Maintenance Of Fear Research Articles

Distinct Circuits From the Central Lateral Amygdala to the Ventral Part of the Bed Nucleus of Stria Terminalis Regulate Different Fear Memory

BackgroundThe ability to differentiate stimuli that predict fear is critical for survival; however, the underlying molecular and circuit mechanisms remain poorly understood. MethodsWe combined transgenic mice, in vivo transsynaptic circuit-dissecting anatomical approaches, optogenetics, pharmacological methods, and electrophysiological recording to investigate the involvement of specific extended amygdala circuits in different fear memory. ResultsWe identified the projections from central lateral amygdala (CeL) protein kinase C δ (PKCδ)–positive neurons and somatostatin (SST)-positive neurons to GABAergic (gamma-aminobutyric acidergic) and glutamatergic neurons in the ventral part of the bed nucleus of stria terminalis (vBNST). Prolonged optogenetic activation or inhibition of the PKCδCeL-vBNST pathway specifically reduced context fear memory, whereas the SSTCeL-vBNST pathway mainly reduced tone fear memory. Intriguingly, optogenetic manipulation of vBNST neurons that received the projection from PKCδCeL neurons exerted bidirectional regulation of context fear, whereas manipulation of vBNST neurons that received the projection from SSTCeL neurons could bidirectionally regulate both context and tone fear memory. We subsequently demonstrated the presence of δ and κ opioid receptor protein expression within the CeL-vBNST circuits, potentially accounting for the discrepancy between prolonged activation of GABAergic circuits and inhibition of downstream vBNST neurons. Finally, administration of an opioid receptor antagonist cocktail on the PKCδCeL-vBNST or SSTCeL-vBNST pathway successfully restored context or tone fear memory reduction induced by prolonged activation of the circuits. ConclusionsTogether, these findings establish a functional role for distinct CeL-vBNST circuits in the differential regulation and appropriate maintenance of fear.

A Cross-Sectional Study on Cognitive Vulnerability Patterns in Dental Anxiety: The Italian Validation of the Dental Fear Maintenance Questionnaire (DFMQ).

Dental anxiety is a crucial problem for dentistry because it may represent a significant risk to oral health. Within the framework of the Cognitive Vulnerability Model (CVM), which sheds light on the cognitive vulnerability patterns that may cause dental anxiety, this study aimed to assess the psychometric characteristics of the Italian version of the Dental Fear Maintenance Questionnaire (DFMQ). The DFMQ is a 32-item questionnaire that assesses four cognitive vulnerability patterns, i.e., dangerousness, disgust, unpredictability, and uncontrollability. In a sample of 200 dental patients who had accessed public-university-hospital dental surgery, this study assessed the model fit of the DFMQ and different types of validity (i.e., predictive, convergent, construct, and discriminant validity). In addition, potential differences between DFMQ dimensions were assessed based on gender (men vs. women) and age ranges. All indicators of cognitive vulnerability were significantly associated with high dental anxiety when each variable was included independently. In contrast, when the DFMQ subscales were considered together, only unpredictability and uncontrollability were found to be associated with high dental anxiety. Women had higher scores for unpredictability, uncontrollability, and general dangerousness than men. In addition, older patients had higher scores for some vulnerability cognitive patterns than younger patients. This study provides Italian dentists and researchers with a valid questionnaire to assess cognitive factors associated with dental anxiety.

A Voxel-Based Morphometric Study of Gray Matter in Specific Phobia.

The objective of this study was to analyze the neurostructural abnormalities of brain areas responsible for the acquisition and maintenance of fear in small animal phobia by comparing gray matter volume (GMV) in individuals with phobia and non-fearful controls. Structural magnetic resonance imaging was obtained from 62 adults (79% female) assigned to one of two groups: 31 were diagnosed with small animal phobia and 31 were non-fearful controls. To investigate structural alterations, a whole-brain voxel-based morphometry analysis was conducted to compare the GMV of the brain areas involved in fear between both groups. The results indicated that individuals with a small animal specific phobia showed smaller GMV in cortical regions, such as the orbitofrontal (OFC) and medial frontal cortex, and greater GMV in the putamen than non-fearful controls. These brain areas are responsible for avoidant behavior (putamen) and emotional regulation processes or inhibitory control (prefrontal cortex (PFC)), which might suggest a greater vulnerability of phobic individuals to acquiring non-adaptive conditioned responses and emotional dysregulation. The findings provide preliminary support for the involvement of structural deficits in OFC and medial frontal cortex in phobia, contributing to clarify the neurobiological substrates for phobias.

