new information during reconsolidation can modify the original memory. We propose that avoidance behavior is a relevant factor that prevents subjects from obtaining new safety information during reconsolidation. Postretrieval extinction training without avoidance behavior reduced the fear response to conditioned stimulus and prevented spontaneous recovery in the current study, which corresponded with previous studies. Under the condition of postretrieval extinction training with avoidance behavior, the fear response was not reduced as much as it was in the condition without avoidance. It is possible that avoidance behavior prevents receiving new safety information during postretrieval extinction training. [ABSTRACT FROM AUTHOR]

Impaired learning and memory functioning are prime markers for Alzheimer's disease (AD). Although initial evidence points to impaired fear acquisition in later AD, no study has investigated fear conditioning in early stages and amnestic mild cognitive impairment (aMCI), a condition often preceding AD. The present study examined if fear conditioning gradually decays from healthy elderly to patients with aMCI, to patients with AD. Patients with AD (n = 43), patients with aMCI (n = 43), and matched healthy controls (n = 40) underwent a classical fear conditioning paradigm. During acquisition, a neutral face (conditioned stimulus, CS+) was paired with an electrical stimulus, whereas another face (unconditioned stimulus, CS−) was unpaired. Conditioned responses were measured by unconditioned stimulus expectancy, valence, and skin conductance. Compared to healthy controls, both patient groups showed less differential (CS+ vs. CS−) fear acquisition across all measures. Patients further displayed slowed extinction indexed by higher unconditioned stimulus expectancy and reduced positive valence for CS+, declining from aMCI to AD. Groups did not differ in responses during a preconditioning habituation phase and in unconditioned responding. Diminished differential fear acquisition and slowed extinction could represent prognostic markers for AD onset. • Fear conditioning in antidementia medication–free early Alzheimer's disease. • Acquisition deficits increase from healthy controls to early Alzheimer's disease. • Slowed extinction in early Alzheimer's disease compared with healthy controls. • Mild cognitive impairment as a transitional stage regarding conditioning deficits. • Fear conditioning deficits may be an early marker to predict Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Aversive events induce the release of glucocorticoid stress hormones that facilitate long-term memory consolidation, an effect that depends on the activation of glucocorticoid receptors (GRs). GRs are distributed widely in the hippocampus. The dorsal region of the hippocampus has been related to cognitive functions and the ventral region to stress and emotion. GR acts as a transcription factor which after hormone binding becomes phosphorylated, affecting its cellular distribution and transcriptional activity. Two functionally well-described GR phosphorylation sites are serine 232 (pSer232), which enhances gene expression, and serine 246 (pSer246), having the opposite effect. Since gene expression is one of the plastic mechanisms needed for memory consolidation, we investigated if an aversive learning task would induce GR phosphorylation in the dorsal (DH) and the ventral (VH) hippocampus. We trained rats in contextual fear conditioning (CFC) using different foot-shock intensities (0.0, 0.5, or 1.5 mA). One subgroup of animals trained with each intensity was sacrificed 15 min after training and blood was collected to quantify corticosterone (CORT) levels in serum. Another subgroup was sacrificed 1 h after training and brains were collected to evaluate the immunoreactivity (IR) to GR, pSer232 and pSer246 by SDS-PAGE/Western blot in DH and VH, and by immunohistochemistry in dorsal and ventral CA1, CA2, CA3, and dentate gyrus (DG) hippocampal regions. The conditioned freezing response increased in animals trained with 0.5 and 1.5 mA during training and extinction sessions. The degree of retention and CORT levels were directly related to the intensity of the foot-shock. Although total GR-IR remained unaffected after conditioning, we observed a significant increase of pSer246-IR in the dorsal region of CA1 and in both dorsal and ventral DG. The only region in which pSer232-IR was significantly elevated was ventral CA3. Our results indicate that fear conditioning training is related to GR phosphorylation in specific subregions of the hippocampus, suggesting that its transcriptional activity for gene expression is favored in ventral CA3, whereas its repressor activity for gene-silencing is increased in dorsal CA1 and in both dorsal and ventral DG. [ABSTRACT FROM AUTHOR]

There is now ample evidence that the strength and underlying mechanisms of memory formation can be drastically altered by prior experience. However, the prior work using rodent models on this topic has used only males as subjects, and as a result, we do know whether or not the effects of prior experience on subsequent learning are similar in both sexes. As a first step towards addressing this shortcoming, rats of both sexes were given auditory fear conditioning, or fear conditioning with unsignaled shocks, followed an hour or a day later by a single pairing of light and shock. Fear memory for each experience was assessed by measuring freezing behavior to the auditory cue and fear-potentiated startle to the light. Results showed that males trained with auditory fear conditioning showed facilitated learning to the subsequent visual fear conditioning session when the two training sessions were separated by one hour or one day. Females showed evidence of facilitation in rats given auditory conditioning when they were spaced by an hour but not when they were spaced by one day. Contextual fear conditioning did not support the facilitation of subsequent learning under any conditions. These results indicate that the mechanism by which prior fear conditioning facilitates subsequent learning differs between sexes, and they set the stage for mechanistic studies to understand the neurobiological basis of this sex difference. [ABSTRACT FROM AUTHOR]

Background: Extinction-based procedures are often used to inhibit maladaptive fear responses. However, because extinction procedures show efficacy limitations, transcranial direct current stimulation (tDCS) has been suggested as a promising add-on enhancer. Objective: In this study, we tested how cathodal tDCS over the right dorsolateral prefrontal cortex affects extinction and tried to unveil the processes at play that boost the effectiveness of extinction procedures and its translational potential to the treatment of anxiety disorders. Methods: We implemented a fear conditioning paradigm whereby 41 healthy women (mean age = 20.51 ± 5.0) were assigned to either cathodal tDCS (n = 27) or sham tDCS (n = 16). Fear responses were measured with self-reports, autonomic responses, and implicit avoidance tendencies. Results: Cathodal tDCS shows no statistically significant effect in extinction, according to self-reports, and seems to even negatively affect fear conditioned skin conductance responses. However, one to three months after the tDCS session and extinction, we found a group difference in the action tendencies towards the neutral stimuli (F (1, 41) = 12.04, p = .001, ηp2 = .227), with the cathodal tDCS group (as opposed to the sham group) showing a safety learning (a positive bias towards the CS-), with a moderate effect size. This suggests that cathodal tDCS may foster stimuli discrimination, leading to a decreased generalization effect. Discussion: Cathodal tDCS may have enhanced long-term distinctiveness between threatening cues and perceptively similar neutral cues through a disambiguation process of the value of the neutral stimuli—a therapeutic target in anxiety disorders. Future studies should confirm these results and extend the study of cathodal tDCS effect on short term avoidance tendencies. [ABSTRACT FROM AUTHOR]

