Fear Processing Research Articles

Morphological correlates of anxiety-related experiences during a ketamine infusion

Objectives: Ketamine exerts rapid antidepressant effects by enhancing neuroplasticity, particularly in the amygdala and hippocampus—regions involved in fear processing and learning. While the role of ketamine’s dissociative effects in its antidepressant response is debated, anxiety experienced during infusion has been negatively correlated with treatment outcomes. Methods: In this single-blind, placebo-controlled study, a subset of 17 healthy volunteers (6 males, 23.12 ± 1.9 years) received intravenously a placebo in the first and 0.5 mg/kg racemic ketamine in the second session. Anxiety-related experiences were assessed by the 5D-ASC score obtained post-infusion, structural magnetic resonance imaging scans were acquired 4 h post-infusion. An anxiety-score was obtained from the 5D-ASC. Relation between post-placebo amygdala volume, hippocampal volume, and its subfields with the anxiety-score were assessed using linear regression models. Results: Results showed a statistically significant negative relation between hippocampal head volume and the anxiety score (β = −0.733, p = 0.006), with trending negative association for each subfield’s head and the score. Conclusion: These findings suggest that anxiety-related experiences during ketamine infusion may be mediated by the hippocampus, with smaller hippocampal volumes leading to more anxiety-related experiences. Thus, hippocampal subfield volumes may be used as a predictor for anxiety-related events during ketamine use and might predict treatment outcome in future approaches.

P2X7 receptors modulate acquisition of cue fear extinction and contextual background memory generalization in male mice

The purinergic P2X7 receptors (P2X7R) are activated by adenosine triphosphate (ATP) in several brain regions, particularly those involved with emotional control and the regulation of fear-related memories. Here, we investigate the role of P2X7R in fear learning memory, specifically in the acquisition and consolidation phases of the cued fear conditioning paradigm. C57Bl/6 wildtype (WT) male mice that received a single i.p. injection of the selective P2X7R antagonist A438079 prior the conditioning session showed generalization of cued fear memory and impaired fear extinction recall in the test session, while those treated prior the extinction session exhibited a similar behavior profile accompanied by resistance in the extinction learning. However, no effects were observed when this drug was administered immediately after the conditioning, extinction, or before the test session. Our results with P2X7R knockout (P2X7 KO) mice showed a behavioral profile that mirrored the collective effects observed across all pharmacological treatment conditions. This suggests that the P2X7R KO model effectively replicates the behavioral changes induced by the pharmacological interventions, demonstrating that we have successfully isolated the role of P2X7R in the fear and extinction phases of memory. These findings highlight the role of P2X7R in the acquisition and recall of extinction memory and supports P2X7R as a promising candidate for controlling abnormal fear processing, with potential applications for stress exposure-related disorders such as post-traumatic stress disorder (PTSD).

State- and Circuit-Dependent Opponent Processing of Fear.

The presence of valence coding neurons in the basolateral amygdala (BLA) that form distinct projections to other brain regions implies functional opposition between aversion and reward during learning. However, evidence for opponent interactions in fear learning is sparse and may only be apparent under certain conditions. Here we test this possibility by studying the roles of the BLA→central amygdala (CeA) and BLA→nucleus accumbens (Acb) pathways in fear learning in male rats. First, we assessed the organization of these pathways in the rat brain. BLA→CeA and BLA→Acb pathways were largely segregated in the BLA but shared overlapping molecular profiles. Then we assessed activity of the BLA→CeA and BLA→Acb pathways during two different forms of fear learning-fear learning in a neutral context and fear learning in a reward context. BLA→CeA neurons were robustly recruited by footshock regardless of where fear learning occurred, whereas recruitment of BLA→Acb neurons was state-dependent because footshock only recruited this pathway in a reward context. Finally, we assessed the causal roles of activity in these pathways in fear learning. Photoinhibition of the BLA→CeA pathway during the footshock US impaired fear learning, regardless of where fear learning occurred. In contrast, photoinhibition of the BLA→Acb pathway augmented fear learning, but only in the reward context. Taken together, our findings show circuit- and state-dependent opponent processing of fear. Footshock activity in the BLA→Acb pathway limits how much fear is learned.