The role of fear in hierarchical processing of fear-related stimuli.

According to a widely accepted definition, visual objects are composed of hierarchical structures classified as either global or local, depending on their location in the hierarchy. Previous research has demonstrated that fear and anxiety are associated with faster identification of local level stimuli, supporting the popular view that fear narrows attention. Nevertheless, the modulating role of fear in hierarchical processing has never been examined for stimuli that are personally relevant. To fill this research gap, we used emotional modification of a global-local paradigm to examine hierarchical processing of spider and snake stimuli among participants with high specific fear of spiders or snakes, respectively. The results indicate that personal fear facilitates identification of an animal's global configuration and interferes with identification of its local features (i.e., body pattern). This effect was found in comparison with participants with low fear and in comparison with other threatening but fear-irrelevant stimulus. Furthermore, a general global bias was found, highlighting the ecological validity of Navon's theory. The current findings are inconsistent with the view that anxiety narrows attention to local features. We suggest that the results can be reconciled with existing literature if we consider the narrowing of attention to the global level. The current study offers initial evidence for the role of fear in hierarchical processing of fear-relevant information, which may, in turn, play an important role in the etiology and maintenance of fear and serve as a new target for interventions. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Girls' Stuff? Maternal Gender Stereotypes and Their Daughters' Fear.

One of the most robust findings in psychopathology is the fact that specific phobias are more prevalent in women than in men. Although there are several theoretical accounts for biological and social contributions to this gender difference, empirical data are surprisingly limited. Interestingly, there is evidence that individuals with stereotypical feminine characteristics are more fearful than those with stereotypical masculine characteristics; this is beyond biological sex. Because gender role stereotypes are reinforced by parental behavior, we aimed to examine the relationship of maternal gender stereotypes and children’s fear. Dyads of 38 mothers and their daughters (between ages 6 and 10) were included. We assessed maternal implicit and explicit gender stereotypes as well as their daughters’ self-reported general fearfulness, specific fear of snakes, and approach behavior toward a living snake. First, mothers’ fear of snakes significantly correlated with their daughters’ fear of snakes. Second, mothers’ gender stereotypes significantly correlated with their daughters’ self-reported fear. Specifically, maternal implicit gender stereotypes were associated with daughters’ fear of snakes and fear ratings in response to the snake. Moreover, in children, self-reported fear correlated with avoidance of the fear-relevant animal. Together, these results provide first evidence for a potential role of parental gender stereotypes in the development and maintenance of fear in their offspring.

Reappraising fear: is up-regulation more efficient than down-regulation?

Catastrophizing thoughts may contribute to the development of anxiety, but functional emotion regulation may help to improve treatment. No study so far directly compared up- and down-regulation of fear by cognitive reappraisal. Here, healthy individuals took part in a cued fear experiment, in which multiple pictures of faces were paired twice with an unpleasant scream or presented as safety stimuli. Participants (N = 47) were asked (within-subjects) to down-regulate, to up-regulate and to maintain their natural emotional response. Valence and arousal ratings indicated successful up- and down-regulation of the emotional experience, while heart rate and pupil dilation increased during up-regulation, but showed no reduction in down-regulation. State and trait anxiety correlated with evaluations of safety but not threat stimuli, which supports the role of deficient safety learning in anxiety. Reappraisal did not modulate this effect. In conclusion, this study reveals evidence for up-regulation effects in fear, which might be even more efficient than down-regulation on a physiological level and highlights the importance of catastrophizing thoughts for the maintenance of fear and anxiety.