Background : Δ9-Tetrahydrocannabinol (THC, a CB1 receptor agonist) and Cannabidiol (CBD, a non-competitive antagonist of endogenous CB1 and CB2 ligands) are two primary components of Cannabis species, and may modulate fear learning in mammals. The CB1 receptor is widely distributed throughout the cortex and some limbic regions typically associated with fear learning. Humans with posttraumatic disorder (PTSD) have widespread upregulation of CB1 receptor density and reduced availability of endogenous cannabinoid anandamide, suggesting a role for the endocannabinoid system in PTSD. Pharmacological blockade of memory reconsolidation following recall of a conditioned response modulates the expression of learned fear and may represent a viable target for the development of new treatments for PTSD. In this study, we focused on assessing the impact of the key compounds of the marijuana plant both singly and, more importantly, in concert on attenuation of learned fear. Specifically, we assessed the impact of THC, CBD, and/or the remaining plant materials (post-extraction; background material), on reconsolidation of learned fear. Method : Male Sprague-Dawley rats received six 1.0 mA continuous foot shocks (contextual training). Twenty-four hours later, rats were re-exposed to the context. Immediately following memory retrieval (recall) rats received oral administration of low dose THC, high dose THC, CBD, CBD + low THC, CBD + high THC [as isolated phytochemicals and, in separate experiments, in combination with plant background material (BM)]. Rodents were tested for freezing response context re-exposure at 24 h and 7 days following training. Results : CBD alone, but not THC alone, significantly attenuated fear memory reconsolidation when administered immediately after recall. The effect persisted for at least 7 days. A combination of CBD and THC also attenuated the fear response. Plant BM also significantly attenuated reconsolidation of learned fear both on its own and in combination with THC and CBD. Finally, THC attenuated reconsolidation of learned fear only when co-administered with CBD or plant BM. Conclusion : CBD may provide a novel treatment strategy for targeting fear-memories. Furthermore, plant BM also significantly attenuated the fear response. However, whereas THC alone had no significant effects, its effects were modulated by the addition of other compounds. Future research should investigate some of the other components present in the plant BM (such as terpenes) for their effects alone, or in combination with isolated pure cannabinoids, on fear learning. [ABSTRACT FROM AUTHOR]

The purpose of the present study was to determine whether age would disrupt fear retention and extinction memory in rats pre-exposed to maternal separation and isolation stress; these rats are called MS rats. MS stress was induced by exposing rat pups into maternal separation followed by isolation stress from peer groups (MS) daily/6 h during stress hyporesponsive period, while controls rats that were undisturbed during this period are called NMS rats. 5, 8, 15 and 52 weeks later, these animals were exposed to classical fear conditioning test by pairing auditory stimulus (conditioned stimulus, CS+) with electric footshock. 24 h later, conditioned freezing response to CS+ was measured during fear retention, extinction and extinction recall trials. The normal ageing per se did not affect the formation of fear memory, retention and fear extinction memory. MS stress, on the other hand, disrupted fear memory at young adulthood age exhibiting increased freezing response to CS+ during retention test and reduced during fear extinction memory test when compared to NMS groups. On the other hand, rats at adolescence age exhibited reduced freezing during fear retention and enhanced freezing response to CS+ during extinction recall test. However, MS-induced changes in freezing response during fear retention and extinction tests were not seen in adulthood and 1-year-old age groups. These data demonstrate the young adulthood age is highly vulnerable to fear memory and extinction processes. The differences in freezing response to CS+ during fear conditioning from adolescence to old age, thus, appear to be related to the maturation of the limbic circuit. [ABSTRACT FROM AUTHOR]

Rationale: The ability to memorize threat-associated cues and subsequently react to them, exhibiting escape or avoidance responses, is an essential, often life-saving behavioral mechanism that can be experimentally studied using the fear (threat) conditioning training paradigm. Presently, there is substantial evidence supporting the Synaptic Plasticity-Memory (SPM) hypothesis in relation to the mechanisms underlying the acquisition, retention, and extinction of conditioned fear memory.Objectives: The purpose of this review article is to summarize findings supporting the SPM hypothesis in the context of conditioned fear control, applying the set of criteria and tests which were proposed as necessary to causally link lasting changes in synaptic transmission in corresponding neural circuits to fear memory acquisition and extinction with an emphasis on their pharmacological diversity.Results: The mechanisms of synaptic plasticity in fear circuits exhibit complex pharmacological profiles and satisfy all four SPM criteria—detectability, anterograde alteration, retrograde alteration, and mimicry.Conclusion: The reviewed findings, accumulated over the last two decades, provide support for both necessity and sufficiency of synaptic plasticity in fear circuits for fear memory acquisition and retention, and, in part, for fear extinction, with the latter requiring additional experimental work. [ABSTRACT FROM AUTHOR]

In the recent decade, fear conditioning has evolved as a standard procedure for testing cognitive abilities such as memory acquisition, consolidation, recall, reconsolidation, and extinction, preferentially in genetically modified mice. The reasons for the popularity of this powerful approach are its ease to perform, the short duration of training and testing, and its well-described neural basis. So why to bother about flaws in standardization of test procedures and analytical routines? Simplicity does not preclude the existence of fallacies. A short survey of the literature revealed an indifferent use of acoustic stimuli in terms of quality (i.e., white noise vs. sine wave), duration, and intensity. The same applies to the shock procedures. In the present article, I will provide evidence for the importance of qualitative and quantitative parameters of conditioned and unconditioned stimuli for the experimental outcome. Moreover, I will challenge frequently applied interpretations of short-term vs. long-term extinction and spontaneous recovery. On the basis of these concerns, I suggest a guideline for standardization of fear conditioning experiments in mice to improve the comparability of the experimental data. [ABSTRACT FROM AUTHOR]

Post-traumatic stress disorder (PTSD) is a psychiatric disorder associated with memories of traumatic experiences. Conditioned fear memory, a representative model of traumatic memories, is observed across species from lower to higher animals, including humans. Numerous studies have investigated the mechanisms of conditioned fear memory and have led to the identification of the underlying processes involved in fear memory regulation, including cellular and systems consolidation of fear conditioning, destabilization/reconsolidation and extinction after fear memory retrieval, and forgetting of fear memory. These studies suggested that mechanisms for fear memory regulation are shared by humans and other higher animals. Additionally, rodent studies have identified the mechanisms of fear memory at the molecular, cellular, and circuit levels. Findings from these studies in rodents have been applied to facilitate the development and improvement of PTSD intervention. For instance, reconsolidation and extinction of fear memories have been applied for PTSD treatment to improve prolonged exposure (PE) therapy, an effective psychotherapy for PTSD. Combination of medications weakening retrieved traumatic memory (e.g., by facilitating both destabilization and extinction) with PE therapy may contribute to improvement of PTSD. Interestingly, a recent study in mice identified forgetting of fear memory as another potential therapeutic target for PTSD. A better understanding of the mechanisms involved in fear memory processes is likely to facilitate the development of better treatments for PTSD. This review describes fear memory processes and their mechanisms and discusses the pros and cons of applying how this knowledge can be applied in the development of interventions for PTSD. [ABSTRACT FROM AUTHOR]