Starting the pill during adolescence: Age of onset and duration of use influence morphology of the hippocampus and ventromedial prefrontal cortex.

From adolescence, women become more likely to experience fear dysregulation. Oral contraceptives (OCs) can modulate the brain regions involved in fear processes. OCs are generally used for years and often initiated during adolescence, a sensitive period where certain brain regions involved in the fear circuitry are still undergoing important reorganization. It remains unknown whether OC use during adolescence may induce long-lasting changes in the fear circuitry. This study aimed to examine whether age of onset moderated the relationship between duration of use and fear-related brain structures. We collected structural MRI data in 98 healthy adult women (61 current users, 37 past users) and extracted grey matter volumes (GMV) and cortical thickness (CT) of key regions of the fear circuitry. Non-linear multiple regressions revealed interaction effects between age of onset and quadratic duration of use on GMV of the right hippocampus and right ventromedial prefrontal cortex (vmPFC). Among women who initiated OCs earlier in adolescence, a short duration of use was associated with smaller hippocampal GMV and thicker vmPFC compared to a longer duration of use. For both GMV and CT of the right vmPFC, women with an early OC onset had more grey matter at a short duration of use than those with a later onset. Our results suggest that OC use earlier in adolescence may induce lasting effects on structural correlates of fear learning and its regulation. These findings support further investigation into the timing of OC use to better comprehend how OCs could disrupt normal brain development processes.

Perception of emotional facial expressions in aggression and psychopathy.

Altered affective state recognition is assumed to be a root cause of aggressive behavior, a hallmark of psychopathologies such as psychopathy and antisocial personality disorder. However, the two most influential models make markedly different predictions regarding the underlying mechanism. According to the integrated emotion system theory (IES), aggression reflects impaired processing of social distress cues such as fearful faces. In contrast, the hostile attribution bias (HAB) model explains aggression with a bias to interpret ambiguous expressions as angry. In a set of four experiments, we measured processing of fearful and angry facial expressions (compared to neutral and other expressions) in a sample of 65 male imprisoned violent offenders rated using the Hare Psychopathy Checklist-Revised (PCL-R, Hare, R. D. (1991). The psychopathy checklist-revised. Toronto, ON: Multi-Health Systems) and in 60 age-matched control participants. There was no evidence for a fear deficit in violent offenders or for an association of psychopathy or aggression with impaired processing of fearful faces. Similarly, there was no evidence for a perceptual bias for angry faces linked to psychopathy or aggression. However, using highly ambiguous stimuli and requiring explicit labeling of emotions, violent offenders showed a categorization bias for anger and this anger bias correlated with self-reported trait aggression (but not with psychopathy). These results add to a growing literature casting doubt on the notion that fear processing is impaired in aggressive individuals and in psychopathy and provide support for the idea that aggression is related to a hostile attribution bias that emerges from later cognitive, post-perceptual processing stages.

The unique face of comorbid anxiety and depression: Increased frontal, insula and cingulate cortex response during Pavlovian fear-conditioning