Sensation seeking and neuroticism in fear conditioning and extinction: The role of avoidance behaviour

Maladaptive avoidance behaviour, a key symptom of anxiety-related disorders, prevents extinction learning and maintains anxiety. Individual personality traits likely influence avoidance propensity: high sensation-seeking may decrease avoidance, thereby increasing extinction, and neuroticism may have the reverse effect. However, research on this is scarce. Using a naturalistic conditioned avoidance paradigm, 163 women underwent differential fear acquisition to a conditioned stimulus (CSplus). Next, during extinction, participants could either choose a risky shortcut, anticipating shock signalled by CSplus, or a time-consuming avoidance option (lengthy detour). Across participants, increased skin conductance (SCR) acquisition learning predicted subsequent instrumental avoidance. Avoidance, in turn, predicted elevated post-extinction SCR and shock-expectancy, i.e., ‘protection-from-extinction’. Mediation analyses revealed that sensation seeking decreased protection-from-extinction—both for shock-expectancy and SCR—via attenuating avoidance. Neither sensation seeking nor neuroticism were related to acquisition learning and neuroticism was neither related to avoidance nor extinction. Transcranial direct current stimulation administered before extinction did not influence present results. Results highlight the important role of elevated avoidance propensity in fear maintenance. Results moreover provide evidence for reduced sensation-seeking and increased acquisition learning to be avoidance-driving mechanisms. Since approach-avoidance conflicts are faced by anxiety patients on a daily basis, strengthening sensation-seeking-congruent attitudes and approach behaviours may optimize individualized treatment.

Defence response mobilization in response to provocation or imagery of interoceptive sensations in adolescents with chronic pain: a study protocol

Introduction:Fear of pain seems to be a key factor in the development and maintenance of chronic pain and pain-related disability. Interoceptive fear conditioning is assumed to constitute an important mechanism in the origins and maintenance of fear of pain. If conditioned stimuli such as internal bodily sensations are repeatedly paired with pain (unconditioned stimulus), they in turn elicit a conditioned fear response, including defence mobilization such as startle modulation and changes in heart rate and electrodermal activity. Research into emotional imagery suggests that defensive responses can also be elicited through imagery of fear scripts.Objectives:We present 2 novel paradigms adapted from research on anxiety disorders, which allow to test, if perceived or imagined sensations locally proximal to the main pain location trigger heightened defence response mobilization in adolescents with chronic headaches and abdominal pain.Methods:The provocation paradigm includes the anticipation and provocation of locally proximal and locally distal interoceptive sensations through disorder-specific muscle tensing tasks (tightening the neck or the abdominal muscles). The imagery paradigm includes 3 imagery scripts (standard neutral, standard fear, and disorder-specific). Startle probes are presented in both paradigms. Defence response mobilization is assessed using psychophysiological measures (startle response modulation, skin conductance level, and heart rate), as well as self-reported measures of fear.Perspective:The paradigms will give insight into the defence response of adolescents with chronic pain, when confronted with or imagining interoceptive sensations. Results may inform the improvement of clinical interventions aimed to decrease fear of bodily sensations such as interoceptive exposure or interoceptive imagery exposure.

A Novel Retrieval-Dependent Memory Process Revealed by the Arrest of ERK1/2 Activation in the Basolateral Amygdala.