Rationale: Memories can return to a labile state and become amenable to modification by pharmacological and behavioral manipulations after retrieval. This process may reduce the impact of aversive memories and provide a promising therapeutic technique for the treatment of anxiety disorders. A growing body of evidence suggests that the mammalian neuropeptide oxytocin (OT) plays a role in the regulation of emotional memories in animals. However, the effects of OT on threat memory in humans remain largely unknown.Objectives: This study aimed to investigate the effects of OT administration following threat memory retrieval on subsequent memory expression in human participants.Methods: In a double-blind, randomized, placebo-controlled, between-subject design, 61 healthy human individuals completed a 3-day experiment. All the participants underwent threat conditioning on day 1. On day 2, the participants were randomized to receive an intranasal dose of OT (40 IU) or placebo after memory retrieval, or an intranasal dose of OT (40 IU) without retrieval. On day 3, the participants were tested for extinction and reinstatement.Results: On day 3, all groups showed equivalent stimulus discrimination during the early phase of extinction. However, the group that received OT following a memory reminder showed a greater decline in stimulus discrimination by the late phase of extinction relative to the two other groups.Conclusions: The results indicate that OT did not block reconsolidation to prevent the return of threat memory but rather interacted with post-retrieval processes to facilitate next day extinction. The study provides novel preliminary evidence for the role of OT in human threat memory. [ABSTRACT FROM AUTHOR]

Rationale: Many studies have found that ethanol intoxication and withdrawal impair initial acquisition or extinction of learned behaviors. Rapid reconditioning following extinction is a form of post-extinction re-emergence of conditioned behavior that has not been studied for its interaction with ethanol intoxication or withdrawal.Objectives: The goals of this paper were to define the parameters that allow rapid post-extinction reacquisition of fear in mice and investigate the effect of acute ethanol withdrawal and intoxication on acquisition, extinction, and post-extinction reconditioning.Methods: We examined acquisition, extinction, and post-extinction reconditioning of contextual fear in male C57BL/6 mice. Acute ethanol withdrawal occurred 6 h following a 4 g/kg injection of 20% ethanol and acute ethanol intoxication occurred 5 min following a 1.5 g/kg injection of 20% ethanol.Results: A weak context-shock pairing caused rapid reacquisition of conditioned freezing following moderate, but not extensive extinction. Acute ethanol intoxication impaired initial conditioning and acute ethanol withdrawal impaired rapid reacquisition after extinction, but not reconditioning or extinction itself.Conclusions: These findings show that rapid reconditioning occurs following moderate but not extensive extinction in C57BL/6J mice. Additionally, acute ethanol withdrawal and intoxication may differentially affect different phases of conditioning. Results are discussed in terms of current ideas about post-extinction behavior and ethanol's effects on memory. [ABSTRACT FROM AUTHOR]

Rationale: Stress disorders cause abnormal regulation of fear-related behaviors. In most rodent models of these effects, stress was administered before fear conditioning, thereby assessing its impact on both the formation and extinction of fear memories, not the latter alone. Here, we dissociated the two processes by also administering stress after fear conditioning, and then compared how pre-conditioning versus post-conditioning exposure to chronic stress affects subsequent acquisition and recall of fear extinction.Methods: Male Wistar rats were subjected to chronic immobilization stress (2 h/day, 10 days); the morphological effects of which were analyzed using modified Golgi-Cox staining across brain areas mediating the formation and extinction of fear memories. Separate groups of rats underwent fear conditioning followed by acquisition and recall of extinction, wherein stress was administered either before or after fear conditioning.Results: When fear memories were formed after chronic stress, both acquisition and retrieval of extinction was impaired. Strikingly, these deficits were absent when fear memories were formed before the same stress. Chronic stress also reduced dendritic spine density in the infralimbic prefrontal cortex, but enhanced it in the basolateral amygdala.Conclusion: Chronic stress, administered either before or after fear learning, had distinct effects on the acquisition and recall of fear extinction memories. Stress also strengthened the structural basis of synaptic connectivity in the amygdala, but weakened it in the prefrontal cortex. Thus, despite eliciting a specific pattern of brain region-specific morphological changes, the timing of the same stress gave rise to strikingly different behavioral effects on the extinction of fear. [ABSTRACT FROM AUTHOR]

Fear learning and extinction are controlled by the activity of three interconnected regions: the amygdala, hippocampus, and prefrontal cortex. Of these, the medial prefrontal cortex modulates specific aspects in fear and extinction via a top-down regulation. In recent years, extensive progress has been made in our understanding of the neural circuits that mediate fear-related behaviors and their modulation by ascending systems. The development of new experimental techniques is now revealing the details of the intrinsic circuits within these structures as well as the connections between them. Here, we highlight recent advances in our understanding of how the prefrontal cortex may mediate such a top-down regulation. [ABSTRACT FROM AUTHOR]

Previous studies showed that emotional faces break through interocular suppression more easily compared to neutral faces under the continuous flash suppression (CFS) paradigm. However, there is controversy over whether emotional content or low-level properties contributed to the results. In this study, we directly manipulated the meaningfulness of facial expression to test the role of emotional content in breaking CFS (b-CFS). In addition, an explicit emotion judgment for different facial expressions (happy, neutral, and fearful) used in the b-CFS task was also conducted afterwards to examine the relationship between b-CFS time and emotion judgment. In Experiment 1, face orientation and luminance polarity were manipulated to generate upright-positive and inverted-negative faces. In Experiment 2, Asian and Caucasian faces were presented to Taiwanese participants so that these stimuli served as own-race and other-race faces, respectively. We found robust face familiarity effects in both experiments within the same experimental framework: upright-positive and own-race faces had shorter b-CFS times than inverted-negative and other-race faces, respectively. This indicates potential involvement of high-level processing under interocular suppression. In Experiment 1, different b-CFS times were found between emotional and neutral faces in both upright-positive and inverted-negative conditions. Furthermore, with sufficient duration (1000 ms) participants could still extract emotional content in explicit valence judgment even from inverted-negative faces, though with a smaller degree than upright-positive faces. In Experiment 2, differential b-CFS times were found between emotional and neutral faces with own-race but not other-race faces. Correlation analyses from both experiments showed that the magnitude of emotion judgment was correlated with b-CFS time only for familiar (upright-positive / own-race) but not unfamiliar (inverted-negative / other-race) faces. These results suggest that emotional content can be extracted under interocular suppression with familiar faces, and low-level properties in unfamiliar faces may play a major role in the b-CFS time. [ABSTRACT FROM AUTHOR]