BackgroundDysregulation of fear processing through altered sensitivity to threat is thought to contribute to the development of anxiety disorders and major depressive disorder (MDD). However, fewer studies have examined fear processing in MDD than in anxiety disorders. The current study used propensity matching to examine the hypothesis that comorbid MDD and anxiety (AnxMDD) shows greater neural correlates of fear processing than MDD, suggesting that the co-occurrence of AnxMDD is exemplified by exaggerated defense related processes. Methods195 individuals with MDD (N = 65) or AnxMDD (N = 130) were recruited from the community and completed multi-level assessments, including a Pavlovian fear learning task during functional imaging. Visual images paired with threat (conditioned stimuli: CS+) were compared to stimuli not paired with threat (CS-). ResultsMDD and AnxMDD showed significantly different patterns of activation for CS+ vs CS- in the dorsal anterior insula/inferior frontal gyrus (partial eta squared; ηp2 = 0.02), dorsolateral prefrontal cortex (ηp2 = 0.01) and dorsal anterior/mid cingulate cortex (ηp2 = 0.01). These differences were driven by greater activation to the CS+ in AnxMDD versus MDD. LimitationsLimitations include the cross-sectional design, a scream US rather than shock and half the number of MDD as AnxMDD participants. ConclusionsAnxMDD showed a pattern of increased activation in regions identified with fear processing. Effects were consistently driven by threat, further suggesting fear signaling as the emergent target process. Differences emerged in regions associated with salience processing, attentional orienting/conflict, self-relevant processing and executive functioning in comorbid anxiety and depression, thereby highlighting potential treatment targets for this prevalent and treatment resistant group.

Impact of NPSR1 gene variation on the neural correlates of phasic and sustained fear in spider phobia-an imaging genetics and independent replication approach.

The functional neuropeptide S receptor 1 (NPSR1) gene A/T variant (rs324981) is associated with fear processing. We investigated the impact of NPSR1 genotype on fear processing and on symptom reduction following treatment in individuals with spider phobia. A replication approach was applied [discovery sample: Münster (MS) nMS = 104; replication sample Würzburg (WZ) nWZ = 81]. Participants were genotyped for NPSR1 rs324981 [T-allele carriers (risk) versus AA homozygotes (no-risk)]. A sustained and phasic fear paradigm was applied during functional magnetic resonance imaging. A one-session virtual reality exposure treatment was conducted. Change of symptom severity from pre to post treatment and within session fear reduction were assessed. T-allele carriers in the discovery sample displayed lower anterior cingulate cortex (ACC) activation compared to AA homozygotes independent of condition. For sustained fear, this effect was replicated within a small cluster and medium effect size. No association with symptom reduction was found. Within-session fear reduction was negatively associated with ACC activation in T-allele carriers in the discovery sample. NPSR1 rs324981 genotype might be associated with fear processing in the ACC in spider phobia. Interpretation as potential risk-increasing function of the NPSR1 rs324981 T-allele via impaired top-down control of limbic structures remains speculative. Potential association with symptom reduction warrants further research.

Behavioral and neural correlates of diverse conditioned fear responses in male and female rats.

Pavlovian fear conditioning is a widely used tool that models associative learning in rodents. For decades the field has used predominantly male rodents and focused on a sole conditioned fear response: freezing. However, recent work from our lab and others has identified darting as a female-biased conditioned response, characterized by an escape-like movement across a fear conditioning chamber. It is also accompanied by a behavioral phenotype: Darters reliably show decreased freezing compared to Non-darters and males and reach higher velocities in response to the foot shock ("shock response"). However, the relationship between shock response and conditioned darting is not known. This study investigated if this link is due to differences in general processing of aversive stimuli between Darters, Non-darters and males. Across a variety of modalities, including corticosterone measures, the acoustic startle test, and sensitivity to thermal pain, Darters were found not to be more reactive or sensitive to aversive stimuli, and, in some cases, they appear less reactive to Non-darters and males. Analyses of cFos activity in regions involved in pain and fear processing following fear conditioning identified discrete patterns of expression among Darters, Non-darters, and males exposed to low and high intensity foot shocks. The results from these studies further our understanding of the differences between Darters, Non-darters and males and highlight the importance of studying individual differences in fear conditioning as indicators of fear state.

Climbing Fiber Activation Induced by Footshock in the Cerebellar Vermis Lobule IV/V of Freely Moving Mice.

Parallel fibers (PFs) in the cerebellar cortex are involved in a series of coordinated responses in the fear conditioning paradigm induced by footshock. However, whether footshock can activate cerebellar climbing fibers (CFs) remains unclear. In this study, we recorded calcium (Ca2+) activity in CFs by optical fiber photometry in the cerebellar vermis lobule IV/V of freely moving mice with footshock stimulation. We found that the activation of CFs in the lobule IV/V was highly correlated with footshock stimulation but not with the sound stimulation used as a control. This result suggests that afferent information from CFs might be associated with the motor initiation of fear-related behaviors or fear emotion itself. Thus, our results suggest that a characteristic CF signal in the cerebellar cortex might be related to fear processing or footshock-related behaviors (such as startle responses or pain sensation).

