associative fear learning: Topics by Science.gov

Sample records for associative fear learning

The influence of personality on neural mechanisms of observational fear and reward learning

PubMed Central

Hooker, Christine I.; Verosky, Sara C.; Miyakawa, Asako; Knight, Robert T.; D’Esposito, Mark

2012-01-01

Fear and reward learning can occur through direct experience or observation. Both channels can enhance survival or create maladaptive behavior. We used fMRI to isolate neural mechanisms of observational fear and reward learning and investigate whether neural response varied according to individual differences in neuroticism and extraversion. Participants learned object-emotion associations by observing a woman respond with fearful (or neutral) and happy (or neutral) facial expressions to novel objects. The amygdala-hippocampal complex was active when learning the object-fear association, and the hippocampus was active when learning the object-happy association. After learning, objects were presented alone; amygdala activity was greater for the fear (vs. neutral) and happy (vs. neutral) associated object. Importantly, greater amygdala-hippocampal activity during fear (vs. neutral) learning predicted better recognition of learned objects on a subsequent memory test. Furthermore, personality modulated neural mechanisms of learning. Neuroticism positively correlated with neural activity in the amygdala and hippocampus during fear (vs. neutral) learning. Low extraversion/high introversion was related to faster behavioral predictions of the fearful and neutral expressions during fear learning. In addition, low extraversion/high introversion was related to greater amygdala activity during happy (vs. neutral) learning, happy (vs. neutral) object recognition, and faster reaction times for predicting happy and neutral expressions during reward learning. These findings suggest that neuroticism is associated with an increased sensitivity in the neural mechanism for fear learning which leads to enhanced encoding of fear associations, and that low extraversion/high introversion is related to enhanced conditionability for both fear and reward learning. PMID:18573512
A role for midline and intralaminar thalamus in the associative blocking of Pavlovian fear conditioning.

PubMed

Sengupta, Auntora; McNally, Gavan P

2014-01-01

Fear learning occurs in response to positive prediction error, when the expected outcome of a conditioning trial exceeds that predicted by the conditioned stimuli present. This role for error in Pavlovian association formation is best exemplified by the phenomenon of associative blocking, whereby prior fear conditioning of conditioned stimulus (CS) A is able to prevent learning to CSB when they are conditioned in compound. The midline and intralaminar thalamic nuclei (MIT) are well-placed to contribute to fear prediction error because they receive extensive projections from the midbrain periaqueductal gray-which has a key role in fear prediction error-and project extensively to prefrontal cortex and amygdala. Here we used an associative blocking design to study the role of MIT in fear learning. In Stage I rats were trained to fear CSA via pairings with shock. In Stage II rats received compound fear conditioning of CSAB paired with shock. On test, rats that received Stage I training expressed less fear to CSB relative to control rats that did not receive this training. Microinjection of bupivacaine into MIT prior to Stage II training had no effect on the expression of fear during Stage II and had no effect on fear learning in controls, but prevented associative blocking and so enabled fear learning to CSB. These results show an important role for MIT in predictive fear learning and are discussed with reference to previous findings implicating the midline and posterior intralaminar thalamus in fear learning and fear responding.
Does fear extinction in the laboratory predict outcomes of exposure therapy? A treatment analog study.

PubMed

Forcadell, Eduard; Torrents-Rodas, David; Vervliet, Bram; Leiva, David; Tortella-Feliu, Miquel; Fullana, Miquel A

2017-11-01

Fear extinction models have a key role in our understanding of anxiety disorders and their treatment with exposure therapy. Here, we tested whether individual differences in fear extinction learning and fear extinction recall in the laboratory were associated with the outcomes of an exposure therapy analog (ETA). Fifty adults with fear of spiders participated in a two-day fear-learning paradigm assessing fear extinction learning and fear extinction recall, and then underwent a brief ETA. Correlational analyses indicated that enhanced extinction learning was associated with better ETA outcome. Our results partially support the idea that individual differences in fear extinction learning may be associated with exposure therapy outcome, but suggest that further research in this area is needed. Copyright © 2017 Elsevier B.V. All rights reserved.
Elevated Arc/Arg 3.1 protein expression in the basolateral amygdala following auditory trace-cued fear conditioning.

PubMed

Chau, Lily S; Prakapenka, Alesia; Fleming, Stephen A; Davis, Ashley S; Galvez, Roberto

2013-11-01

The underlying neuronal mechanisms of learning and memory have been heavily explored using associative learning paradigms. Two of the more commonly employed learning paradigms have been contextual and delay fear conditioning. In fear conditioning, a subject learns to associate a neutral stimulus (conditioned stimulus; CS), such as a tone or the context of the room, with a fear provoking stimulus (unconditioned stimulus; US), such as a mild footshock. Utilizing these two paradigms, various analyses have elegantly demonstrated that the amygdala plays a role in both fear-related associative learning paradigms. However, the amygdala's involvement in trace fear conditioning, a forebrain-dependent fear associative learning paradigm that has been suggested to tap into higher cognitive processes, has not been closely investigated. Furthermore, to our knowledge, the specific amygdala nuclei involved with trace fear conditioning has not been examined. The present study used Arc expression as an activity marker to determine the amygdala's involvement in trace fear associative learning and to further explore involvement of specific amygdalar nuclei. Arc is an immediate early gene that has been shown to be associated with neuronal activation and is believed to be necessary for neuronal plasticity. Findings from the present study demonstrated that trace-conditioned mice, compared to backward-conditioned (stimulation-control), delay-conditioned and naïve mice, exhibited elevated amygdalar Arc expression in the basolateral (BLA) but not the central (CeA) or the lateral amygdala (LA). These findings are consistent with previous reports demonstrating that the amygdala plays a critical role in trace conditioning. Furthermore, these findings parallel studies demonstrating hippocampal-BLA activation following contextual fear conditioning, suggesting that trace fear conditioning and contextual fear conditioning may involve similar amygdala nuclei. Together, findings from this study demonstrate similarities in the pathway for trace and contextual fear conditioning, and further suggest possible underlying mechanisms for acquisition and consolidation of these two types of fear-related learning. Copyright © 2013 Elsevier Inc. All rights reserved.
Adult Hippocampal Neurogenesis Modulates Fear Learning through Associative and Nonassociative Mechanisms

PubMed Central

Seo, Dong-oh; Carillo, Mary Ann; Chih-Hsiung Lim, Sean; Tanaka, Kenji F.

2015-01-01

Adult hippocampal neurogenesis is believed to support hippocampus-dependent learning and emotional regulation. These putative functions of adult neurogenesis have typically been studied in isolation, and little is known about how they interact to produce adaptive behavior. We used trace fear conditioning as a model system to elucidate mechanisms through which adult hippocampal neurogenesis modulates processing of aversive experience. To achieve a specific ablation of neurogenesis, we generated transgenic mice that express herpes simplex virus thymidine kinase specifically in neural progenitors and immature neurons. Intracerebroventricular injection of the prodrug ganciclovir caused a robust suppression of neurogenesis without suppressing gliogenesis. Neurogenesis ablation via this method or targeted x-irradiation caused an increase in context conditioning in trace but not delay fear conditioning. Data suggest that this phenotype represents opposing effects of neurogenesis ablation on associative and nonassociative components of fear learning. Arrest of neurogenesis sensitizes mice to nonassociative effects of fear conditioning, as evidenced by increased anxiety-like behavior in the open field after (but not in the absence of) fear conditioning. In addition, arrest of neurogenesis impairs associative trace conditioning, but this impairment can be masked by nonassociative fear. The results suggest that adult neurogenesis modulates emotional learning via two distinct but opposing mechanisms: it supports associative trace conditioning while also buffering against the generalized fear and anxiety caused by fear conditioning. SIGNIFICANCE STATEMENT The role of adult hippocampal neurogenesis in fear learning is controversial, with some studies suggesting neurogenesis is needed for aspects of fear learning and others suggesting it is dispensable. We generated transgenic mice in which neural progenitors can be selectively and inducibly ablated. Our data suggest that adult neurogenesis supports fear learning through two distinct mechanisms: it supports the ability to learn associations between traumatic events (unconditioned stimuli) and predictors (conditioned stimuli) while also buffering against nonassociative, anxiogenic effects of a traumatic experience. As a result, arrest of neurogenesis can enhance or impair learned fear depending on intensity of the traumatic experience and the extent to which it recruits associative versus nonassociative learning. PMID:26269640
Amygdala's involvement in facilitating associative learning-induced plasticity: a promiscuous role for the amygdala in memory acquisition

PubMed Central

Chau, Lily S.; Galvez, Roberto

2012-01-01

It is widely accepted that the amygdala plays a critical role in acquisition and consolidation of fear-related memories. Some of the more widely employed behavioral paradigms that have assisted in solidifying the amygdala's role in fear-related memories are associative learning paradigms. With most associative learning tasks, a neutral conditioned stimulus (CS) is paired with a salient unconditioned stimulus (US) that elicits an unconditioned response (UR). After multiple CS-US pairings, the subject learns that the CS predicts the onset or delivery of the US, and thus elicits a learned conditioned response (CR). Most fear-related associative paradigms have suggested that an aspect of the fear association is stored in the amygdala; however, some fear-motivated associative paradigms suggest that the amygdala is not a site of storage, but rather facilitates consolidation in other brain regions. Based upon various learning theories, one of the most likely sites for storage of long-term memories is the neocortex. In support of these theories, findings from our laboratory, and others, have demonstrated that trace-conditioning, an associative paradigm where there is a separation in time between the CS and US, induces learning-specific neocortical plasticity. The following review will discuss the amygdala's involvement, either as a site of storage or facilitating storage in other brain regions such as the neocortex, in fear- and non-fear-motivated associative paradigms. In this review, we will discuss recent findings suggesting a broader role for the amygdala in increasing the saliency of behaviorally relevant information, thus facilitating acquisition for all forms of memory, both fear- and non-fear-related. This proposed promiscuous role of the amygdala in facilitating acquisition for all memories further suggests a potential role of the amygdala in general learning disabilities. PMID:23087626
Amygdala's involvement in facilitating associative learning-induced plasticity: a promiscuous role for the amygdala in memory acquisition.