Extinction learning, which creates new safety associations, is thought to be the mechanism underlying exposure therapy, commonly used for the treatment of anxiety disorders and posttraumatic stress disorder. The relative strength and availability for retrieval of both the fear and safety memories determine the response in a given situation. While the fear memory is often context-independent and may easily generalize, extinction memory is highly context-specific. "Renewal" of the extinguished fear memory might thus occur following a shift in context. The aim of the current work was to create an enhanced and generalized extinction memory to a discrete stimulus using stress exposure before extinction learning, thereby preventing renewal. In our contextual fear conditioning paradigm, 40 healthy men acquired (Day 1), retrieved and extinguished (Day 2) the fear memories, with no differences between the stress and the control group. A significant difference between the groups emerged in the renewal test (Day 3). A renewal effect was seen in the control group (N = 20), confirming the context-dependency of the extinction memory. In contrast, the stress group (N = 20) showed no renewal effect. Fear reduction was generalized to the acquisition context as well, suggesting that stress rendered the extinction memory more context-independent. These results are in line with previous studies that showed contextualization disruption as a result of pre-learning stress, mediated by the rapid effects of glucocorticoids on the hippocampus. Our findings support research investigating the use of glucocorticoids or stress induction in exposure therapy and suggest the right timing of administration in order to optimize their effects. [ABSTRACT FROM AUTHOR]

The ventral hippocampus (vHPC) has been implicated in learning and memory functions that seem to differ from its dorsal counterpart. The goal of this series of experiments was to provide further insight into the functional contributions of the vHPC. Our previous work implicated the vHPC in spatial learning, inhibitory learning, and fear conditioning to context. However, the specific role of vHPC on these different forms of learning are not clear. Accordingly, we assessed the effects of neurotoxic lesions of the ventral hippocampus on retention of a conditioned inhibitory association, early versus late spatial navigation in the water task, and discriminative fear conditioning to context under high ambiguity conditions. The results showed that the vHPC was necessary for the expression of conditioned inhibition, early spatial learning, and discriminative fear conditioning to context when the paired and unpaired contexts have high cue overlap. We argue that this pattern of effects, combined with previous work, suggests a key role for vHPC in the utilization of broad contextual representations for inhibition and discriminative memory in high ambiguity conditions. [ABSTRACT FROM AUTHOR]

The basolateral amygdala (BLA) is a major target and modulator of stress and has a critical role in the neural circuitry presenting learned fear behaviors. On the other hand, both the endocannabinoid and noradrenergic systems may be involved in regulating the stress responses, fear, and anxiety. Considering the aforementioned, we have investigated the involvement of the BLA β1-adrenoceptors in conditioned fear responses induced by ACPA, a CB1 receptor (CB1R) agonist. In adult male NMRI mice, freezing responses to context and cue were measured using a Pavlovian fear conditioning apparatus. Pre-training intra-BLA microinjection of xamoterol (0.01 and 0.02 µg/mouse), a partial β1-adrenoceptor agonist, or atenolol (0.5 µg/mouse), a β1-adrenoceptor antagonist, decreased freezing behavior, which suggests an impairment of contextual and auditory fear retrieval. Similar results were found with pre-training intraperitoneal administration of ACPA (0.5 mg/kg). A sub-threshold dose of xamoterol, infused into the BLA, decreased ACPA (0.005 and 0.05 mg/kg) effect on both memories, while atenolol increased ACPA response to the context at the middle dose and decreased ACPA response to the tone at the lower dose. It can be concluded that the blockade of BLA β1-adrenoceptors differentially affects ACPA response on the contextual and auditory conditioned fear memories. [ABSTRACT FROM AUTHOR]

Classical fear conditioning is perhaps the premier model system used to study the neurobiological basis of memory formation. Prior work has resulted in a good understanding of both the molecular mechanisms and neural circuits supporting this form of learning. However, much of what is known about these mechanisms comes from studies in which fear memory is acquired using a single, isolated training session. Given that we cannot divorce the acquisition of new information from the backdrop on which it occurs, studies are needed to determine how the acquisition of fear memory is affected by other learning events. Here, we used rats to describe the time course by which auditory fear conditioning can facilitate learning to a different fear learning event, which alone is insufficient to support long-term fear memory. First, we replicated previous findings showing that although a single trial of light and shock produces little evidence of memory, two identical trials spaced 60 min or 24 h apart support long-term memory. Next, we report that a typical auditory fear conditioning session facilitated memory formation when rats were subsequently exposed to a single trial of light and shock 60 min or 24 h, but not 4 min, later. Finally, we show that learning can be enhanced retroactively if auditory fear conditioning occurs 60 min, but not 24 h, after a single light-shock pairing. These data demonstrate that a weak fear conditioning trial can be enhanced by prior and subsequent fear conditioning depending on the timing between training events. [ABSTRACT FROM AUTHOR]

Ketamine, principally an antagonist of N-methyl-ᴅ-aspartate receptors, induces schizophrenia-like symptoms in adult humans, warranting its use in the investigation of psychosis-related phenotypes in animal models. Genomic studies further implicate N-methyl-ᴅ-aspartate receptor-mediated processes in schizophrenia pathology, together with more broadly-defined synaptic plasticity and associative learning processes. Strong pathophysiological links have been demonstrated between fear learning and psychiatric disorders such as schizophrenia. To further investigate the impact of ketamine on associative fear learning, we studied the effects of pre- and post-training ketamine on the consolidation and extinction of contextual fear memory in rats. Administration of 25 mg/kg ketamine prior to fear conditioning did not affect consolidation when potentially confounding effects of state dependency were controlled for. Pre-training ketamine (25 mg/kg) impaired the extinction of the conditioned fear response, which was mirrored with the use of a lower dose (8 mg/kg). Post-training ketamine (25 mg/kg) had no effect on the consolidation or extinction of conditioned fear. These observations implicate processes relating to the extinction of contextual fear memory in the manifestation of ketamine-induced phenotypes, and are consistent with existing hypotheses surrounding abnormal associative learning in schizophrenia. [ABSTRACT FROM AUTHOR]