Deficits in prefrontal metabotropic glutamate receptor 5 are associated with functional alterations during emotional processing in bipolar disorder

BackgroundElucidating biological mechanisms contributing to bipolar disorder (BD) is key to improved diagnosis and treatment development. With converging evidence implicating the metabotropic glutamate receptor 5 (mGlu5) in the pathology of BD, here, we therefore test the hypothesis that recently identified deficits in mGlu5 are associated with functional brain differences during emotion processing in BD. MethodsPositron emission tomography (PET) with [18F]FPEB was used to measure mGlu5 receptor availability and functional imaging (fMRI) was performed while participants completed an emotion processing task. Data were analyzed from 62 individuals (33 ± 12 years, 45 % female) who completed both PET and fMRI, including individuals with BD (n = 18), major depressive disorder (MDD: n = 20), and psychiatrically healthy comparisons (HC: n = 25). ResultsConsistent with some prior reports, the BD group displayed greater activation during fear processing relative to MDD and HC, notably in right lateralized frontal and parietal brain regions. In BD, (but not MDD or HC) lower prefrontal mGlu5 availability was associated with greater activation in bilateral pre/postcentral gyri and cuneus during fear processing. Furthermore, greater prefrontal mGlu5-related brain activity in BD was associated with difficulties in psychomotor function (r≥0.904, p≤0.005) and attention (r≥0.809, p≤0.028). LimitationsThe modest sample size is the primary limitation. ConclusionsDeficits in prefrontal mGlu5 in BD were linked to increased cortical activation during fear processing, which in turn was associated with impulsivity and attentional difficulties. These data further implicate an mGlu5-related mechanism unique to BD. More generally these data suggest integrating PET and fMRI can provide novel mechanistic insights.

Cortical and Subcortical Brain Alterations in Specific Phobia and Its Animal and Blood-Injection-Injury Subtypes: A Mega-Analysis From the ENIGMA Anxiety Working Group.

Specific phobia is a common anxiety disorder, but the literature on associated brain structure alterations exhibits substantial gaps. The ENIGMA Anxiety Working Group examined brain structure differences between individuals with specific phobias and healthy control subjects as well as between the animal and blood-injection-injury (BII) subtypes of specific phobia. Additionally, the authors investigated associations of brain structure with symptom severity and age (youths vs. adults). Data sets from 31 original studies were combined to create a final sample with 1,452 participants with phobia and 2,991 healthy participants (62.7% female; ages 5-90). Imaging processing and quality control were performed using established ENIGMA protocols. Subcortical volumes as well as cortical surface area and thickness were examined in a preregistered analysis. Compared with the healthy control group, the phobia group showed mostly smaller subcortical volumes, mixed surface differences, and larger cortical thickness across a substantial number of regions. The phobia subgroups also showed differences, including, as hypothesized, larger medial orbitofrontal cortex thickness in BII phobia (N=182) compared with animal phobia (N=739). All findings were driven by adult participants; no significant results were observed in children and adolescents. Brain alterations associated with specific phobia exceeded those of other anxiety disorders in comparable analyses in extent and effect size and were not limited to reductions in brain structure. Moreover, phenomenological differences between phobia subgroups were reflected in diverging neural underpinnings, including brain areas related to fear processing and higher cognitive processes. The findings implicate brain structure alterations in specific phobia, although subcortical alterations in particular may also relate to broader internalizing psychopathology.