Fully consolidated fear memories can be maintained or inhibited by retrieval-dependent mechanisms depending on the degree of re-exposure to fear cues. Short exposures promote memory maintenance through reconsolidation, and long exposures promote inhibition through extinction. Little is known about the neural mechanisms by which increasing cue exposure overrides reconsolidation and instead triggers extinction. Using auditory fear conditioning in male rats, we analyzed the role of a molecular mechanism common to reconsolidation and extinction of fear, ERK1/2 activation within the basolateral amygdala (BLA), after intermediate conditioned stimulus (CS) exposure events. We show that an intermediate re-exposure (four CS presentations) failed to activate ERK1/2 in the BLA, suggesting the absence of reconsolidation or extinction mechanisms. Supporting this hypothesis, pharmacologically inhibiting the BLA ERK1/2-dependent signaling pathway in conjunction with four CS presentations had no effect on fear expression, and the NMDA receptor partial agonist d-cycloserine, which enhanced extinction and ERK1/2 activation in partial extinction protocols (seven CSs), had no behavioral or molecular effect when given in association with four CS presentations. These molecular and behavioral data reveal a novel retrieval-dependent memory phase occurring along the transition between conditioned fear maintenance and inhibition. CS-dependent molecular events in the BLA may arrest reconsolidation intracellular signaling mechanism in an extinction-independent manner. These findings are critical for understanding the molecular underpinnings of fear memory persistence after retrieval both in health and disease.SIGNIFICANCE STATEMENT Consolidated fear memories can be altered by retrieval-dependent mechanisms. Whereas a brief conditioned stimulus (CS) exposure promotes fear memory maintenance through reconsolidation, a prolonged exposure engages extinction and fear inhibition. The nature of this transition and whether an intermediate degree of CS exposure engages reconsolidation or extinction is unknown. We show that an intermediate cue exposure session (four CSs) produces the arrest of ERK1/2 activation in the basolateral amygdala, a common mechanism for reconsolidation and extinction. Amnestic or hypermnestic treatments given in association with four CSs had no behavioral or molecular effects, respectively. This evidence reveals a novel retrieval-dependent memory phase. Intermediate degrees of CS exposure fail to trigger reconsolidation or extinction, leaving the original memory in an insensitive state.

Quantified Coexpression Analysis of Central Amygdala Subpopulations.

Molecular identification and characterization of fear controlling circuitries is a promising path towards developing targeted treatments of fear-related disorders. Three-color in situ hybridization analysis was used to determine whether somatostatin (SOM, Sst), neurotensin (NTS, Nts), corticotropin-releasing factor (CRF, Crf), tachykinin 2 (TAC2, Tac2), protein kinase c-δ (PKC-δ, Prkcd), and dopamine receptor 2 (DRD2, Drd2) mRNA colocalize in male mouse amygdala neurons. Expression and colocalization was examined across capsular (CeC), lateral (CeL), and medial (CeM) compartments of the central amygdala. The greatest expression of Prkcd and Drd2 were found in CeC and CeL. Crf was expressed primarily in CeL, while Sst-, Nts-, and Tac2-expressing neurons were distributed between CeL and CeM. High levels of colocalization were identified between Sst, Nts, Crf, and Tac2 within the CeL, while little colocalization was detected between any mRNAs within the CeM. These findings provide a more detailed understanding of the molecular mechanisms that regulate the development and maintenance of fear and anxiety behaviors.

Trait Worry and Neural Correlates of Emotion Regulation

Abstract. Pathological worrying is of high transdiagnostic relevance and is related to maladaptive emotion regulation processes. Dysfunctional emotion regulation and its underlying neural mechanisms might contribute to the maintenance of fear over time. Therefore, this functional magnetic resonance imaging (fMRI) study aims at investigating the association of trait worry with neural correlates of emotion regulation. Twenty-six healthy females were instructed to passively look at aversive pictures, to distract themselves with a neutral thought, or to down- and up-regulate negative feelings via cognitive reappraisal in response to repeatedly presented aversive pictures. Trait worry was not related to cognitive reappraisal but to distraction, which leads to a greater reduction of self-reported negative feelings and insula activation in individuals with higher trait worry. The current study indicates that the neural mechanisms underlying distraction seem to be altered in pathological worrying and may prevent adaptive emotional processing of aversive stimuli leading to the maintenance of fear.

Chronic Pain and Selective Attention to Pain Arousing Daily Activity Pictures: Evidence From an Eye Tracking Study.