Background and Objectives: Stimuli associated with the trauma are important triggers for intrusive memories after a traumatic event. Clinical models assume that fear conditioning for neutral stimuli encountered during traumatic events is a potential cause of these intrusions, and that memory integration has the effect of reducing these associations, thereby also reducing intrusions. This study examines whether conditioned associations lead to intrusive trauma memories and how they are affected by memory integration.Methods: Forty-eight healthy participants watched a neutral and a "traumatic" film, both containing neutral sounds, and, on the following day, were randomly allocated to memory integration of either the "traumatic" film or the neutral film. Intrusive memories were monitored for one week. Participants repeatedly completed a memory triggering task, in order to assess how durable conditioned intrusive memories are over time.Results: Trauma-associated sounds elicited intrusive memories and anxiety when encountered directly after film presentation, as well as one and seven days later. Furthermore, enhanced conditionability predicted subsequent ambulatory trauma intrusions. No evidence was found for the assumption that memory integration of the "traumatic" film reduced conditioned reactions.Limitations: The presented film is a relatively mild stressor as compared to a real-life trauma. Further studies are needed to explore the role of conditioned intrusions for real-life trauma.Conclusions: This study provides evidence for the assumption that intrusive trauma memories can be explained by conditioned responses to neutral stimuli encountered during the trauma and that these effects are stable over time. Implications for PTSD and its treatment are discussed. [ABSTRACT FROM AUTHOR]

Time plays an important role in conditioning, it is not only possible to associate stimuli with events that overlap, as in delay fear conditioning, but it is also possible to associate stimuli that are discontinuous in time, as shown in trace conditioning for a discrete stimuli. The environment itself can be a powerful conditioned stimulus (CS) and be associated to unconditioned stimulus (US). Thus, the aim of the present study was to determine the parameters in which contextual fear conditioning occurs by the maintenance of a contextual representation over short and long time intervals. The results showed that a contextual representation can be maintained and associated after 5 s, even in the absence of a 15 s re-exposure to the training context before US delivery. The same effect was not observed with a 24 h interval of discontinuity. Furthermore, optimal conditioned response with a 5 s interval is produced only when the contexts (of pre-exposure and shock) match. As the pre-limbic cortex (PL) is necessary for the maintenance of a continuous representation of a stimulus, the involvement of the PL in this temporal and contextual processing was investigated. The reversible inactivation of the PL by muscimol infusion impaired the acquisition of contextual fear conditioning with a 5 s interval, but not with a 24 h interval, and did not impair delay fear conditioning. The data provided evidence that short and long intervals of discontinuity have different mechanisms, thus contributing to a better understanding of PL involvement in contextual fear conditioning and providing a model that considers both temporal and contextual factors in fear conditioning. [ABSTRACT FROM AUTHOR]

Many studies suggest that fear conditioning influences sleep. It is, however, not known if the changes in sleep architecture after fear conditioning are essentially associated with the consolidation of fearful memory or with fear itself. Here, we have observed that within sleep, NREM sleep consistently remained augmented after the consolidation of cued fear-conditioned memory. But a similar change did not occur after impairing memory consolidation by blocking new protein synthesis and glutamate transmission between glial-neuronal loop in the lateral amygdala (LA). Anisomycin (a protein synthesis inhibitor) and DL-α–amino-adipic acid (DL- α -AA) (a glial glutamine synthetase enzyme inhibitor) were microinjected into the LA soon after cued fear-conditioning to induce memory impairment. On the post-conditioning day, animals in both the groups exhibited significantly less freezing. In memory-consolidated groups (vehicle groups), NREM sleep significantly increased during 2nd to 5th hours after training compared to their baseline days. However, in memory impaired groups (anisomycin and DL- α -AA microinjected groups), similar changes were not observed. Our results thus suggest that changes in sleep architecture after cued fear-conditioning are indeed a consolidation dependent event. [ABSTRACT FROM AUTHOR]

Currently the model of associative memory in mammals most frequently used in neurobiological studies consists of acquisition of a conditioned reflex freezing reaction. As most studies address the mechanisms of learning in response to a sound stimulus, the question of the extent to which the patterns of forming associative memory are universal and apply to other conditioned stimuli remains open. The aim of the present work was to compare the dynamics of the formation and reproduction of a memory in mice on acquisition of a conditioned freezing reaction to light and sound conditioned stimuli. Training using a light stimulus was found to occur in this model significantly more slowly than using a sound signal. In addition, the dynamics of memory reproduction differed in animals trained using sound and light stimuli, being slower using light stimuli, which may reflect different consolidation or extraction processes for these types of memory. The results of this study are critically important for understanding the common and specific conditions for the formation of associative memory in this model. [ABSTRACT FROM AUTHOR]

Background: Considerable research has revealed impaired fear extinction to be a significant predictor of PTSD. Fear extinction is also considered the primary mechanism of exposure therapy, and a critical factor in PTSD recovery. The cognitive theory of PTSD proposes that symptoms persist due to excessive negative appraisals about the trauma and its sequelae. Research has not yet examined the relationship between fear extinction and negative appraisals in PTSD.Methods: A cross-sectional sample of participants with PTSD (n =21), and trauma-exposed controls (n =33) underwent a standardized differential fear conditioning and extinction paradigm, with skin conductance response (SCR) amplitude serving as the index of conditioned responses. The Posttraumatic Cognitions Inventory (PTCI) was used to index catastrophic negative appraisals.Results: Participants with PTSD demonstrated a slower decrease in overall SCR responses during extinction and greater negative appraisals compared to the group. A moderation analysis revealed that both negative trauma-relevant appraisals and fear extinction learning were independently associated with PTSD symptoms, but there was no moderation interaction.Limitations: The current study was limited by a modest sample size, leading to the inclusion of participants with subclinical PTSD symptoms. Further, the current study only assessed fear extinction learning; including a second day extinction recall task may show alternative effects.Conclusions: These findings indicate that negative appraisals and fear extinction did not interact, but had independent relationships with PTSD symptoms. Here we show for the first time in an experimental framework that negative appraisals and fear extinction play separate roles in PTSD symptoms. [ABSTRACT FROM AUTHOR]