Modulation of response times in early-stage Parkinson’s disease during emotional processing of embodied and non-embodied stimuli

Valence (positive and negative) and content (embodied vs non-embodied) characteristics of visual stimuli have been shown to influence motor readiness, as tested with response time paradigms. Both embodiment and emotional processing are affected in Parkinson’s disease (PD) due to basal ganglia dysfunction. Here we aimed to investigate, using a two-choice response time paradigm, motor readiness when processing embodied (emotional body language [EBL] and emotional facial expressions [FACS]) vs non-embodied (emotional scenes [IAPS]) stimuli with neutral, happy, and fearful content. We enrolled twenty-five patients with early-stage PD and twenty-five age matched healthy participants. Motor response during emotional processing was assessed by measuring response times (RTs) in a home-based, forced two-choice discrimination task where participants were asked to discriminate the emotional stimulus from the neutral one. Rating of valence and arousal was also performed. A clinical and neuropsychological evaluation was performed on PD patients. Results showed that RTs for PD patients were longer for all conditions compared to HC and that RTs were generally longer in both groups for EBL compared to FACS and IAPS, with the sole exception retrieved for PD, where in discriminating fearful stimuli, RTs for EBL were longer compared to FACS but not to IAPS. Furthermore, in PD only, when discriminating fearful respect to neutral stimuli, RTs were shorter when discriminating FACS compared to IAPS. This study shows that PD patients were faster in discriminating fearful embodied stimuli, allowing us to speculate on mechanisms involving an alternative, compensatory, emotional motor pathway for PD patients undergoing fear processing.

How movies move us - movie preferences are linked to differences in neuronal emotion processing of fear and anger: an fMRI study.

As a source of audio-visual stimulation, movies expose people to various emotions. Interestingly, several genres are characterized by negative emotional content. Albeit theoretical approaches exist, little is known about preferences for specific movie genres and the neuronal processing of negative emotions. We investigated associations between movie genre preference and limbic and reward-related brain reactivity to close this gap by employing an fMRI paradigm with negative emotional faces in 257 healthy participants. We compared the functional activity of the amygdala and the nucleus accumbens (NAcc) between individuals with a preference for a particular movie genre and those without such preference. Amygdala activation was relatively higher in individuals with action movie preference (p TFCE-FWE = 0.013). Comedy genre preference was associated with increased amygdala (p TFCE-FWE = 0.038) and NAcc activity (p TFCE-FWE = 0.011). In contrast, crime/thriller preference (amygdala: p TFCE-FWE ≤ 0.010, NAcc: p TFCE-FWE = 0.036), as well as documentary preference, was linked to the decreased amygdala (p TFCE-FWE = 0.012) and NAcc activity (p TFCE-FWE = 0.015). The study revealed associations between participants' genre preferences and brain reactivity to negative affective stimuli. Interestingly, preferences for genres with similar emotion profiles (action, crime/thriller) were associated with oppositely directed neural activity. Potential links between brain reactivity and susceptibility to different movie-related gratifications are discussed.

An ethologically relevant paradigm to assess defensive response to looming visual contrast stimuli

In the animal kingdom, threat information is perceived mainly through vision. The subcortical visual pathway plays a critical role in the rapid processing of visual information-induced fear, and triggers a response. Looming-evoked behavior in rodents, mimicking response to aerial predators, allowed identify the neural circuitry underlying instinctive defensive behaviors; however, the influence of disk/background contrast on the looming-induced behavioral response has not been examined, either in rats or mice. We studied the influence of the dark disk/gray background contrast in the type of rat and mouse defensive behavior in the looming arena, and we showed that rat and mouse response as a function of disk/background contrast adjusted to a sigmoid-like relationship. Both sex and age biased the contrast-dependent response, which was dampened in rats submitted to retinal unilateral or bilateral ischemia. Moreover, using genetically manipulated mice, we showed that the three type of photoresponsive retinal cells (i.e., cones, rods, and intrinsically photoresponsive retinal ganglion cells (ipRGCs)), participate in the contrast-dependent response, following this hierarchy: cones > > rods > > > ipRGCs. The cone and rod involvement was confirmed using a mouse model of unilateral non-exudative age-related macular degeneration, which only damages canonical photoreceptors and significantly decreased the contrast sensitivity in the looming arena.