PubMed

Chau, Lily S; Galvez, Roberto

2012-01-01

It is widely accepted that the amygdala plays a critical role in acquisition and consolidation of fear-related memories. Some of the more widely employed behavioral paradigms that have assisted in solidifying the amygdala's role in fear-related memories are associative learning paradigms. With most associative learning tasks, a neutral conditioned stimulus (CS) is paired with a salient unconditioned stimulus (US) that elicits an unconditioned response (UR). After multiple CS-US pairings, the subject learns that the CS predicts the onset or delivery of the US, and thus elicits a learned conditioned response (CR). Most fear-related associative paradigms have suggested that an aspect of the fear association is stored in the amygdala; however, some fear-motivated associative paradigms suggest that the amygdala is not a site of storage, but rather facilitates consolidation in other brain regions. Based upon various learning theories, one of the most likely sites for storage of long-term memories is the neocortex. In support of these theories, findings from our laboratory, and others, have demonstrated that trace-conditioning, an associative paradigm where there is a separation in time between the CS and US, induces learning-specific neocortical plasticity. The following review will discuss the amygdala's involvement, either as a site of storage or facilitating storage in other brain regions such as the neocortex, in fear- and non-fear-motivated associative paradigms. In this review, we will discuss recent findings suggesting a broader role for the amygdala in increasing the saliency of behaviorally relevant information, thus facilitating acquisition for all forms of memory, both fear- and non-fear-related. This proposed promiscuous role of the amygdala in facilitating acquisition for all memories further suggests a potential role of the amygdala in general learning disabilities.
Worrying affects associative fear learning: a startle fear conditioning study.

PubMed

Gazendam, Femke J; Kindt, Merel

2012-01-01

A valuable experimental model for the pathogenesis of anxiety disorders is that they originate from a learned association between an intrinsically non-aversive event (Conditioned Stimulus, CS) and an anticipated disaster (Unconditioned Stimulus, UCS). Most anxiety disorders, however, do not evolve from a traumatic experience. Insights from neuroscience show that memory can be modified post-learning, which may elucidate how pathological fear can develop after relatively mild aversive events. Worrying--a process frequently observed in anxiety disorders--is a potential candidate to strengthen the formation of fear memory after learning. Here we tested in a discriminative fear conditioning procedure whether worry strengthens associative fear memory. Participants were randomly assigned to either a Worry (n = 23) or Control condition (n = 25). After fear acquisition, the participants in the Worry condition processed six worrisome questions regarding the personal aversive consequences of an electric stimulus (UCS), whereas the Control condition received difficult but neutral questions. Subsequently, extinction, reinstatement and re-extinction of fear were tested. Conditioned responding was measured by fear-potentiated startle (FPS), skin conductance (SCR) and UCS expectancy ratings. Our main results demonstrate that worrying resulted in increased fear responses (FPS) to both the feared stimulus (CS(+)) and the originally safe stimulus (CS(-)), whereas FPS remained unchanged in the Control condition. In addition, worrying impaired both extinction and re-extinction learning of UCS expectancy. The implication of our findings is that they show how worry may contribute to the development of anxiety disorders by affecting associative fear learning.
Retrieval cues that trigger reconsolidation of associative fear memory are not necessarily an exact replica of the original learning experience.

PubMed

Soeter, Marieke; Kindt, Merel

2015-01-01

Disrupting the process of memory reconsolidation may point to a novel therapeutic strategy for the permanent reduction of fear in patients suffering from anxiety disorders. However both in animal and human studies the retrieval cue typically involves a re-exposure to the original fear-conditioned stimulus (CS). A relevant question is whether abstract cues not directly associated with the threat event also trigger reconsolidation, given that anxiety disorders often result from vicarious or unobtrusive learning for which no explicit memory exists. Insofar as the fear memory involves a flexible representation of the original learning experience, we hypothesized that the process of memory reconsolidation may also be triggered by abstract cues. We addressed this hypothesis by using a differential human fear-conditioning procedure in two distinct fear-learning groups. We predicted that if fear learning involves discrimination on basis of perceptual cues within one semantic category (i.e., the perceptual-learning group, n = 15), the subsequent ambiguity of the abstract retrieval cue would not trigger memory reconsolidation. In contrast, if fear learning involves discriminating between two semantic categories (i.e., categorical-learning group, n = 15), an abstract retrieval cue would unequivocally reactivate the fear memory and might subsequently trigger memory reconsolidation. Here we show that memory reconsolidation may indeed be triggered by another cue than the one that was present during the original learning occasion, but this effect depends on the learning history. Evidence for fear memory reconsolidation was inferred from the fear-erasing effect of one pill of propranolol (40 mg) systemically administered upon exposure to the abstract retrieval cue. Our finding that reconsolidation of a specific fear association does not require exposure to the original retrieval cue supports the feasibility of reconsolidation-based interventions for emotional disorders.
Neuroimaging of Fear-Associated Learning

PubMed Central

Greco, John A; Liberzon, Israel

2016-01-01

Fear conditioning has been commonly used as a model of emotional learning in animals and, with the introduction of functional neuroimaging techniques, has proven useful in establishing the neurocircuitry of emotional learning in humans. Studies of fear acquisition suggest that regions such as amygdala, insula, anterior cingulate cortex, and hippocampus play an important role in acquisition of fear, whereas studies of fear extinction suggest that the amygdala is also crucial for safety learning. Extinction retention testing points to the ventromedial prefrontal cortex as an essential region in the recall of the safety trace, and explicit learning of fear and safety associations recruits additional cortical and subcortical regions. Importantly, many of these findings have implications in our understanding of the pathophysiology of psychiatric disease. Recent studies using clinical populations have lent insight into the changes in regional activity in specific disorders, and treatment studies have shown how pharmaceutical and other therapeutic interventions modulate brain activation during emotional learning. Finally, research investigating individual differences in neurotransmitter receptor genotypes has highlighted the contribution of these systems in fear-associated learning. PMID:26294108
Nothing is safe: Intolerance of uncertainty is associated with compromised fear extinction learning.

PubMed

Morriss, Jayne; Christakou, Anastasia; van Reekum, Carien M

2016-12-01

Extinction-resistant fear is considered to be a central feature of pathological anxiety. Here we sought to determine if individual differences in Intolerance of Uncertainty (IU), a potential risk factor for anxiety disorders, underlies compromised fear extinction. We tested this hypothesis by recording electrodermal activity in 38 healthy participants during fear acquisition and extinction. We assessed the temporality of fear extinction, by examining early and late extinction learning. During early extinction, low IU was associated with larger skin conductance responses to learned threat vs. safety cues, whereas high IU was associated with skin conductance responding to both threat and safety cues, but no cue discrimination. During late extinction, low IU showed no difference in skin conductance between learned threat and safety cues, whilst high IU predicted continued fear expression to learned threat, indexed by larger skin conductance to threat vs. safety cues. These findings suggest a critical role of uncertainty-based mechanisms in the maintenance of learned fear. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.
Disrupted Prediction Error Links Excessive Amygdala Activation to Excessive Fear.

PubMed

Sengupta, Auntora; Winters, Bryony; Bagley, Elena E; McNally, Gavan P

2016-01-13

Basolateral amygdala (BLA) is critical for fear learning, and its heightened activation is widely thought to underpin a variety of anxiety disorders. Here we used chemogenetic techniques in rats to study the consequences of heightened BLA activation for fear learning and memory, and to specifically identify a mechanism linking increased activity of BLA glutamatergic neurons to aberrant fear. We expressed the excitatory hM3Dq DREADD in rat BLA glutamatergic neurons and showed that CNO acted selectively to increase their activity, depolarizing these neurons and increasing their firing rates. This chemogenetic excitation of BLA glutamatergic neurons had no effect on the acquisition of simple fear learning, regardless of whether this learning led to a weak or strong fear memory. However, in an associative blocking task, chemogenetic excitation of BLA glutamatergic neurons yielded significant learning to a blocked conditioned stimulus, which otherwise should not have been learned about. Moreover, in an overexpectation task, chemogenetic manipulation of BLA glutamatergic neurons prevented use of negative prediction error to reduce fear learning, leading to significant impairments in fear inhibition. These effects were not attributable to the chemogenetic manipulation enhancing arousal, increasing asymptotic levels of fear learning or fear memory consolidation. Instead, chemogenetic excitation of BLA glutamatergic neurons disrupted use of prediction error to regulate fear learning. Several neuropsychiatric disorders are characterized by heightened activation of the amygdala. This heightened activation has been hypothesized to underlie increased emotional reactivity, fear over generalization, and deficits in fear inhibition. Yet the mechanisms linking heightened amygdala activation to heightened emotional learning are elusive. Here we combined chemogenetic excitation of rat basolateral amygdala glutamatergic neurons with a variety of behavioral approaches to show that, although simple fear learning is unaffected, the use of prediction error to regulate this learning is profoundly disrupted, leading to formation of inappropriate fear associations and impaired fear inhibition. Copyright © 2016 the authors 0270-6474/16/360385-11$15.00/0.
MOLECULAR MECHANISMS OF FEAR LEARNING AND MEMORY

PubMed Central

Johansen, Joshua P.; Cain, Christopher K.; Ostroff, Linnaea E.; LeDoux, Joseph E.

2011-01-01

Pavlovian fear conditioning is a useful behavioral paradigm for exploring the molecular mechanisms of learning and memory because a well-defined response to a specific environmental stimulus is produced through associative learning processes. Synaptic plasticity in the lateral nucleus of the amygdala (LA) underlies this form of associative learning. Here we summarize the molecular mechanisms that contribute to this synaptic plasticity in the context of auditory fear conditioning, the form of fear conditioning best understood at the molecular level. We discuss the neurotransmitter systems and signaling cascades that contribute to three phases of auditory fear conditioning: acquisition, consolidation, and reconsolidation. These studies suggest that multiple intracellular signaling pathways, including those triggered by activation of Hebbian processes and neuromodulatory receptors, interact to produce neural plasticity in the LA and behavioral fear conditioning. Together, this research illustrates the power of fear conditioning as a model system for characterizing the mechanisms of learning and memory in mammals, and potentially for understanding fear related disorders, such as PTSD and phobias. PMID:22036561
Learning to fear a second-order stimulus following vicarious learning.

PubMed

Reynolds, Gemma; Field, Andy P; Askew, Chris

2017-04-01

Vicarious fear learning refers to the acquisition of fear via observation of the fearful responses of others. The present study aims to extend current knowledge by exploring whether second-order vicarious fear learning can be demonstrated in children. That is, whether vicariously learnt fear responses for one stimulus can be elicited in a second stimulus associated with that initial stimulus. Results demonstrated that children's (5-11 years) fear responses for marsupials and caterpillars increased when they were seen with fearful faces compared to no faces. Additionally, the results indicated a second-order effect in which fear-related learning occurred for other animals seen together with the fear-paired animal, even though the animals were never observed with fearful faces themselves. Overall, the findings indicate that for children in this age group vicariously learnt fear-related responses for one stimulus can subsequently be observed for a second stimulus without it being experienced in a fear-related vicarious learning event. These findings may help to explain why some individuals do not recall involvement of a traumatic learning episode in the development of their fear of a specific stimulus.
Opioid receptors regulate blocking and overexpectation of fear learning in conditioned suppression.