Introduction:According to the pain research literature, attentional bias for pain is the mechanism responsible for the development and maintenance of fear of pain in patients with chronic pain. However, there is still some debate about the exact mechanism and the role of faster engagement versus difficulty in disengagement in the development of attentional bias.Methods:To investigate attentional bias in patients with chronic pain, we used an eye-tracker with the pictures of pain-provoking activities and compared the results with an age- and gender-matched group of pain-free participants. In addition, other measures of pain-related cognition and pain severity ratings were included to assess their contribution to the attentional bias toward pain-related information.Results:Calculating the frequency of the first fixations showed that both groups fixated initially on pain-provoking pictures compared to neutral one. Calculating the speed of fixations showed that control participants were faster in fixating on neutral stimuli, but patients with pain were faster in fixating on pain-provoking pictures, indicating a relative vigilance for the pain-related stimuli among them. These patients reported that the intensity of pain in the previous week was positively correlated with the speed of their fixation on the painful stimuli.Conclusion:Although these results did not provide unequivocal support for the vigilance-avoidance hypothesis, they are generally consistent with the results of studies using eye tracking technology. Furthermore, our findings put a question over characterization of attentional biases in patients with chronic pain by simply relating that to difficulty in disengaging from pain-related stimuli.

Le rôle de l’optimisme et de l’anxiété dans la peur de l’accouchement : une étude exploratoire

Resume La peur de l’accouchement suscite un interet grandissant dans la litterature scientifique, et ce, du fait de son impact sur le vecu de la grossesse, et sur le deroulement de l’accouchement. Cette etude exploratoire cherche a determiner l’impact de l’optimisme et de l’anxiete sur la peur de l’accouchement. Quatre-vingt douze femmes enceintes ont participe a cette etude. Parmi elles, 54 etaient primipares. La moyenne d’âge des participantes etait d’environ 30 ans (21–42). La duree de la grossesse variait de 7 a 9 mois. Les participantes ont repondu a differents questionnaires permettant de recueillir les informations concernant les antecedents psychologiques et gynecologiques et le vecu de la grossesse, et de mesurer la peur de l’accouchement, les symptomes anxio-depressifs antenataux, le niveau d’optimisme et le niveau de satisfaction de vie. Les resultats indiquent que les facteurs favorisant la peur de l’accouchement sont la primiparite, les complications medicales rencontrees durant la grossesse et la presence d’une symptomatologie anxieuse. Trente-huit femmes (41,3 %) presentaient des symptomes d’anxiete. L’anxiete a un role mediateur dans la relation entre l’optimisme et la peur de l’accouchement. Cette etude apporte un eclairage supplementaire concernant le role de l’anxiete dans la peur de l’accouchement, mais il serait interessant de la reproduire avec une evaluation longitudinale.

Instructed knowledge shapes feedback-driven aversive learning in striatum and orbitofrontal cortex, but not the amygdala.

Socially-conveyed rules and instructions strongly shape expectations and emotions. Yet most neuroscientific studies of learning consider reinforcement history alone, irrespective of knowledge acquired through other means. We examined fear conditioning and reversal in humans to test whether instructed knowledge modulates the neural mechanisms of feedback-driven learning. One group was informed about contingencies and reversals. A second group learned only from reinforcement. We combined quantitative models with functional magnetic resonance imaging and found that instructions induced dissociations in the neural systems of aversive learning. Responses in striatum and orbitofrontal cortex updated with instructions and correlated with prefrontal responses to instructions. Amygdala responses were influenced by reinforcement similarly in both groups and did not update with instructions. Results extend work on instructed reward learning and reveal novel dissociations that have not been observed with punishments or rewards. Findings support theories of specialized threat-detection and may have implications for fear maintenance in anxiety.

Patterns of attention to threat across tasks in behaviorally inhibited children at risk for anxiety.