Corticosterone after early adolescent stress prevents social avoidance, aversive behavior, and morphine-conditioned place preference in adulthood.

Stress during childhood or adolescence increases vulnerability to psychiatric disorders in adults. In adult rodents, the delayed effects of stress can increase anxiety-like behavior. These effects, however, can be prevented with post-stress administration of corticosterone (CORT). The effectiveness of CORT in preventing adolescent stress-induced emotional behavior alterations in adulthood has yet to be investigated. Here, we investigated the interactions between early adolescent stress and exogenous corticosterone on adult social, aversive, and drug-seeking behavior in mice, which are translationally related to symptoms associated with psychiatric and substance abuse disorders. A single administration of CORT in drinking water (400ug/mL) for 24h after social defeat or context fear conditioning prevents defeat-induced social avoidance, alters fear processing, prevents adolescent stress-induced anhedonia, and prevents stress-potentiated morphine place preference in adulthood. Exogenous CORT did not immediately prevent stress-induced potentiation of morphine conditioned-place preference in adolescents but did so in adult mice. However, when administered to adolescent mice, CORT also prevented the incubation of morphine-conditioned place preference into adulthood. Lastly, exogenous CORT administration blunted endogenous corticosterone but was unrelated to freezing behavior during a fear test. This is the first demonstration of adolescent post-stress CORT promoting socio-emotional resilience and preventing drug-seeking behavior. Our data suggest elevated corticosterone after a stress experience promotes resilience for at least 40 days across the developmental transition from adolescence to adulthood and is effective for socio-emotional and drug-seeking behavior. These results are critical for understanding how adolescent stress impacts emotional and drug-seeking behavior into adulthood.

Loss of mGlu5 receptors in somatostatin-expressing neurons alters negative emotional states.

Subtype 5 metabotropic glutamate receptors (mGlu5) are known to play an important role in regulating cognitive, social and valence systems. However, it remains largely unknown at which circuits and neuronal types mGlu5 act to influence these behavioral domains. Altered tissue- or cell-specific expression or function of mGlu5 has been proposed to contribute to the exacerbation of neuropsychiatric disorders. Here, we examined how these receptors regulate the activity of somatostatin-expressing (SST+) neurons, as well as their influence on behavior and brain rhythmic activity. Loss of mGlu5 in SST+ neurons elicited excitatory synaptic dysfunction in a region and sex-specific manner together with a range of emotional imbalances including diminished social novelty preference, reduced anxiety-like behavior and decreased freezing during retrieval of fear memories. In addition, the absence of mGlu5 in SST+ neurons during fear processing impaired theta frequency oscillatory activity in the medial prefrontal cortex and ventral hippocampus. These findings reveal a critical role of mGlu5 in controlling SST+ neurons excitability necessary for regulating negative emotional states.

Specialization of amygdala subregions in emotion processing.

The amygdala is important for human fear processing. However, recent research has failed to reveal specificity, with evidence that the amygdala also responds to other emotions. A more nuanced understanding of the amygdala's role in emotion processing, particularly relating to fear, is needed given the importance of effective emotional functioning for everyday function and mental health. We studied 86 healthy participants (44 females), aged 18-49 (mean 26.12 ± 6.6) years, who underwent multiband functional magnetic resonance imaging. We specifically examined the reactivity of four amygdala subregions (using regions of interest analysis) and related brain connectivity networks (using generalized psycho-physiological interaction) to fear, angry, and happy facial stimuli using an emotional face-matching task. All amygdala subregions responded to all stimuli (p-FDR < .05), with this reactivity strongly driven by the superficial and centromedial amygdala (p-FDR < .001). Yet amygdala subregions selectively showed strong functional connectivity with other occipitotemporal and inferior frontal brain regions with particular sensitivity to fear recognition and strongly driven by the basolateral amygdala (p-FDR < .05). These findings suggest that amygdala specialization to fear may not be reflected in its local activity but in its connectivity with other brain regions within a specific face-processing network.