PubMed

Arico, Carolyn; McNally, Gavan P

2014-04-01

Endogenous opioids play an important role in prediction error during fear learning. However, the evidence for this role has been obtained almost exclusively using the species-specific defense response of freezing as the measure of learned fear. It is unknown whether opioid receptors regulate predictive fear learning when other measures of learned fear are used. Here, we used conditioned suppression as the measure of learned fear to assess the role of opioid receptors in fear learning. Experiment 1a studied associative blocking of fear learning. Rats in an experimental group received conditioned stimulus A (CSA) + training in Stage I and conditioned stimulus A and B (CSAB) + training in Stage II, whereas rats in a control group received only CSAB + training in Stage II. The prior fear conditioning of CSA blocked fear learning to conditioned stimulus B (CSB) in the experimental group. In Experiment 1b, naloxone (4 mg/kg) administered before Stage II prevented this blocking, thereby enabling normal fear learning to CSB. Experiment 2a studied overexpectation of fear. Rats received CSA + training and CSB + training in Stage I, and then rats in the experimental group received CSAB + training in Stage II whereas control rats did not. The Stage II compound training of CSAB reduced fear to CSA and CSB on test. In Experiment 2b, naloxone (4 mg/kg) administered before Stage II prevented this overexpectation. These results show that opioid receptors regulate Pavlovian fear learning, augmenting learning in response to positive prediction error and impairing learning in response to negative prediction error, when fear is assessed via conditioned suppression. These effects are identical to those observed when freezing is used as the measure of learned fear. These findings show that the role for opioid receptors in regulating fear learning extends across multiple measures of learned fear.
Where There is Smoke There is Fear-Impaired Contextual Inhibition of Conditioned Fear in Smokers.

PubMed

Haaker, Jan; Lonsdorf, Tina B; Schümann, Dirk; Bunzeck, Nico; Peters, Jan; Sommer, Tobias; Kalisch, Raffael

2017-07-01

The odds-ratio of smoking is elevated in populations with neuropsychiatric diseases, in particular in the highly prevalent diagnoses of post-traumatic stress and anxiety disorders. Yet, the association between smoking and a key dimensional phenotype of these disorders-maladaptive deficits in fear learning and fear inhibition-is unclear. We therefore investigated acquisition and memory of fear and fear inhibition in healthy smoking and non-smoking participants (N=349, 22% smokers). We employed a well validated paradigm of context-dependent fear and safety learning (day 1) including a memory retrieval on day 2. During fear learning, a geometrical shape was associated with an aversive electrical stimulation (classical fear conditioning, in danger context) and fear responses were extinguished within another context (extinction learning, in safe context). On day 2, the conditioned stimuli were presented again in both contexts, without any aversive stimulation. Autonomic physiological measurements of skin conductance responses as well as subjective evaluations of fear and expectancy of the aversive stimulation were acquired. We found that impairment of fear inhibition (extinction) in the safe context during learning (day 1) was associated with the amount of pack-years in smokers. During retrieval of fear memories (day 2), smokers showed an impairment of contextual (safety context-related) fear inhibition as compared with non-smokers. These effects were found in physiological as well as subjective measures of fear. We provide initial evidence that smokers as compared with non-smokers show an impairment of fear inhibition. We propose that smokers have a deficit in integrating contextual signs of safety, which is a hallmark of post-traumatic stress and anxiety disorders.
The Future of Contextual Fear Learning for PTSD Research: A Methodological Review of Neuroimaging Studies.

PubMed

Glenn, Daniel E; Risbrough, Victoria B; Simmons, Alan N; Acheson, Dean T; Stout, Daniel M

2017-10-21

There has been a great deal of recent interest in human models of contextual fear learning, particularly due to the use of such paradigms for investigating neural mechanisms related to the etiology of posttraumatic stress disorder. However, the construct of "context" in fear conditioning research is broad, and the operational definitions and methods used to investigate contextual fear learning in humans are wide ranging and lack specificity, making it difficult to interpret findings about neural activity. Here we will review neuroimaging studies of contextual fear acquisition in humans. We will discuss the methodology associated with four broad categories of how contextual fear learning is manipulated in imaging studies (colored backgrounds, static picture backgrounds, virtual reality, and configural stimuli) and highlight findings for the primary neural circuitry involved in each paradigm. Additionally, we will offer methodological recommendations for human studies of contextual fear acquisition, including using stimuli that distinguish configural learning from discrete cue associations and clarifying how context is experimentally operationalized.
Molecular mechanisms of fear learning and memory.

PubMed

Johansen, Joshua P; Cain, Christopher K; Ostroff, Linnaea E; LeDoux, Joseph E

2011-10-28

Pavlovian fear conditioning is a particularly useful behavioral paradigm for exploring the molecular mechanisms of learning and memory because a well-defined response to a specific environmental stimulus is produced through associative learning processes. Synaptic plasticity in the lateral nucleus of the amygdala (LA) underlies this form of associative learning. Here, we summarize the molecular mechanisms that contribute to this synaptic plasticity in the context of auditory fear conditioning, the form of fear conditioning best understood at the molecular level. We discuss the neurotransmitter systems and signaling cascades that contribute to three phases of auditory fear conditioning: acquisition, consolidation, and reconsolidation. These studies suggest that multiple intracellular signaling pathways, including those triggered by activation of Hebbian processes and neuromodulatory receptors, interact to produce neural plasticity in the LA and behavioral fear conditioning. Collectively, this body of research illustrates the power of fear conditioning as a model system for characterizing the mechanisms of learning and memory in mammals and potentially for understanding fear-related disorders, such as PTSD and phobias. Copyright © 2011 Elsevier Inc. All rights reserved.
Individual differences in learning predict the return of fear.

PubMed

Gershman, Samuel J; Hartley, Catherine A

2015-09-01

Using a laboratory analogue of learned fear (Pavlovian fear conditioning), we show that there is substantial heterogeneity across individuals in spontaneous recovery of fear following extinction training. We propose that this heterogeneity might stem from qualitative individual differences in the nature of extinction learning. Whereas some individuals tend to form a new memory during extinction, leaving their fear memory intact, others update the original threat association with new safety information, effectively unlearning the fear memory. We formalize this account in a computational model of fear learning and show that individuals who, according to the model, are more likely to form new extinction memories tend to show greater spontaneous recovery compared to individuals who appear to only update a single memory. This qualitative variation in fear and extinction learning may have important implications for understanding vulnerability and resilience to fear-related psychiatric disorders.
Cellular and oscillatory substrates of fear extinction learning.

PubMed

Davis, Patrick; Zaki, Yosif; Maguire, Jamie; Reijmers, Leon G

2017-11-01

The mammalian brain contains dedicated circuits for both the learned expression and suppression of fear. These circuits require precise coordination to facilitate the appropriate expression of fear behavior, but the mechanisms underlying this coordination remain unclear. Using a combination of chemogenetics, activity-based neuronal-ensemble labeling and in vivo electrophysiology, we found that fear extinction learning confers on parvalbumin-expressing (PV) interneurons in the basolateral amygdala (BLA) a dedicated role in the selective suppression of a previously encoded fear memory and BLA fear-encoding neurons. In addition, following extinction learning, PV interneurons enable a competing interaction between a 6-12 Hz oscillation and a fear-associated 3-6 Hz oscillation within the BLA. Loss of this competition increases a 3-6 Hz oscillatory signature, with BLA→medial prefrontal cortex directionality signaling the recurrence of fear expression. The discovery of cellular and oscillatory substrates of fear extinction learning that critically depend on BLA PV interneurons could inform therapies aimed at preventing the pathological recurrence of fear following extinction learning.

Cellular and Oscillatory Substrates of Fear Extinction Learning

PubMed Central

Davis, Patrick; Zaki, Yosif; Maguire, Jamie; Reijmers, Leon G.

2018-01-01

The mammalian brain contains dedicated circuits for both the learned expression and suppression of fear. These circuits require precise coordination to facilitate the appropriate expression of fear behavior, but the mechanisms underlying this coordination remain unclear. Using a novel combination of chemogenetics, activity-based neuronal-ensemble labeling, and in vivo electrophysiology, we found that fear extinction learning confers parvalbumin-expressing (PV) interneurons in the basolateral amygdala (BLA) with a dedicated role in the selective suppression of a previously encoded fear memory and BLA fear-encoding neurons. In addition, following extinction learning, PV interneurons enable a competing interaction between a 6–12 Hz oscillation and a fear-associated 3–6 Hz oscillation within the BLA. Loss of this competition increases a 3–6 Hz oscillatory signature, with BLA→mPFC directionality signaling the recurrence of fear expression. The discovery of cellular and oscillatory substrates of fear extinction learning that critically depend on BLA PV-interneurons could inform therapies aimed at preventing the pathological recurrence of fear following extinction learning. PMID:28967909
A role of nucleus accumbens dopamine receptors in the nucleus accumbens core, but not shell, in fear prediction error.

PubMed

Li, Susan S Y; McNally, Gavan P

2015-08-01

Two experiments used an associative blocking design to study the role of dopamine receptors in the nucleus accumbens shell (AcbSh) and core (AcbC) in fear prediction error. Rats in the experimental groups were trained to a visual fear-conditioned stimulus (conditional stimulus [CS]) A in Stage I, whereas rats in the control groups were not. In Stage II, all rats received compound fear conditioning of the visual CSA and an auditory CSB. Rats were later tested for their fear responses to CSB. All rats received microinjections of saline or the D1-D2 receptor antagonist cis-(z)-flupenthixol prior to Stage II. These microinjections targeted either the AcbSh (Experiment 1) or the AcbC (Experiment 2). In each experiment, Stage I fear conditioning of CSA blocked fear learning to CSB. Microinjection of cis-(z)-flupenthixol (10 or 20 μg) into the AcbSh (Experiment 1) had no effect on fear learning or associative blocking. In contrast, microinjection of cis-(z)-flupenthixol (10 or 20 μg) into the AcbC (Experiment 2) attenuated blocking and so enabled fear learning to CSB. These results identify the AcbC as the critical locus for dopamine receptor contributions to fear prediction error and the associative blocking of fear learning. (c) 2015 APA, all rights reserved).
Lifelong disturbance of serotonin transporter functioning results in fear learning deficits: Reversal by blockade of CRF1 receptors.