The median raphe region (MRR) is believed to control the fear circuitry indirectly, by influencing the encoding and retrieval of fear memories by amygdala, hippocampus and prefrontal cortex. Here we show that in addition to this established role, MRR stimulation may alone elicit the emergence of remote but not recent fear memories. We substituted electric shocks with optic stimulation of MRR in C57BL/6N male mice in an optogenetic conditioning paradigm and found that stimulations produced agitation, but not fear, during the conditioning trial. Contextual fear, reflected by freezing was not present the next day, but appeared after a 7 days incubation. The optogenetic silencing of MRR during electric shocks ameliorated conditioned fear also seven, but not one day after conditioning. The optogenetic stimulation patterns (50Hz theta burst and 20Hz) used in our tests elicited serotonin release in vitro and lead to activation primarily in the periaqueductal gray examined by c-Fos immunohistochemistry. Earlier studies demonstrated that fear can be induced acutely by stimulation of several subcortical centers, which, however, do not generate persistent fear memories. Here we show that the MRR also elicits fear, but this develops slowly over time, likely by plastic changes induced by the area and its connections. These findings assign a specific role to the MRR in fear learning. Particularly, we suggest that this area is responsible for the durable sensitization of fear circuits towards aversive contexts, and by this, it contributes to the persistence of fear memories. This suggests the existence a bottom-up control of fear circuits by the MRR, which complements the top-down control exerted by the medial prefrontal cortex. [ABSTRACT FROM AUTHOR]

Cholinergic neurotransmission plays a key role in learning and memory. Prior research with rats indicated that a low dose of pre-training scopolamine (0.1 mg/kg), a cholinergic receptor antagonist, did not affect cued fear conditioning, but did block renewal when injected before extinguishing a conditioned tone, opening up opportunities to pharmacologically improve exposure therapy for anxiety patients. Before translating these findings to the clinic, it is important to carefully examine how scopolamine affects contextual fear memories. Here, we investigated the effects of scopolamine on encoding of contextual anxiety and its generalization in male Wistar rats. We found a profound disruption of context conditioning, suggesting that, even at a low dose, systemic scopolamine may influence contextual encoding in the hippocampus, particularly when the context is the best predictor for the presence of shocks. [ABSTRACT FROM AUTHOR]

Background: Although substantial evidence suggests that dopamine (DA) enhances conditioned fear responses, few studies have examined the role of DA in unconditioned fear states. Whereas DA does not cross the blood-brain barrier, intranasally-applied dopamine reaches the brain directly via the nose-brain pathways in rodents, providing an alternative means of targeting DA receptors. Intranasal dopamine (IN-DA) has been demonstrated to bind to DA transporters and to increase extracellular DA in the striatum as well as having memory-promoting effects in rats. The purpose of this study was to examine the influence of IN-DA in three tests of fear/anxiety.Methods: The three doses of DA hydrochloride (0.03, 0.3, or 1 mg/kg) were applied in a viscous castor oil gel in a volume of 5 µl to each of both nostrils of adult Wistar rats prior to testing of (a) escape from a bright light, using a two-chamber procedure, (b) restraint-induced 22 kHz ultrasound vocalizations (USVs), and (c) exploratory behavior in the elevated plus-maze (EPM).Results: IN-DA dose-dependently reduced escape from bright light and the number of USV responses to restraint. It had no influence on the exploratory behavior in the EPM.Conclusions: IN-DA application reduced escape behavior in two tests of unconditioned fear (escape from bright light and USV response to immobilization). These findings may be interpreted in light of the known antidepressant action of IN-DA and DA reuptake blockers. The results also confirm the promise of the nasal route as an alternative means for targeting the brain's dopaminergic receptors with DA. [ABSTRACT FROM AUTHOR]

Importance: The fear conditioning and extinction neurocircuitry has been extensively studied in healthy and clinical populations, with a particular focus on posttraumatic stress disorder. Despite significant overlap of symptoms between posttraumatic stress disorder and anxiety disorders, the latter has received less attention. Given that dysregulated fear levels characterize anxiety disorders, examining the neural correlates of fear and extinction learning may shed light on the pathogenesis of underlying anxiety disorders.Objectives: To investigate the psychophysiological and neural correlates of fear conditioning and extinction recall in anxiety disorders and to document how these features differ as a function of multiple diagnoses or anxiety severity.Design, Setting, and Participants: This investigation was a cross-sectional, case-control, functional magnetic resonance imaging study at an academic medical center. Participants were healthy controls and individuals with at least 1 of the following anxiety disorders: generalized anxiety disorder, social anxiety disorder, specific phobia, and panic disorder. The study dates were between March 2013 and May 2015.Exposures: Two-day fear conditioning and extinction paradigm.Main Outcomes and Measures: Skin conductance responses, blood oxygenation level-dependent responses, trait anxiety scores from the State Trait Anxiety Inventory-Trait Form, and functional connectivity.Results: This study included 21 healthy controls (10 women) and 61 individuals with anxiety disorders (36 women). P values reported for the neuroimaging results are all familywise error corrected. Skin conductance responses during extinction recall did not differ between individuals with anxiety disorders and healthy controls (ηp2 = 0.001, P = .79), where ηp2 is partial eta squared. The anxiety group had lower activation of the ventromedial prefrontal cortex (vmPFC) during extinction recall (ηp2 = 0.178, P = .02). A similar hypoactive pattern was found during early conditioning (ηp2 = 0.106, P = .009). The vmPFC hypoactivation was associated with anxiety symptom severity (r = -0.420, P = .01 for conditioning and r = -0.464, P = .004 for extinction recall) and the number of co-occuring anxiety disorders diagnosed (ηp2 = 0.137, P = .009 for conditioning and ηp2 = 0.227, P = .004 for extinction recall). Psychophysiological interaction analyses revealed that the fear network connectivity differed between healthy controls and the anxiety group during fear learning (ηp2 range between 0.088 and 0.176 and P range between 0.02 and 0.003) and extinction recall (ηp2 range between 0.111 and 0.235 and P range between 0.02 and 0.002).Conclusions and Relevance: Despite no skin conductance response group differences during extinction recall, brain activation patterns between anxious and healthy individuals differed. These findings encourage future studies to examine the conditions longitudinally and in the context of treatment trials to improve and guide therapeutics via advanced neurobiological understanding of each disorder. [ABSTRACT FROM AUTHOR]

We previously showed that a single weak fear conditioning trial, that does not produce a long-term fear memory (LTM), appeared to prime memory formation such that when a second trial followed within a circumscribed time window a robust and long-lasting fear memory was formed. We also showed that this priming effect could be blocked if we interfered with protein kinase A (PKA) signaling in the amygdala during the first conditioning trial. The goals of the current study were to determine if LTM formation after the second trial depends on PKA signaling in the amygdala and to characterize the underlying memory processes engaged during the second trial that allows for LTM formation. Our interpretation of the original findings is that the second conditioning trial triggers LTM from a metaplastic state that is engaged by the first conditioning trial. However, it is also possible that the second conditioning trial acts as a reminder of the first and engages a reconsolidation-like process. Several experiments were conducted to distinguish between these two possibilities. We show that interfering with PKA signaling during the second conditioning trial disrupts memory formation. However, if a third trial follows the second or if the second trial was presented without shock, the PKA inhibitor was no longer effective. Our findings demonstrate that the induction of fear memory from a metaplastic state involves new learning that is distinct from retrieval-dependent updating of memories. [ABSTRACT FROM AUTHOR]