No Association of Stathmin1 Gene Polymorphism with Trait or State Anxiety in the Chinese Population.

Stathmin 1 (Stmn1) is a neuronal growth-associated protein which was found to be involved in fear processing both in animals and humans. Moreover, it has been demonstrated that 2 single nucleotide polymorphisms (SNPs) of the Stmn1 gene (rs182455 and rs213641) significantly impacted individual fear and anxiety responses in German. However, there have been no reports on the correlation between Stmn1 SNPs and anxiety in Chinese. The present study thus aimed to explore such correlation. A sample of 567 healthy Han Chinese adults were genotyped for the Stmn1 SNP, namely rs182455, using polymerase chain reaction and restriction fragment length polymorphism analysis. Anxiety was assessed by the Chinese version of 40-item State-Trait Anxiety Inventory (STAI), which measures 2 anxiety dimensions, state and trait anxiety. The numbers of CC, CT, and TT genotypes of rs182455 polymorphism were 227 (40.0%), 263 (46.4%), and 77 (13.6%), respectively. The genotype distribution did not deviate from the Hardy-Weinberg equilibrium (χ 2 = 0.004, P = .953). There were no significant differences in either state or trait anxiety among the 3 rs182455 genotype groups (F = 0.457, 0.415, P = .634, .660), between the 2 dominant model groups (t = 0.865, -0.195, P = .388, .845), or between the 2 recessive model groups (t = 0.106, 0.906, P = .916, .365). Moreover, no significant gender-specific differences in any STAI scores were found among the rs182455 genotype groups (all P > .05). No evidence was demonstrated for the association of the Stmn1 gene polymorphism rs182455 with either trait or state anxiety in Chinese adults.

Cannabidiol effects on fear processing and implications for PTSD: Evidence from rodent and human studies.

Cannabidiol (CBD) modulates aversive memory and its extinction, with potential implications for treating anxiety- and stress-related disorders. Here, we summarize and discuss scientific evidence showing that CBD administered after the acquisition (consolidation) and retrieval (reconsolidation) of fear memory attenuates it persistently in rats and mice. CBD also reduces fear expression and enhances fear extinction. These effects involve the activation of cannabinoid type-1 (CB1) receptors in the dorsal hippocampus, bed nucleus of stria terminalis, and medial prefrontal cortex, comprising the anterior cingulate, prelimbic, and infralimbic subregions. Serotonin type-1A (5-HT1A) receptors also mediate some CBD effects on fear memory. CBD effects on fear memory acquisition vary, depending on the aversiveness of the conditioning procedure. While rodent findings are relatively consistent and encouraging, human studies investigating CBD's efficacy in modulating aversive/traumatic memories are still limited. More studies are needed to investigate CBD's effects on maladaptive, traumatic memories, particularly in post-traumatic stress disorder patients.

Stable coding of aversive associations in medial prefrontal populations.

The medial prefrontal cortex (mPFC) is at the core of numerous psychiatric conditions, including fear and anxiety-related disorders. Whereas an abundance of evidence suggests a crucial role of the mPFC in regulating fear behaviour, the precise role of the mPFC in this process is not yet entirely clear. While studies at the single-cell level have demonstrated the involvement of this area in various aspects of fear processing, such as the encoding of threat-related cues and fear expression, an increasingly prevalent idea in the systems neuroscience field is that populations of neurons are, in fact, the essential unit of computation in many integrative brain regions such as prefrontal areas. What mPFC neuronal populations represent when we face threats? To address this question, we performed electrophysiological single-unit population recordings in the dorsal mPFC while mice faced threat-predicting cues eliciting defensive behaviours, and performed pharmacological and optogenetic inactivations of this area and the amygdala. Our data indicated that the presence of threat-predicting cues induces a stable coding dynamics of internally driven representations in the dorsal mPFC, necessary to drive learned defensive behaviours. Moreover, these neural population representations primary reflect learned associations rather than specific defensive behaviours, and the construct of such representations relies on the functional integrity of the amygdala.