PubMed

Bijlsma, Elisabeth Y; Hendriksen, Hendrikus; Baas, Johanna M P; Millan, Mark J; Groenink, Lucianne

2015-10-01

The inability to associate aversive events with relevant cues (i.e. fear learning) may lead to maladaptive anxiety. To further study the role of the serotonin transporter (SERT) in fear learning, classical fear conditioning was studied in SERT knockout rats (SERT(-/-)) using fear potentiation of the startle reflex. Next, fear acquisition and concomitant development of contextual conditioned fear were monitored during training. To differentiate between developmental and direct effects of reduced SERT functioning, effects of acute and chronic SSRI treatment were studied in adult rats. Considering the known interactions between serotonin and corticotropin-releasing factor (CRF), we studied the effect of the CRFR1 antagonist CP154,526 on behavioral changes observed and determined CRF1 receptor levels in SERT(-/-) rats. SERT(-/-) showed blunted fear potentiation and enhanced contextual fear, which resulted from a deficit in fear acquisition. Paroxetine treatment did not affect acquisition or expression of fear-potentiated startle, suggesting that disturbed fear learning in SERT(-/-) results from developmental changes and not from reduced SERT functioning. Although CRF1 receptor levels did not differ significantly between genotypes, CP154,526 treatment normalized both cue- and contextual fear in SERT(-/-) during acquisition, but not expression of fear-potentiated startle. The disrupted fear acquisition and concomitant increase in contextual conditioned fear-potentiated startle fear in SERT(-/-) resembles the associative learning deficit seen in patients with panic disorder and suggests that normal SERT functioning is crucial for the development of an adequate fear neuro-circuitry. Moreover, the normalization of fear acquisition by CP154,526 suggests a role for central CRF signaling in the generalization of fear. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.
Associative fear learning and perceptual discrimination: a perceptual pathway in the development of chronic pain.

PubMed

Zaman, Jonas; Vlaeyen, Johan W S; Van Oudenhove, Lukas; Wiech, Katja; Van Diest, Ilse

2015-04-01

Recent neuropsychological theories emphasize the influence of maladaptive learning and memory processes on pain perception. However, the precise relationship between these processes as well as the underlying mechanisms remain poorly understood; especially the role of perceptual discrimination and its modulation by associative fear learning has received little attention so far. Experimental work with exteroceptive stimuli consistently points to effects of fear learning on perceptual discrimination acuity. In addition, clinical observations have revealed that in individuals with chronic pain perceptual discrimination is impaired, and that tactile discrimination training reduces pain. Based on these findings, we present a theoretical model of which the central tenet is that associative fear learning contributes to the development of chronic pain through impaired interoceptive and proprioceptive discrimination acuity. Copyright © 2015 Elsevier Ltd. All rights reserved.
Synaptic plasticity associated with a memory engram in the basolateral amygdala.

PubMed

Nonaka, Ayako; Toyoda, Takeshi; Miura, Yuki; Hitora-Imamura, Natsuko; Naka, Masamitsu; Eguchi, Megumi; Yamaguchi, Shun; Ikegaya, Yuji; Matsuki, Norio; Nomura, Hiroshi

2014-07-09

Synaptic plasticity is a cellular mechanism putatively underlying learning and memory. However, it is unclear whether learning induces synaptic modification globally or only in a subset of neurons in associated brain regions. In this study, we genetically identified neurons activated during contextual fear learning and separately recorded synaptic efficacy from recruited and nonrecruited neurons in the mouse basolateral amygdala (BLA). We found that the fear learning induces presynaptic potentiation, which was reflected by an increase in the miniature EPSC frequency and by a decrease in the paired-pulse ratio. Changes occurred only in the cortical synapses targeting the BLA neurons that were recruited into the fear memory trace. Furthermore, we found that fear learning reorganizes the neuronal ensemble responsive to the conditioning context in conjunction with the synaptic plasticity. In particular, the neuronal activity during learning was associated with the neuronal recruitment into the context-responsive ensemble. These findings suggest that synaptic plasticity in a subset of BLA neurons contributes to fear memory expression through ensemble reorganization. Copyright © 2014 the authors 0270-6474/14/349305-05$15.00/0.
Inhibition of Vicariously Learned Fear in Children Using Positive Modeling and Prior Exposure

PubMed Central

2015-01-01

One of the challenges to conditioning models of fear acquisition is to explain how different individuals can experience similar learning events and only some of them subsequently develop fear. Understanding factors moderating the impact of learning events on fear acquisition is key to understanding the etiology and prevention of fear in childhood. This study investigates these moderators in the context of vicarious (observational) learning. Two experiments tested predictions that the acquisition or inhibition of fear via vicarious learning is driven by associative learning mechanisms similar to direct conditioning. In Experiment 1, 3 groups of children aged 7 to 9 years received 1 of 3 inhibitive information interventions—psychoeducation, factual information, or no information (control)—prior to taking part in a vicarious fear learning procedure. In Experiment 2, 3 groups of children aged 7 to 10 years received 1 of 3 observational learning interventions—positive modeling (immunization), observational familiarity (latent inhibition), or no prevention (control)—before vicarious fear learning. Results indicated that observationally delivered manipulations inhibited vicarious fear learning, while preventions presented via written information did not. These findings confirm that vicarious learning shares some of the characteristics of direct conditioning and can explain why not all individuals will develop fear following a vicarious learning event. They also suggest that the modality of inhibitive learning is important and should match the fear learning pathway for increased chances of inhibition. Finally, the results demonstrate that positive modeling is likely to be a particularly effective method for preventing fear-related observational learning in children. PMID:26653136
Inhibition of vicariously learned fear in children using positive modeling and prior exposure.

PubMed

Askew, Chris; Reynolds, Gemma; Fielding-Smith, Sarah; Field, Andy P

2016-02-01

One of the challenges to conditioning models of fear acquisition is to explain how different individuals can experience similar learning events and only some of them subsequently develop fear. Understanding factors moderating the impact of learning events on fear acquisition is key to understanding the etiology and prevention of fear in childhood. This study investigates these moderators in the context of vicarious (observational) learning. Two experiments tested predictions that the acquisition or inhibition of fear via vicarious learning is driven by associative learning mechanisms similar to direct conditioning. In Experiment 1, 3 groups of children aged 7 to 9 years received 1 of 3 inhibitive information interventions-psychoeducation, factual information, or no information (control)-prior to taking part in a vicarious fear learning procedure. In Experiment 2, 3 groups of children aged 7 to 10 years received 1 of 3 observational learning interventions-positive modeling (immunization), observational familiarity (latent inhibition), or no prevention (control)-before vicarious fear learning. Results indicated that observationally delivered manipulations inhibited vicarious fear learning, while preventions presented via written information did not. These findings confirm that vicarious learning shares some of the characteristics of direct conditioning and can explain why not all individuals will develop fear following a vicarious learning event. They also suggest that the modality of inhibitive learning is important and should match the fear learning pathway for increased chances of inhibition. Finally, the results demonstrate that positive modeling is likely to be a particularly effective method for preventing fear-related observational learning in children. (c) 2016 APA, all rights reserved).
Selective early-acquired fear memories undergo temporary suppression during adolescence

PubMed Central

Pattwell, Siobhan S.; Bath, Kevin G.; Casey, B. J.; Ninan, Ipe; Lee, Francis S.

2011-01-01

Highly conserved neural circuitry between rodents and humans has allowed for in-depth characterization of behavioral and molecular processes associated with emotional learning and memory. Despite increased prevalence of affective disorders in adolescent humans, few studies have characterized how associative-emotional learning changes during the transition through adolescence or identified mechanisms underlying such changes. By examining fear conditioning in mice, as they transitioned into and out of adolescence, we found that a suppression of contextual fear occurs during adolescence. Although contextual fear memories were not expressed during early adolescence, they could be retrieved and expressed as the mice transitioned out of adolescence. This temporary suppression of contextual fear was associated with blunted synaptic activity in the basal amygdala and decreased PI3K and MAPK signaling in the hippocampus. These findings reveal a unique form of brain plasticity in fear learning during early adolescence and may prove informative for understanding endogenous mechanisms to suppress unwanted fear memories. PMID:21220344
The effect of ketamine on the consolidation and extinction of contextual fear memory

PubMed Central

Thomas, Kerrie L; Hall, Jeremy

2018-01-01

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. PMID:29338491
Attentional Control and Fear Extinction in Subclinical Fear: An Exploratory Study

PubMed Central

Forcadell, Eduard; Torrents-Rodas, David; Treen, Devi; Fullana, Miquel A.; Tortella-Feliu, Miquel

2017-01-01

Attentional control (AC) and fear extinction learning are known to be involved in pathological anxiety. In this study we explored whether individual differences in non-emotional AC were associated with individual differences in the magnitude and gradient of fear extinction (learning and recall). In 50 individuals with fear of spiders, we collected measures of non-emotional AC by means of self-report and by assessing the functioning of the major attention networks (executive control, orienting, and alerting). The participants then underwent a paradigm assessing fear extinction learning and extinction recall. The two components of the orienting network functioning (costs and benefits) were significantly associated with fear extinction gradient over and above the effects of trait anxiety. Specifically, participants with enhanced orienting costs (i.e., difficulties in disengaging attention from cues not relevant for the task) showed faster extinction learning, while those with enhanced orienting benefits (i.e., attention facilitated by valid cues) exhibited faster extinction recall as measured by fear-potentiated startle and Unconditioned Stimulus expectancies, respectively. Our findings suggest that, in non-emotional conditions, the orienting component of attention may be predictive of fear extinction. They also show that the use of fear extinction gradients and the exploration of individual differences in non-emotional AC (using performance-based measures of attentional network functioning) can provide a better understanding of individual differences in fear learning. Our findings also may help to understand differences in exposure therapy outcomes. PMID:29018384
Extinction of Learned Fear Induces Hippocampal Place Cell Remapping

PubMed Central

Wang, Melissa E.; Yuan, Robin K.; Keinath, Alexander T.; Ramos Álvarez, Manuel M.

2015-01-01

The extinction of learned fear is a hippocampus-dependent process thought to embody new learning rather than erasure of the original fear memory, although it is unknown how these competing contextual memories are represented in the hippocampus. We previously demonstrated that contextual fear conditioning results in hippocampal place cell remapping and long-term stabilization of novel representations. Here we report that extinction learning also induces place cell remapping in C57BL/6 mice. Specifically, we observed cells that preferentially remapped during different stages of learning. While some cells remapped in both fear conditioning and extinction, others responded predominantly during extinction, which may serve to modify previous representations as well as encode new safe associations. Additionally, we found cells that remapped primarily during fear conditioning, which could facilitate reacquisition of the original fear association. Moreover, we also observed cells that were stable throughout learning, which may serve to encode the static aspects of the environment. The short-term remapping observed during extinction was not found in animals that did not undergo fear conditioning, or when extinction was conducted outside of the conditioning context. Finally, conditioning and extinction produced an increase in spike phase locking to the theta and gamma frequencies. However, the degree of remapping seen during conditioning and extinction only correlated with gamma synchronization. Our results suggest that the extinction learning is a complex process that involves both modification of pre-existing memories and formation of new ones, and these traces coexist within the same hippocampal representation. PMID:26085635
Anxiety symptoms and children's eye gaze during fear learning.