Background: Amygdala-prefrontal cortex (PFC) functional connectivity may be influenced by anxiety and development. A prior study on anxiety found age-specific dysfunction in the ventromedial PFC (vmPFC), but not amygdala, associated with threat-safety discrimination during extinction recall (Britton et al.). However, translational research suggests that amygdala-PFC circuitry mediates responses following learned extinction. Anxiety-related perturbations may emerge in functional connectivity within this circuit during extinction recall tasks. The current report uses data from the prior study to examine how anxiety and development relate to task-dependent amygdala-PFC connectivity.Methods: Eighty-two subjects (14 anxious youths, 15 anxious adults, 25 healthy youths, 28 healthy adults) completed an extinction recall task, which directed attention to different aspects of stimuli. Generalized psychophysiological interaction analysis tested whether task-dependent functional connectivity with anatomically defined amygdala seed regions differed across anxiety and age groups.Results: Whole-brain analyses showed significant interactions of anxiety, age, and attention task (i.e., threat appraisal, explicit threat memory, physical discrimination) on left amygdala functional connectivity with the vmPFC and ventral anterior cingulate cortex (Talairach XYZ coordinates: -16, 31, -6 and 1, 36, -4). During threat appraisal and explicit threat memory (vs. physical discrimination), anxious youth showed more negative amygdala-PFC coupling, whereas anxious adults showed more positive coupling.Conclusions: In the context of extinction recall, anxious youths and adults manifested opposite directions of amygdala-vmPFC coupling, specifically when appraising and explicitly remembering previously learned threat. Future research on anxiety should consider associations of both development and attention to threat with functional connectivity perturbations. [ABSTRACT FROM AUTHOR]

The neuropeptide corticotropin-releasing factor (CRF) coordinates the physiological and behavioural responses to stress. CRF receptors are highly expressed in the ventral tegmental area (VTA), an important region for motivated behaviour. Therefore, we examined the role of CRF receptor type 1 (CRFR1) in the VTA in conditioned fear, using a viral-mediated RNA interference approach. Following stereotaxic injection of a lentivirus that contained either shCRF-R1 or a control sequence, mice received tone-footshock pairings. Intra-VTA shCRF-R1 did not affect tone-elicited freezing during conditioning. Once conditioned fear was acquired, however, shCRF-R1 mice consistently showed stronger freezing to the tone even after extinction and reinstatement. These results implicate a novel role of VTA CRF-R1 in conditioned fear, and suggest how stress may modulate aversive learning and memory. [ABSTRACT FROM AUTHOR]

Objective: Exposure-based therapy, an effective treatment for posttraumatic stress disorder (PTSD), relies on extinction learning principles. In PTSD patients, dysfunctional patterns in the neural circuitry underlying fear extinction have been observed using resting-state or functional activation measures. It remains undetermined whether resting activity predicts activations during extinction recall or PTSD symptom severity. Moreover, it remains unclear whether trauma exposure per se affects resting activity in this circuitry. The authors employed a multimodal approach to examine the relationships among resting metabolism, clinical symptoms, and activations during extinction recall.Method: Three cohorts were recruited: PTSD patients (N=24), trauma-exposed individuals with no PTSD (TENP) (N=20), and trauma-unexposed healthy comparison subjects (N=21). Participants underwent a resting positron emission tomography scan 4 days before a functional MRI fear conditioning and extinction paradigm.Results: Amygdala resting metabolism negatively correlated with clinical functioning (as measured by the Global Assessment of Functioning Scale) in the TENP group, and hippocampal resting metabolism negatively correlated with clinical functioning in the PTSD group. In the PTSD group, dorsal anterior cingulate cortex (dACC) resting metabolism positively correlated with PTSD symptom severity, and it predicted increased dACC activations but decreased hippocampal and ventromedial prefrontal cortex activations during extinction recall. The TENP group had lower amygdala resting metabolism compared with the PTSD and healthy comparison groups, and it exhibited lower hippocampus resting metabolism relative to the healthy comparison group.Conclusions: Resting metabolism in the fear circuitry correlated with functioning, PTSD symptoms, and extinction recall activations, further supporting the relevance of this network to the pathophysiology of PTSD. The study findings also highlight the fact that chronic dysfunction in the amygdala and hippocampus is demonstrable in PTSD and other trauma-exposed individuals, even without exposure to an evocative stimulus. [ABSTRACT FROM AUTHOR]

Behavioral studies have suggested a key role for the cannabinoid system in the modulation of conditioned fear memory. Likewise, much of the literature has revealed that the serotonergic system affects Pavlovian fear conditioning and extinction. A high level of functional overlap between the serotonin and cannabinoid systems has also been reported. To clarify the interaction between the hippocampal serotonin (5-HT4) receptor and the cannabinoid CB1 receptor in the acquisition of fear memory, the effects of 5-HT4 agents, arachidonylcyclopropylamide (ACPA; CB1 receptor agonist), and the combined use of these drugs on fear learning were studied in a fear conditioning task in adult male NMRI mice. Pre-training intraperitoneal administration of ACPA (0.1 mg/kg) decreased the percentage of freezing time in both context- and tone-dependent fear conditions, suggesting impairment of the acquisition of fear memory. Pre-training, intra-hippocampal (CA1) microinjection of RS67333, a 5-HT4 receptor agonist, at doses of 0.1 and 0.2 or 0.2 µg/mouse impaired contextual and tone fear memory, respectively. A subthreshold dose of RS67333 (0.005 µg/mouse) did not alter the ACPA response in either condition. Moreover, intra-CA1 microinjection of RS23597 as a 5-HT4 receptor antagonist did not alter context-dependent fear memory acquisition, but it did impair tone-dependent fear memory acquisition. However, a subthreshold dose of the RS23597 (0.01 µg/mouse) potentiated ACPA-induced fear memory impairment in both conditions. Therefore, we suggest that the blockade of hippocampal 5-HT4 serotonergic system modulates cannabinoid signaling induced by the activation of CB1 receptors in conditioned fear. [ABSTRACT FROM AUTHOR]