Although attention bias towards threat has been causally implicated in the development and maintenance of fear and anxiety, the expected associations do not appear consistently. Reliance on a single task to capture attention bias, in this case overwhelmingly the dot-probe task, may contribute to this inconsistency. Comparing across attentional bias measures could help capture patterns of behavior that have implications for anxiety. This study examines the patterns of attentional bias across two related measures in a sample of children at temperamental risk for anxiety. Children (Meanage = 10.19±0.96) characterized as behaviorally inhibited (N=50) or non-inhibited (N=64) via parent-report completed the dot-probe and affective Posner tasks to measure attentional bias to threat. Parent-report diagnostic interviews assessed children's social anxiety. Behavioral inhibition was not associated with performance in the dot-probe task, but was associated with increased attentional bias to threat in the affective Posner task. Cross-task convergence was dependent on temperament, such that attention bias across the two tasks was only related in behaviorally inhibited children. Finally, children who were consistently biased across tasks (showing high or low attentional bias scores in both tasks, rather than high in one but low in the other) had higher levels of anxiety. Convergence across attention bias measures may be dependent on individuals' predispositions (e.g. temperament). Moreover, convergence of attention bias across measures may be a stronger marker of information processing patterns that shape socioemotional outcomes than performance in a single task.

Region-specific roles of the prelimbic cortex, the dorsal CA1, the ventral DG and ventral CA1 of the hippocampus in the fear return evoked by a sub-conditioning procedure in rats

The return of learned fear is an important issue in anxiety disorder research since an analogous process may contribute to long-term fear maintenance or clinical relapse. A number of studies demonstrate that mPFC and hippocampus are important in the modulation of post-extinction re-expression of fear memory. However, the region-specific role of these structures in the fear return evoked by a sub-threshold conditioning (SC) is not known. In the present experiments, we first examined specific roles of the prelimbic cortex (PL), the dorsal hippocampus (DH, the dorsal CA1 area in particular), the ventral hippocampus (the ventral dentate gyrus (vDG) and the ventral CA1 area in particular) in this fear return process. Then we examined the role of connections between PL and vCA1 with this behavioral approach. Rats were subjected to five tone-shock pairings (1.0-mA shock) to induce conditioned fear (freezing), followed by three fear extinction sessions (25 tone-alone trials each session). After a post-test for extinction memory, some rats were retrained with the SC procedure to reinstate tone-evoked freezing. Rat groups were injected with low doses of the GABAA agonist muscimol to selectively inactivate PL, DH, vDG, or vCA1 120min before the fear return test. A disconnection paradigm with ipsilateral or contralateral muscimol injection of the PL and the vCA1 was used to examine the role of this pathway in the fear return. We found that transient inactivation of these areas significantly impaired fear return (freezing): inactivation of the prelimbic cortex blocked SC-evoked fear return in particular but did not influence fear expression in general; inactivation of the DH area impaired fear return, but had no effect on the extinction retrieval process; both ventral DG and ventral CA1 are required for the return of extinguished fear whereas only ventral DG is required for the extinction retrieval. These findings suggest that PL, DH, vDG, and vCA1 all contribute to the fear return and connections between PL and vCA1 may be involved in the modulation of this process.