PubMed

Michalska, Kalina J; Machlin, Laura; Moroney, Elizabeth; Lowet, Daniel S; Hettema, John M; Roberson-Nay, Roxann; Averbeck, Bruno B; Brotman, Melissa A; Nelson, Eric E; Leibenluft, Ellen; Pine, Daniel S

2017-11-01

The eye region of the face is particularly relevant for decoding threat-related signals, such as fear. However, it is unclear if gaze patterns to the eyes can be influenced by fear learning. Previous studies examining gaze patterns in adults find an association between anxiety and eye gaze avoidance, although no studies to date examine how associations between anxiety symptoms and eye-viewing patterns manifest in children. The current study examined the effects of learning and trait anxiety on eye gaze using a face-based fear conditioning task developed for use in children. Participants were 82 youth from a general population sample of twins (aged 9-13 years), exhibiting a range of anxiety symptoms. Participants underwent a fear conditioning paradigm where the conditioned stimuli (CS+) were two neutral faces, one of which was randomly selected to be paired with an aversive scream. Eye tracking, physiological, and subjective data were acquired. Children and parents reported their child's anxiety using the Screen for Child Anxiety Related Emotional Disorders. Conditioning influenced eye gaze patterns in that children looked longer and more frequently to the eye region of the CS+ than CS- face; this effect was present only during fear acquisition, not at baseline or extinction. Furthermore, consistent with past work in adults, anxiety symptoms were associated with eye gaze avoidance. Finally, gaze duration to the eye region mediated the effect of anxious traits on self-reported fear during acquisition. Anxiety symptoms in children relate to face-viewing strategies deployed in the context of a fear learning experiment. This relationship may inform attempts to understand the relationship between pediatric anxiety symptoms and learning. © 2017 Association for Child and Adolescent Mental Health.
Differential Involvement of the Medial Prefrontal Cortex across Variants of Contextual Fear Conditioning

ERIC Educational Resources Information Center

Heroux, Nicholas A.; Robinson-Drummer, Patrese A.; Sanders, Hollie R.; Rosen, Jeffrey B.; Stanton, Mark E.

2017-01-01

The context preexposure facilitation effect (CPFE) is a contextual fear conditioning paradigm in which learning about the context, acquiring the context-shock association, and retrieving/expressing contextual fear are temporally dissociated into three distinct phases. In contrast, learning about the context and the context-shock association…
What Predicts Fear of School Violence among U.S. Adolescents?

ERIC Educational Resources Information Center

Akiba, Motoko

2010-01-01

Background/Context: Ensuring a safe learning environment for every student at school is a major responsibility of educators, school administrators, and policy makers in our society. Students' fear associated with school violence affects their school attendance, learning motivation, and academic achievement. Although predictors of adults' fear of…
Out with the old and in with the new: Synaptic mechanisms of extinction in the amygdala

PubMed Central

Maren, Stephen

2014-01-01

Considerable research indicates that long-term synaptic plasticity in the amygdala underlies the acquisition of emotional memories, including those learned during Pavlovian fear conditioning. Much less is known about the synaptic mechanisms involved in other forms of associative learning, including extinction, that update fear memories. Extinction learning might reverse conditioning-related changes (e.g., depotentiation) or induce plasticity at inhibitory synapses (e.g., long-term potentiation) to suppress conditioned fear responses. Either mechanism must account for fear recovery phenomena after extinction, as well as savings of extinction after fear recovery. PMID:25312830
Nicotine disrupts safety learning by enhancing fear associated with a safety cue via the dorsal hippocampus.

PubMed

Connor, David A; Kutlu, Munir G; Gould, Thomas J

2017-07-01

Learned safety, a learning process in which a cue becomes associated with the absence of threat, is disrupted in individuals with post-traumatic stress disorder (PTSD). A bi-directional relationship exists between smoking and PTSD and one potential explanation is that nicotine-associated changes in cognition facilitate PTSD emotional dysregulation by disrupting safety associations. Therefore, we investigated whether nicotine would disrupt learned safety by enhancing fear associated with a safety cue. In the present study, C57BL/6 mice were administered acute or chronic nicotine and trained over three days in a differential backward trace conditioning paradigm consisting of five trials of a forward conditioned stimulus (CS)+ (Light) co-terminating with a footshock unconditioned stimulus followed by a backward CS- (Tone) presented 20 s after cessation of the unconditioned stimulus. Summation testing found that acute nicotine disrupted learned safety, but chronic nicotine had no effect. Another group of animals administered acute nicotine showed fear when presented with the backward CS (Light) alone, indicating the formation of a maladaptive fear association with the backward CS. Finally, we investigated the brain regions involved by administering nicotine directly into the dorsal hippocampus, ventral hippocampus, and prelimbic cortex. Infusion of nicotine into the dorsal hippocampus disrupted safety learning.
A common neural network differentially mediates direct and social fear learning.

PubMed

Lindström, Björn; Haaker, Jan; Olsson, Andreas

2018-02-15

Across species, fears often spread between individuals through social learning. Yet, little is known about the neural and computational mechanisms underlying social learning. Addressing this question, we compared social and direct (Pavlovian) fear learning showing that they showed indistinguishable behavioral effects, and involved the same cross-modal (self/other) aversive learning network, centered on the amygdala, the anterior insula (AI), and the anterior cingulate cortex (ACC). Crucially, the information flow within this network differed between social and direct fear learning. Dynamic causal modeling combined with reinforcement learning modeling revealed that the amygdala and AI provided input to this network during direct and social learning, respectively. Furthermore, the AI gated learning signals based on surprise (associability), which were conveyed to the ACC, in both learning modalities. Our findings provide insights into the mechanisms underlying social fear learning, with implications for understanding common psychological dysfunctions, such as phobias and other anxiety disorders. Copyright © 2017 Elsevier Inc. All rights reserved.
Biased Intensity Judgements of Visceral Sensations After Learning to Fear Visceral Stimuli: A Drift Diffusion Approach.

PubMed

Zaman, Jonas; Madden, Victoria J; Iven, Julie; Wiech, Katja; Weltens, Nathalie; Ly, Huynh Giao; Vlaeyen, Johan W S; Van Oudenhove, Lukas; Van Diest, Ilse

2017-10-01

A growing body of research has identified fear of visceral sensations as a potential mechanism in the development and maintenance of visceral pain disorders. However, the extent to which such learned fear affects visceroception remains unclear. To address this question, we used a differential fear conditioning paradigm with nonpainful esophageal balloon distensions of 2 different intensities as conditioning stimuli (CSs). The experiment comprised of preacquisition, acquisition, and postacquisition phases during which participants categorized the CSs with respect to their intensity. The CS+ was always followed by a painful electrical stimulus (unconditioned stimulus) during the acquisition phase and in 60% of the trials during postacquisition. The second stimulus (CS-) was never associated with pain. Analyses of galvanic skin and startle eyeblink responses as physiological markers of successful conditioning showed increased fear responses to the CS+ compared with the CS-, but only in the group with the low-intensity stimulus as CS+. Computational modeling of response times and response accuracies revealed that differential fear learning affected perceptual decision-making about the intensities of visceral sensations such that sensations were more likely to be categorized as more intense. These results suggest that associative learning might indeed contribute to visceral hypersensitivity in functional gastrointestinal disorders. This study shows that associative fear learning biases intensity judgements of visceral sensations toward perceiving such sensations as more intense. Learning-induced alterations in visceroception might therefore contribute to the development or maintenance of visceral pain. Copyright © 2017 American Pain Society. Published by Elsevier Inc. All rights reserved.
Opioid receptors mediate direct predictive fear learning: evidence from one-trial blocking.

PubMed

Cole, Sindy; McNally, Gavan P

2007-04-01

Pavlovian fear learning depends on predictive error, so that fear learning occurs when the actual outcome of a conditioning trial exceeds the expected outcome. Previous research has shown that opioid receptors, including mu-opioid receptors in the ventrolateral quadrant of the midbrain periaqueductal gray (vlPAG), mediate such predictive fear learning. Four experiments reported here used a within-subject one-trial blocking design to study whether opioid receptors mediate a direct or indirect action of predictive error on Pavlovian association formation. In Stage I, rats were trained to fear conditioned stimulus (CS) A by pairing it with shock. In Stage II, CSA and CSB were co-presented once and co-terminated with shock. Two novel stimuli, CSC and CSD, were also co-presented once and co-terminated with shock in Stage II. The results showed one-trial blocking of fear learning (Experiment 1) as well as one-trial unblocking of fear learning when Stage II training employed a higher intensity footshock than was used in Stage I (Experiment 2). Systemic administrations of the opioid receptor antagonist naloxone (Experiment 3) or intra-vlPAG administrations of the selective mu-opioid receptor antagonist CTAP (Experiment 4) prior to Stage II training prevented one-trial blocking. These results show that opioid receptors mediate the direct actions of predictive error on Pavlovian association formation.
Social modulation of associative fear learning by pheromone communication

PubMed Central

Bredy, Timothy W.; Barad, Mark

2009-01-01

Mice communicate through visual, vocal, and olfactory cues that influence innate, nonassociative behavior. We here report that exposure to a recently fear-conditioned familiar mouse impairs acquisition of conditioned fear and facilitates fear extinction, effects mimicked by both an olfactory chemosignal emitted by a recently fear-conditioned familiar mouse and by the putative stress-related anxiogenic pheromone β-phenylethylamine (β-PEA). Together, these findings suggest social modulation of higher-order cognitive processing through pheromone communication and support the concurrent excitor hypothesis of extinction learning. PMID:19117912

Social modulation of associative fear learning by pheromone communication.

PubMed

Bredy, Timothy W; Barad, Mark

2009-01-01

Mice communicate through visual, vocal, and olfactory cues that influence innate, nonassociative behavior. We here report that exposure to a recently fear-conditioned familiar mouse impairs acquisition of conditioned fear and facilitates fear extinction, effects mimicked by both an olfactory chemosignal emitted by a recently fear-conditioned familiar mouse and by the putative stress-related anxiogenic pheromone beta-phenylethylamine (beta-PEA). Together, these findings suggest social modulation of higher-order cognitive processing through pheromone communication and support the concurrent excitor hypothesis of extinction learning.
Associative learning versus fear habituation as predictors of long-term extinction retention.