Rhodiola Rosea (R. Rosea) is a plant used in traditional popular medicine to enhance cognition and physical performance. R. Rosea medicinal properties have been related to its capability to act as an adaptogen, i.e., a substance able to increase the organism's resistance to a variety of chemical, biological, and physical stressors in a non-specific way. These adaptogen properties have been mainly attributed to the glycoside salidroside, one of the bioactive compounds present in the standardized extracts of R. Rosea. Here, we aimed to investigate whether a single dose of salidroside is able to affect memory and emotional behavior in wild type adult mice. We performed fear conditioning to assess cued and contextual memory, elevated plus maze and open field to evaluate anxiety, and tail suspension test to evaluate depression. Our results showed that a single i.p. administration of salidroside was able to enhance fear memory and exerted an anxiolytic and antidepressant effect. These data confirmed the adaptogenic effect of R. Rosea bioactive compounds in animal models and suggest that salidroside might represent an interesting pharmacological tool to ameliorate cognition and counteract mood disorders. [ABSTRACT FROM AUTHOR]

The article discusses research findings on post-traumatic stress disorder (PTSD)-associated brain changes and behavioral effects. Topics covered include the circumstances in which PTSD-inducing events occur, the common symptoms associated with PTSD such as anxiety and confusion and the reduction in the corpus callosum in patients with PTSD. Also mentioned is an analysis of studies which used magnetic resonance imaging to observe differences in gray matter in the brains of PTSD patients.

It is well established that fear conditioning plays a role in the development and maintenance of anxiety disorders. Moreover, abnormalities in fear generalization, extinction, and extinction recall have also been associated with anxiety. The present study used a generalization paradigm to examine fear processing during phases of generalization, extinction, and extinction recall. Specifically, participants were shocked following a CS+ and were also presented with stimuli that ranged in perceptual similarity to the CS+ (i.e., 20%, 40%, or 60% smaller or larger than the CS+) during a fear generalization phase. Participants were also presented with the same stimuli during an extinction phase and an extinction recall phase 1week later; no shocks were presented during extinction or recall. Lastly, participants completed self-report measures of worry and trait anxiety. Results indicated that fear potentiated startle (FPS) to the CS+ and GS±20% shapes was present in generalization and extinction, suggesting that fear generalization persisted into extinction. FPS to the CS+ was also evident 1 week later during extinction recall. Higher levels of worry were associated with greater FPS to the CS+ during generalization and extinction phases. Moreover, individuals high in worry had fear response gradients that were steeper during both generalization and extinction. This suggests that high levels of worry are associated with greater discriminative fear conditioning to threatening compared to safe stimuli and less fear generalization to perceptually similar stimuli. [ABSTRACT FROM AUTHOR]

Fear-potentiated acoustic startle paradigms have been used to investigate phasic and sustained components of conditioned fear in rats and humans. This study describes a novel training protocol to assess phasic and sustained fear in freely behaving C57BL/ 6J mice, using freezing and/or fear-potentiated startle as measures of fear, thereby, if needed, allowing in vivo application of various techniques, such as optogenetics, electrophysiology and pharmacological intervention, in freely behaving animals. An auditory Pavlovian fear conditioning paradigm, with pseudo-randomized conditioned-unconditioned stimulus presentations at various durations, is combined with repetitive brief auditory white noise burst presentations during fear memory retrieval 24 h after fear conditioning. Major findings are that (1) a motion sensitive platform built on mechano-electrical transducers enables measurement of startle responses in freely behaving mice, (2) absence or presence of startle stimuli during retrieval as well as unpredictability of a given threat determine phasic and sustained fear response profiles and (3) both freezing and startle responses indicate phasic and sustained components of behavioral fear, with sustained freezing reflecting unpredictability of conditioned stimulus ( CS)/unconditioned stimulus ( US) pairings. This paradigm and available genetically modified mouse lines will pave the way for investigation of the molecular and neural mechanisms relating to the transition from phasic to sustained fear. [ABSTRACT FROM AUTHOR]

Background Conditioned fear memories can be updated by extinction during reconsolidation, and this effect is specific to the reactivated conditioned stimulus (CS). However, a traumatic event can be associated with several cues, and each cue can potentially trigger recollection of the event. We introduced a technique to target all diverse cues associated with an aversive event that causes fear. Methods In human experiments, 161 subjects underwent modified fear conditioning, in which they were exposed to an unconditioned stimulus (US) or unreinforced CS to reactivate the memory and then underwent extinction, spontaneous recovery, and reinstatement. In animal experiments, 343 rats underwent contextual fear conditioning under a similar protocol as that used in the human experiments. We also explored the molecular alterations after US reactivation in rats. Results Presentation of a lower intensity US before extinction disrupted the associations between the different CS and reactivated US in both humans and rats. This effect persisted for at least 6 months in humans and was selective to the reactivated US. This procedure was also effective for remote memories in both humans and rats. Compared with the CS, the US induced stronger endocytosis of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid glutamate receptors 1 and 2 and stronger activation of protein kinase A, p70S6 kinase, and cyclic adenosine monophosphate response element binding protein in the dorsal hippocampus in rats. Conclusions These findings demonstrate that a modified US retrieval extinction strategy may have a potential impact on therapeutic approaches to prevent the return of fear. [ABSTRACT FROM AUTHOR]

Abstract: Disruption of the reconsolidation of conditioned fear memories has been suggested as a non-pharmacological means of preventing the return of learned fear in human populations. A reconsolidation update paradigm was developed in which a reconsolidation window is opened by a single isolated retrieval trial of a previously reinforced CS+ which is then followed by Extinction Training within that window. However, follow-up studies in humans using multi-methods fear conditioning indices (e.g., fear-potentiated startle, skin conductance, US-expectancy) have failed to replicate the retrieval+extinction effects. In the present study, we further investigated the retrieval+extinction reconsolidation update paradigm by directly comparing the acquisition, extinction, and return of fear-potentiated startle in the absence or presence of US-expectancy measures (using a trial-by-trial response keypad) with and without retrieval of a previously acquired CS-US association. Participants were fear conditioned to two visual cue CS+’s, one of which was presented as a single, isolated retrieval trial before Extinction Training and one that was extinguished as usual. The results show that the inclusion of US-expectancy measures strengthens the CS–US association to provide enhanced fear conditioning and maintenance of fear memories over the experimental sessions. In addition, in the groups that used on-line US-expectancy measures, the retrieval+extinction procedure reduced reinstatement of fear-potentiated startle to both previously reinforced CS+’s, as compared to the extinction as usual group. [Copyright &y& Elsevier]

Highlights: [•] Systems consolidation predicts that retrieval of remote memories can occur independent of the hippocampus. [•] Hippocampal inactivation impairs expression of recent and remote cocaine CPP, but only affects only recent contextual fear. [•] We discuss models of substance abuse and issues in the translation of memory mechanisms to clinical therapies. [ABSTRACT FROM AUTHOR]