Information Processing in Stuttering

Adults who stutter are at risk of developing a range of psychological issues, and those issueshave been implicated in failed speech rehabilitation. Social anxiety disorder (SAD) is the mostprevalent condition associated with stuttering. SAD has been prominent in psychologicalresearch in effort to understand the cause, maintenance and management of the condition. Toimprove the clinical management of stuttering it is critical to take account of cognitive theories ofSAD to further understanding of the mechanisms of anxiety onset and maintenance.Social anxiety disorder involves excessive, irrational, and debilitating fear of being humiliatedand embarrassed in social situations. Severe cases can result in high levels of avoidancewhich can lead to social isolation and failure to participate in many normal occupational, socialand interpersonal activities. However, not all situations can be avoided. A person with SAD islikely to encounter anxiety inducing situations on many occasions in absence of the fearedevent, and yet their fears persist. Hence, avoidance alone cannot account for this persistence ofanxiety. It is increasingly apparent that expectancies of social harm and fear of negative socialevaluation are central to the nature of anxiety associated with stuttering. Similar to theavoidance reported in SAD, avoidance is a common reaction reported by people who stutter,including avoidance of words, specific situations and eye contact.Cognitive theorists suggest that information processing biases are involved in maintenance offear and anxiety associated with SAD [Clark, D. M., & Wells, A. (1995). A cognitive model ofsocial phobia.In R. G. Heimberg, M. R. Liebowitz, D. A. Hope, & F. R. Schneier. (Eds.) SocialPhobia: Diagnosis, Assessment and Treatment. (pp. 69-93). New York: The Guildford Press;Rapee, R. M., &Heimberg, R. G. (1997). A cognitive-behavioral model of anxiety in socialphobia.Behaviour Research and Therapy, 35, 741-756]. These cognitive processes include (1)self-focused attention, (2) reduced processing of external social cues (3) intrusive mentalimagery, (4) rumination and (5) safety behaviors. Routine clinical psychology interventions toreduce anxiety in SAD involve identifying and eliminating information processing biases andclient safety behaviors. However, a recent publication has shown that during routine clinical treatment of stuttering speech-language pathologists commonly recommend that clients engagein a range of tasks that might function as safety behaviors. In other words, they may perpetuateclient social anxiety.The effects of information processing biases have been well documented in SAD and evidenceis emerging of such biases in adults who stutter. To improve clinical outcomes for people whostutter, there is a critical need for this research to continue. In particular, exploration of theextent to which people who stutter engage in information processing biases that are well knownto maintain anxiety in SAD. The application of models of SAD to stuttering research is crucial tothis line of research.

Reconsolidation and extinction are dissociable and mutually exclusive processes: behavioral and molecular evidence.

Memory persistence is critically influenced by retrieval. In rats, a single presentation of a conditioned fear stimulus induces memory reconsolidation and fear memory persistence, while repeated fear cue presentations result in loss of fear through extinction. These two opposite behavioral outcomes are operationally linked by the number of cue presentations at memory retrieval. However, the behavioral properties and mechanistic determinants of the transition have not yet been explored; in particular, whether reconsolidation and extinction processes coexist or are mutually exclusive, depending on the exposure to non-reinforced retrieval events. We characterized both behaviorally and molecularly the transition from reconsolidation to extinction of conditioned fear and showed that an increase in calcineurin (CaN) in the basolateral amygdala (BLA) supports the shift from fear maintenance to fear inhibition. Gradually increasing the extent of retrieval induces a gradual decrease in freezing responses to the conditioned stimulus and a gradual increase in amygdala CaN level. This newly synthesized CaN is required for the extinction, but not the reconsolidation, of conditioned fear. During the transition from reconsolidation to extinction, we have revealed an insensitive state of the fear memory where NMDA-type glutamate receptor agonist and antagonist drugs are unable either to modulate CaN levels in the BLA or alter the reconsolidation or extinction processes. Together, our data indicate both that reconsolidation and extinction are mutually exclusive processes and also reveal the presence of a transitional, or "limbo," state of the original memory between these two alternative outcomes of fear memory retrieval, when neither process is engaged.

Differential impact of the first and second wave of a stress response on subsequent fear conditioning in healthy men

Stress is a process of multiple neuroendocrine changes over time. We examined effects of the first-wave and second-wave stress response on acquisition and immediate extinction of differential fear conditioning, assessed by skin conductance responses. In Experiment 1, we placed acquisition either close to the (second-wave) salivary cortisol peak, induced by a psychosocial stressor (experimental group, EG), or after non-stressful pretreatment (control group, CG). Contrary to predictions, groups did not differ in differential responding. In the EG only, mean differential responding was negatively correlated with cortisol increases. In Experiment 2, we placed conditioning near the first-wave stress response, induced by a cold pressor test (CPT), or after a warm-water condition (CG). CPT-stress increased extinction resistance. Moreover, acquisition performance after CPT was positively correlated with first-wave blood pressure increases. Data suggest that mediators of the first-wave stress response enhance fear maintenance whereas second-wave cortisol responsivity to stress might attenuate fear learning.

A hypothesis on maintenance of fears

A hypothesis on maintenance of fears