PubMed

Brown, Lily A; LeBeau, Richard T; Chat, Ka Yi; Craske, Michelle G

2017-06-01

Violation of unconditioned stimulus (US) expectancy during extinction training may enhance associative learning and result in improved long-term extinction retention compared to within-session habituation. This experiment examines variation in US expectancy (i.e., expectancy violation) as a predictor of long-term extinction retention. It also examines within-session habituation of fear-potentiated startle (electromyography, EMG) and fear of conditioned stimuli (CS) throughout extinction training as predictors of extinction retention. Participants (n = 63) underwent fear conditioning, extinction and retention and provided continuous ratings of US expectancy and EMG, as well as CS fear ratings before and after each phase. Variation in US expectancy throughout extinction and habituation of EMG and fear was entered into a regression as predictors of retention and reinstatement of levels of expectancy and fear. Greater variation in US expectancy throughout extinction training was significantly predictive of enhanced extinction performance measured at retention test, although not after reinstatement test. Slope of EMG and CS fear during extinction did not predict retention of extinction. Within-session habituation of EMG and self-reported fear is not sufficient for long-term retention of extinction learning, and models emphasizing expectation violation may result in enhanced outcomes.
Acquired fears reflected in cortical sensory processing: A review of electrophysiological studies of human classical conditioning

PubMed Central

Miskovic, Vladimir; Keil, Andreas

2012-01-01

The capacity to associate neutral stimuli with affective value is an important survival strategy that can be accomplished by cell assemblies obeying Hebbian learning principles. In the neuroscience laboratory, classical fear conditioning has been extensively used as a model to study learning related changes in neural structure and function. Here, we review the effects of classical fear conditioning on electromagnetic brain activity in humans, focusing on how sensory systems adapt to changing fear-related contingencies. By considering spatio-temporal patterns of mass neuronal activity we illustrate a range of cortical changes related to a retuning of neuronal sensitivity to amplify signals consistent with fear-associated stimuli at the cost of other sensory information. Putative mechanisms that may underlie fear-associated plasticity at the level of the sensory cortices are briefly considered and several avenues for future work are outlined. PMID:22891639
The Effect of Disgust and Fear Modeling on Children’s Disgust and Fear for Animals

PubMed Central

2014-01-01

Disgust is a protective emotion associated with certain types of animal fears. Given that a primary function of disgust is to protect against harm, increasing children’s disgust-related beliefs for animals may affect how threatening they think animals are and their avoidance of them. One way that children’s disgust beliefs for animals might change is via vicarious learning: by observing others responding to the animal with disgust. In Experiment 1, children (ages 7–10 years) were presented with images of novel animals together with adult faces expressing disgust. Children’s fear beliefs and avoidance preferences increased for these disgust-paired animals compared with unpaired control animals. Experiment 2 used the same procedure and compared disgust vicarious learning with vicarious learning with fear faces. Children’s fear beliefs and avoidance preferences for animals again increased as a result of disgust vicarious learning, and animals seen with disgust or fear faces were also rated more disgusting than control animals. The relationship between increased fear beliefs and avoidance preferences for animals was mediated by disgust for the animals. The experiments demonstrate that children can learn to believe that animals are disgusting and threatening after observing an adult responding with disgust toward them. The findings also suggest a bidirectional relationship between fear and disgust with fear-related vicarious learning leading to increased disgust for animals and disgust-related vicarious learning leading to increased fear and avoidance. PMID:24955571
Time Determines the Neural Circuit Underlying Associative Fear Learning

PubMed Central

Guimarãis, Marta; Gregório, Ana; Cruz, Andreia; Guyon, Nicolas; Moita, Marta A.

2011-01-01

Ultimately associative learning is a function of the temporal features and relationships between experienced stimuli. Nevertheless how time affects the neural circuit underlying this form of learning remains largely unknown. To address this issue, we used single-trial auditory trace fear conditioning and varied the length of the interval between tone and foot-shock. Through temporary inactivation of the amygdala, medial prefrontal-cortex (mPFC), and dorsal-hippocampus in rats, we tested the hypothesis that different temporal intervals between the tone and the shock influence the neuronal structures necessary for learning. With this study we provide the first experimental evidence showing that temporarily inactivating the amygdala before training impairs auditory fear learning when there is a temporal gap between the tone and the shock. Moreover, imposing a short interval (5 s) between the two stimuli also relies on the mPFC, while learning the association across a longer interval (40 s) becomes additionally dependent on a third structure, the dorsal-hippocampus. Thus, our results suggest that increasing the interval length between tone and shock leads to the involvement of an increasing number of brain areas in order for the association between the two stimuli to be acquired normally. These findings demonstrate that the temporal relationship between events is a key factor in determining the neuronal mechanisms underlying associative fear learning. PMID:22207842
Cannabinoid modulation of zebrafish fear learning and its functional analysis investigated by c-Fos expression.

PubMed

Ruhl, Tim; Zeymer, Malou; von der Emde, Gerhard

2017-02-01

It has been shown that zebrafish fear learning proceeds in the same way as reported for rodents. However, in zebrafish fear learning it is possible to substitute the use of electric shocks as unconditioned stimulus and utilize the inborn fear responses to the alarm substance Schreckstoff, instead. The skin extract Schreckstoff elicits typical fear reactions such as preferred bottom dwelling, swimming in a tighter shoal, erratic movements and freezing. This natural fear behavior can be transferred from Schreckstoff to any other sensory stimulus by associative conditioning (fear learning). We presented Schreckstoff simultaneously with a red light stimulus and tested the effectiveness of fear learning during memory retrieval. The two brain regions known to be relevant for learning in zebrafish are the medial and the lateral pallium of the dorsal telencephalon, both containing rich expressions of the endocannabinoid receptor CB1. To test the influence of the zebrafish endocannabinoid system on fear acquisition learning, an experimental group of ten fish was pretreated with the CB1 receptor agonist THC (Δ 9 -tetrahydrocannabinol; 100nM for 1h). We found that CB1 activation significantly inhibited acquisition of fear learning, possibly by impairing stimulus encoding processes in pallial areas. This was supported by analyzes of c-Fos expression in the brains of experimental animals. Schreckstoff exposure during fear acquisition learning and memory retrieval during red light presentation increased the number of labelled cells in pallial structures, but in no other brain region investigated (e.g. striatum, thalamus, and habenula). THC administration before fear conditioning significantly decreased c-Fos expression in these structures to a level similar to the control group without Schreckstoff experience, suggesting that Schreckstoff induced fear learning requires brain circuits restricted mainly to pallial regions of the dorsal telencephalon. Copyright © 2016 Elsevier Inc. All rights reserved.
The inhibition of acquired fear.

PubMed

Izquierdo, Iván; Cammarota, Martín; Vianna, Mónica M R; Bevilaqua, Lía R M

2004-01-01

A conditioned stimulus (CS) associated with a fearsome unconditioned stimulus (US) generates learned fear. Acquired fear is at the root of a variety of mental disorders, among which phobias, generalized anxiety, the posttraumatic stress disorder (PTSD) and some forms of depression. The simplest way to inhibit learned fear is to extinguish it, which is usually done by repeatedly presenting the CS alone, so that a new association, CS-"no US", will eventually overcome the previously acquired CS-US association. Extinction was first described by Pavlov as a form of "internal inhibition" and was recommended by Freud and Ferenczi in the 1920s (who called it "habituation") as the treatment of choice for phobic disorders. It is used with success till this day, often in association with anxiolytic drugs. Extinction has since then been applied, also successfully and also often in association with anxiolytics, to the treatment of panic, generalized anxiety disorders and, more recently, PTSD. Extinction of learned fear involves gene expression, protein synthesis, N-methyl-D-aspartate (NMDA) receptors and signaling pathways in the hippocampus and the amygdala at the time of the first CS-no US association. It can be enhanced by increasing the exposure to the "no US" component at the time of behavioral testing, to the point of causing the complete uninstallment of the original fear response. Some theorists have recently proposed that reiteration of the CS alone may induce a reconsolidation of the learned behavior instead of its extinction. Reconsolidation would preserve the original memory from the labilization induced by its retrieval. If true, this would of course be disastrous for the psychotherapy of fear-motivated disorders. Here we show that neither the CS nor retrieval cause anything remotely like reconsolidation, but just extinction. In fact, our findings indicate that the reconsolidation hypothesis is essentially incorrect, at least for the form of contextual fear most commonly studied in rodents. Therefore, it seems safe to continue using extinction-based forms of therapy for disorders secondary to acquired fear. Further, it is useful and desirable to device procedures by which the "no US" component of the extinction is strengthened in order to alleviate the symptoms of victims of acquired fear.
Effects of sleep on memory for conditioned fear and fear extinction

PubMed Central

Pace-Schott, Edward F.; Germain, Anne; Milad, Mohammed R.

2015-01-01

Learning and memory for extinction of conditioned fear is a basic mammalian mechanism for regulating negative emotion. Sleep promotes both the consolidation of memory and the regulation of emotion. Sleep can influence consolidation and modification of memories associated with both fear and its extinction. After brief overviews of the behavior and neural circuitry associated with fear conditioning, extinction learning and extinction memory in the rodent and human, interactions of sleep with these processes will be examined. Animal and human studies suggest that sleep can serve to consolidate both fear and extinction memory. In humans, sleep also promotes generalization of extinction memory. Time-of-day effects on extinction learning and generalization are also seen. REM may be a sleep stage of particular importance for the consolidation of both fear and extinction memory as evidenced by selective REM deprivation experiments. REM sleep is accompanied by selective activation of the same limbic structures implicated in the learning and memory of fear and extinction. Preliminary evidence also suggests extinction learning can take place during slow wave sleep. Study of low-level processes such as conditioning, extinction and habituation may allow sleep effects on emotional memory to be identified and inform study of sleep’s effects on more complex, emotionally salient declarative memories. Anxiety disorders are marked by impairments of both sleep and extinction memory. Improving sleep quality may ameliorate anxiety disorders by strengthening naturally acquired extinction. Strategically timed sleep may be used to enhance treatment of anxiety by strengthening therapeutic extinction learned via exposure therapy. PMID:25894546
Effects of sleep on memory for conditioned fear and fear extinction.

PubMed

Pace-Schott, Edward F; Germain, Anne; Milad, Mohammed R

2015-07-01

Learning and memory for extinction of conditioned fear is a basic mammalian mechanism for regulating negative emotion. Sleep promotes both the consolidation of memory and the regulation of emotion. Sleep can influence consolidation and modification of memories associated with both fear and its extinction. After brief overviews of the behavior and neural circuitry associated with fear conditioning, extinction learning, and extinction memory in the rodent and human, interactions of sleep with these processes will be examined. Animal and human studies suggest that sleep can serve to consolidate both fear and extinction memory. In humans, sleep also promotes generalization of extinction memory. Time-of-day effects on extinction learning and generalization are also seen. Rapid eye movement (REM) may be a sleep stage of particular importance for the consolidation of both fear and extinction memory as evidenced by selective REM deprivation experiments. REM sleep is accompanied by selective activation of the same limbic structures implicated in the learning and memory of fear and extinction. Preliminary evidence also suggests extinction learning can take place during slow wave sleep. Study of low-level processes such as conditioning, extinction, and habituation may allow sleep effects on emotional memory to be identified and inform study of sleep's effects on more complex, emotionally salient declarative memories. Anxiety disorders are marked by impairments of both sleep and extinction memory. Improving sleep quality may ameliorate anxiety disorders by strengthening naturally acquired extinction. Strategically timed sleep may be used to enhance treatment of anxiety by strengthening therapeutic extinction learned via exposure therapy. (PsycINFO Database Record (c) 2015 APA, all rights reserved).
Nonlinear Developmental trajectory of fear learning and memory

PubMed Central

King, Elizabeth C.; Pattwell, Siobhan S.; Sun, Alice; Glatt, Charles E.; Lee, Francis S.

2013-01-01

The transition into and out of adolescence represents a unique developmental period during which neuronal circuits are particularly susceptible to modification by experience. Adolescence is associated with an increased incidence of anxiety disorders in humans,1–3 and an estimated 75% of adults with fear-related disorders met diagnostic criteria as children and adolescents.4,5 Conserved neural circuitry between rodents and humans has facilitated neurodevelopmental studies of behavioral and molecular processes associated with fear learning and memory, which lie at the heart of many anxiety disorders. Here, we review the non-linear developmental aspects of fear learning and memory during a transition period into and out of adolescence and provide a discussion of the molecular mechanisms that may underlie these alterations in behavior. We provide a model that may help to inform novel treatment strategies for children and adolescents with fear-related disorders. PMID:24176014
Social Modulation of Associative Fear Learning by Pheromone Communication

ERIC Educational Resources Information Center

Bredy, Timothy W.; Barad, Mark

2009-01-01

Mice communicate through visual, vocal, and olfactory cues that influence innate, nonassociative behavior. We here report that exposure to a recently fear-conditioned familiar mouse impairs acquisition of conditioned fear and facilitates fear extinction, effects mimicked by both an olfactory chemosignal emitted by a recently fear-conditioned…
Can experimentally induced positive affect attenuate generalization of fear of movement-related pain?

PubMed

Geschwind, Nicole; Meulders, Michel; Peters, Madelon L; Vlaeyen, Johan W S; Meulders, Ann

2015-03-01

Recent experimental data show that associative learning processes are involved not only in the acquisition but also in the spreading of pain-related fear. Clinical studies suggest involvement of positive affect in resilience against chronic pain. Surprisingly, the role of positive affect in associative learning in general, and in fear generalization in particular, has received scant attention. In a voluntary movement paradigm, in which one arm movement (reinforced conditioned stimulus [CS+]) was followed by a painful stimulus and another was not (unreinforced conditioned stimulus [CS-]), we tested generalization of fear inhibition in response to 5 novel but related generalization movements (GSs; within-subjects) after either a positive affect induction or a control exercise (Group = between-subjects) in healthy participants (N = 50). The GSs' similarity with the original CS+ movement and CS- movement varied. Fear learning was assessed via verbal ratings. Results indicated that there was an interaction between the increase in positive affect and the linear generalization gradient. Stronger increases in positive affect were associated with steeper generalization curves because of relatively lower pain-unconditioned stimulus expectancy and less fear of stimuli more similar to the CS-. There was no Group by Stimulus interaction. Results thus suggest that positive affect may enhance safety learning through promoting generalization from known safe movements to novel yet related movements. Improved safety learning may be a central mechanism underlying the association between positive affect and increased resilience against chronic pain. We investigated the extent to which positive affect influences the generalization (ie, spreading) of pain-related fear inhibition in response to situations similar to the original, pain-eliciting situation. Results suggest that increasing positive affect in the acute pain stage may limit the spreading of pain-related fear, thereby potentially inhibiting transition to chronic pain conditions. Copyright © 2015 American Pain Society. Published by Elsevier Inc. All rights reserved.
Zinc transporter 3 is involved in learned fear and extinction, but not in innate fear.

PubMed

Martel, Guillaume; Hevi, Charles; Friebely, Olivia; Baybutt, Trevor; Shumyatsky, Gleb P

2010-11-01

Synaptically released Zn²+ is a potential modulator of neurotransmission and synaptic plasticity in fear-conditioning pathways. Zinc transporter 3 (ZnT3) knock-out (KO) mice are well suited to test the role of zinc in learned fear, because ZnT3 is colocalized with synaptic zinc, responsible for its transport to synaptic vesicles, highly enriched in the amygdala-associated neural circuitry, and ZnT3 KO mice lack Zn²+ in synaptic vesicles. However, earlier work reported no deficiency in fear memory in ZnT3 KO mice, which is surprising based on the effects of Zn²+ on amygdala synaptic plasticity. We therefore reexamined ZnT3 KO mice in various tasks for learned and innate fear. The mutants were deficient in a weak fear-conditioning protocol using single tone-shock pairing but showed normal memory when a stronger, five-pairing protocol was used. ZnT3 KO mice were deficient in memory when a tone was presented as complex auditory information in a discontinuous fashion. Moreover, ZnT3 KO mice showed abnormality in trace fear conditioning and in fear extinction. By contrast, ZnT3 KO mice had normal anxiety. Thus, ZnT3 is involved in associative fear memory and extinction, but not in innate fear, consistent with the role of synaptic zinc in amygdala synaptic plasticity.
From resilience to vulnerability: mechanistic insights into the effects of stress on transitions in critical period plasticity.

PubMed

Callaghan, Bridget L; Graham, Bronwyn M; Li, Stella; Richardson, Rick

2013-01-01

While early experiences are proposed to be important for the emergence of anxiety and other mental health problems, there is little empirical research examining the impact of such experiences on the development of emotional learning. Of the research that has been performed in this area, however, a complex picture has emerged in which the maturation of emotion circuits is influenced by the early experiences of the animal. For example, under typical laboratory rearing conditions infant rats rapidly forget learned fear associations (infantile amnesia) and express a form of extinction learning which is relapse-resistant (i.e., extinction in infant rats may be due to fear erasure). In contrast, adult rats exhibit very long-lasting memories of past learned fear associations, and express a form of extinction learning that is relapse-prone (i.e., the fear returns in a number of situations). However, when rats are reared under stressful conditions then they exhibit adult-like fear retention and extinction behaviors at an earlier stage of development (i.e., good retention of learned fear and relapse-prone extinction learning). In other words, under typical rearing conditions infant rats appear to be protected from exhibiting anxiety whereas after adverse rearing fear learning appears to make those infants more vulnerable to the later development of anxiety. While the effects of different experiences on infant rats' fear retention and extinction are becoming better documented, the mechanisms which mediate the early transition seen following stress remain unclear. Here we suggest that rearing stress may lead to an early maturation of the molecular and cellular signals shown to be involved in the closure of critical period plasticity in sensory modalities (e.g., maturation of GABAergic neurons, development of perineuronal nets), and speculate that these signals could be manipulated in adulthood to reopen infant forms of emotional learning (i.e., those that favor resilience).
Testing neurophysiological markers related to fear-potentiated startle.

PubMed

Seligowski, Antonia V; Bondy, Erin; Singleton, Paris; Orcutt, Holly K; Ressler, Kerry J; Auerbach, Randy P

2018-06-11

Fear-potentiated startle (FPS) paradigms provide insight into fear learning mechanisms that contribute to impairment among individuals with posttraumatic stress symptoms (PTSS). Electrophysiology also has provided insight into these mechanisms through the examination of event-related potentials (ERPs) such as the P100 and LPP. It remains unclear, however, whether the P100 and LPP may be related to fear learning processes within the FPS paradigm. To this end, we tested differences in ERP amplitudes for conditioned stimuli associated (CS+) and not associated (CS-) with an aversive unconditioned stimulus (US) during fear acquisition. Participants included 54 female undergraduate students (mean age = 20.26). The FPS response was measured via electromyography of the orbicularis oculi muscle. EEG data were collected during the FPS paradigm. While the difference between CS+ and CS- P100 amplitude was not significant, LPP amplitudes were significantly enhanced following the CS+ relative to CS-. Furthermore, the LPP difference wave (CS+ minus CS-) was associated with FPS scores for the CS- during the later portion of fear acquisition. These findings suggest that conditioned stimuli may have altered emotional encoding (LPP) during the FPS paradigm. Thus, the LPP may be a promising neurophysiological marker that is related to fear learning processes. Copyright © 2018 Elsevier B.V. All rights reserved.
Optogenetic Activation of Presynaptic Inputs in Lateral Amygdala Forms Associative Fear Memory

ERIC Educational Resources Information Center

Kwon, Jeong-Tae; Nakajima, Ryuichi; Hyung-Su, Kim; Jeong, Yire; Augustine, George J.; Han, Jin-Hee

2014-01-01

In Pavlovian fear conditioning, the lateral amygdala (LA) has been highlighted as a key brain site for association between sensory cues and aversive stimuli. However, learning-related changes are also found in upstream sensory regions such as thalamus and cortex. To isolate the essential neural circuit components for fear memory association, we…
Learning from other people’s fear: amygdala-based social reference learning in social anxiety disorder

PubMed Central

Blair, K. S.; Otero, M.; Teng, C.; Geraci, M.; Lewis, E.; Hollon, N.; Blair, R. J. R.; Ernst, Monique; Grillon, C.; Pine, D. S.

2016-01-01

Background Social anxiety disorder involves fear of social objects or situations. Social referencing may play an important role in the acquisition of this fear and could be a key determinant in future biomarkers and treatment pathways. However, the neural underpinnings mediating such learning in social anxiety are unknown. Using event-related functional magnetic resonance imaging, we examined social reference learning in social anxiety disorder. Specifically, would patients with the disorder show increased amygdala activity during social reference learning, and further, following social reference learning, show particularly increased response to objects associated with other people’s negative reactions? Method A total of 32 unmedicated patients with social anxiety disorder and 22 age-, intelligence quotient- and gender-matched healthy individuals responded to objects that had become associated with others’ fearful, angry, happy or neutral reactions. Results During the social reference learning phase, a significant group × social context interaction revealed that, relative to the comparison group, the social anxiety group showed a significantly greater response in the amygdala, as well as rostral, dorsomedial and lateral frontal and parietal cortices during the social, relative to non-social, referencing trials. In addition, during the object test phase, relative to the comparison group, the social anxiety group showed increased bilateral amygdala activation to objects associated with others’ fearful reactions, and a trend towards decreased amygdala activation to objects associated with others’ happy and neutral reactions. Conclusions These results suggest perturbed observational learning in social anxiety disorder. In addition, they further implicate the amygdala and dorsomedial prefrontal cortex in the disorder, and underscore their importance in future biomarker developments. PMID:27476529
Adult-onset hypothyroidism enhances fear memory and upregulates mineralocorticoid and glucocorticoid receptors in the amygdala.

PubMed

Montero-Pedrazuela, Ana; Fernández-Lamo, Iván; Alieva, María; Pereda-Pérez, Inmaculada; Venero, César; Guadaño-Ferraz, Ana

2011-01-01

Hypothyroidism is the most common hormonal disease in adults, which is frequently accompanied by learning and memory impairments and emotional disorders. However, the deleterious effects of thyroid hormones deficiency on emotional memory are poorly understood and often underestimated. To evaluate the consequences of hypothyroidism on emotional learning and memory, we have performed a classical Pavlovian fear conditioning paradigm in euthyroid and adult-thyroidectomized Wistar rats. In this experimental model, learning acquisition was not impaired, fear memory was enhanced, memory extinction was delayed and spontaneous recovery of fear memory was exacerbated in hypothyroid rats. The potentiation of emotional memory under hypothyroidism was associated with an increase of corticosterone release after fear conditioning and with higher expression of glucocorticoid and mineralocorticoid receptors in the lateral and basolateral nuclei of the amygdala, nuclei that are critically involved in the circuitry of fear memory. Our results demonstrate for the first time that adult-onset hypothyroidism potentiates fear memory and also increases vulnerability to develop emotional memories. Furthermore, our findings suggest that enhanced corticosterone signaling in the amygdala is involved in the pathophysiological mechanisms of fear memory potentiation. Therefore, we recommend evaluating whether inappropriate regulation of fear in patients with post-traumatic stress and other mental disorders is associated with abnormal levels of thyroid hormones, especially those patients refractory to treatment.
Fear acquisition and liking of out-group and in-group members: Learning bias or attention?

PubMed

Koenig, Stephan; Nauroth, Peter; Lucke, Sara; Lachnit, Harald; Gollwitzer, Mario; Uengoer, Metin

2017-10-01

The present study explores the notion of an out-group fear learning bias that is characterized by facilitated fear acquisition toward harm-doing out-group members. Participants were conditioned with two in-group and two out-group faces as conditioned stimuli. During acquisition, one in-group and one out-group face was paired with an aversive shock whereas the other in-group and out-group face was presented without shock. Psychophysiological measures of fear conditioning (skin conductance and pupil size) and explicit and implicit liking exhibited increased differential responding to out-group faces compared to in-group faces. However, the results did not clearly indicate that harm-doing out-group members were more readily associated with fear than harm-doing in-group members. In contrast, the out-group face not paired with shock decreased conditioned fear and disliking at least to the same extent that the shock-associated out-group face increased these measures. Based on these results, we suggest an account of the out-group fear learning bias that relates to an attentional bias to process in-group information. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.
GABAergic interneurons: The orchestra or the conductor in fear learning and memory?

PubMed

Lucas, Elizabeth K; Clem, Roger L

2017-12-02

Fear conditioning is a form of associative learning that is fundamental to survival and involves potentiation of activity in excitatory projection neurons (PNs). Current models stipulate that the mechanisms underlying this process involve plasticity of PN synapses, which exhibit strengthening in response to fear conditioning. However, excitatory PNs are extensively modulated by a diverse array of GABAergic interneurons whose contributions to acquisition, storage, and expression of fear memory remain poorly understood. Here we review emerging evidence that genetically-defined interneurons play important subtype-specific roles in processing of fear-related stimuli and that these dynamics shape PN firing through both inhibition and disinhibition. Furthermore, interneurons exhibit structural, molecular, and electrophysiological evidence of fear learning-induced synaptic plasticity. These studies warrant discarding the notion of interneurons as passive bystanders in long-term memory. Copyright © 2017. Published by Elsevier Inc.

Lmo4 in the Basolateral Complex of the Amygdala Modulates Fear Learning

PubMed Central

Maiya, Rajani; Kharazia, Viktor; Lasek, Amy W.; Heberlein, Ulrike

2012-01-01

Pavlovian fear conditioning is an associative learning paradigm in which mice learn to associate a neutral conditioned stimulus with an aversive unconditioned stimulus. In this study, we demonstrate a novel role for the transcriptional regulator Lmo4 in fear learning. LMO4 is predominantly expressed in pyramidal projection neurons of the basolateral complex of the amygdala (BLC). Mice heterozygous for a genetrap insertion in the Lmo4 locus (Lmo4gt/+), which express 50% less Lmo4 than their wild type (WT) counterparts display enhanced freezing to both the context and the cue in which they received the aversive stimulus. Small-hairpin RNA-mediated knockdown of Lmo4 in the BLC, but not the dentate gyrus region of the hippocampus recapitulated this enhanced conditioning phenotype, suggesting an adult- and brain region-specific role for Lmo4 in fear learning. Immunohistochemical analyses revealed an increase in the number of c-Fos positive puncta in the BLC of Lmo4gt/+ mice in comparison to their WT counterparts after fear conditioning. Lastly, we measured anxiety-like behavior in Lmo4gt/+ mice and in mice with BLC-specific downregulation of Lmo4 using the elevated plus maze, open field, and light/dark box tests. Global or BLC-specific knockdown of Lmo4 did not significantly affect anxiety-like behavior. These results suggest a selective role for LMO4 in the BLC in modulating learned but not unlearned fear. PMID:22509321
Histone Modifications around Individual BDNF Gene Promoters in Prefrontal Cortex Are Associated with Extinction of Conditioned Fear

ERIC Educational Resources Information Center

Bredy, Timothy W.; Wu, Hao; Crego, Cortney; Zellhoefer, Jessica; Sun, Yi E.; Barad, Mark

2007-01-01

Extinction of conditioned fear is an important model both of inhibitory learning and of behavior therapy for human anxiety disorders. Like other forms of learning, extinction learning is long-lasting and depends on regulated gene expression. Epigenetic mechanisms make an important contribution to persistent changes in gene expression; therefore,…
Adult-Onset Hypothyroidism Enhances Fear Memory and Upregulates Mineralocorticoid and Glucocorticoid Receptors in the Amygdala

PubMed Central

Montero-Pedrazuela, Ana; Fernández-Lamo, Iván; Alieva, María; Pereda-Pérez, Inmaculada; Venero, César; Guadaño-Ferraz, Ana

2011-01-01

Hypothyroidism is the most common hormonal disease in adults, which is frequently accompanied by learning and memory impairments and emotional disorders. However, the deleterious effects of thyroid hormones deficiency on emotional memory are poorly understood and often underestimated. To evaluate the consequences of hypothyroidism on emotional learning and memory, we have performed a classical Pavlovian fear conditioning paradigm in euthyroid and adult-thyroidectomized Wistar rats. In this experimental model, learning acquisition was not impaired, fear memory was enhanced, memory extinction was delayed and spontaneous recovery of fear memory was exacerbated in hypothyroid rats. The potentiation of emotional memory under hypothyroidism was associated with an increase of corticosterone release after fear conditioning and with higher expression of glucocorticoid and mineralocorticoid receptors in the lateral and basolateral nuclei of the amygdala, nuclei that are critically involved in the circuitry of fear memory. Our results demonstrate for the first time that adult-onset hypothyroidism potentiates fear memory and also increases vulnerability to develop emotional memories. Furthermore, our findings suggest that enhanced corticosterone signaling in the amygdala is involved in the pathophysiological mechanisms of fear memory potentiation. Therefore, we recommend evaluating whether inappropriate regulation of fear in patients with post-traumatic stress and other mental disorders is associated with abnormal levels of thyroid hormones, especially those patients refractory to treatment. PMID:22039511
Does a child's fear of needles decrease through a learning event with needles?

PubMed

Kajikawa, Natsuki; Maeno, Takami; Maeno, Tetsuhiro

2014-09-01

Most children have a fear of needles. Suitable preparation can decrease the pain and fear of needles in hospitals; however, few have examined how such preparation affects healthy children. This study examined whether learning with needles decreases fear of needles and changes motivation to get vaccinations in school-age children and the possible association between fear of needles and motivation toward vaccinations. This study included children participating in the "Let's Be Doctors" event, which was held in 4 child centers in Tsukuba city, Ibaraki, Japan. In this event, children learned about injections and how a vaccine works, and injected a vaccine (water) into skin (sponge) using a real syringe and imitation needle. Data were collected just before and after the event by anonymous self-assessment questionnaires that used a 4-point Likert scale to assess fear of needles, motivation to get vaccinations, recommendation of vaccinations, and fear toward doctors among the children. Answers were divided into two categories for statistical analysis. In total, 194 children participated in the event and 191 children answered the questionnaire (response rate 98.5%). We analyzed 180 subjects, comprising 79 boys (43.9%) and 94 girls (52.2%), mean age of 8.1 ± 1.0 years. The number of children reporting a fear of needles decreased from 69 (38.3%) before the event to 51 (28.3%) after the event, and those unwilling to get vaccinations decreased from 48 (26.7%) to 27 (15.0%). Children who reported fear of needles before the event were more unwilling to get vaccinations than those with no fear of needles (36 [52.2%] vs. 12 [10.8%]), while after the event the number of needle-fearing children unwilling to get vaccinations decreased to 19 (27.5%). Children's fear of needles and unwillingness to get vaccinations were decreased after experiencing a learning event with needles. The fear of needles is associated with a negative motivation to get vaccinations in children.
The Narrow Fellow in the Grass: Human Infants Associate Snakes and Fear

ERIC Educational Resources Information Center

DeLoache, Judy S.; LoBue, Vanessa

2009-01-01

Why are snakes such a common target of fear? One current view is that snake fear is one of several innate fears that emerge spontaneously. Another is that humans have an evolved predisposition to learn to fear snakes. In the first study reported here, 9- to 10-month-old infants showed no differential spontaneous reaction to films of snakes versus…
Maltreatment Exposure, Brain Structure, and Fear Conditioning in Children and Adolescents.

PubMed

McLaughlin, Katie A; Sheridan, Margaret A; Gold, Andrea L; Duys, Andrea; Lambert, Hilary K; Peverill, Matthew; Heleniak, Charlotte; Shechner, Tomer; Wojcieszak, Zuzanna; Pine, Daniel S

2016-07-01

Alterations in learning processes and the neural circuitry that supports fear conditioning and extinction represent mechanisms through which trauma exposure might influence risk for psychopathology. Few studies examine how trauma or neural structure relates to fear conditioning in children. Children (n=94) aged 6-18 years, 40.4% (n=38) with exposure to maltreatment (physical abuse, sexual abuse, or domestic violence), completed a fear conditioning paradigm utilizing blue and yellow bells as conditioned stimuli (CS+/CS-) and an aversive alarm noise as the unconditioned stimulus. Skin conductance responses (SCR) and self-reported fear were acquired. Magnetic resonance imaging data were acquired from 60 children. Children without maltreatment exposure exhibited strong differential conditioning to the CS+ vs CS-, based on SCR and self-reported fear. In contrast, maltreated children exhibited blunted SCR to the CS+ and failed to exhibit differential SCR to the CS+ vs CS- during early conditioning. Amygdala and hippocampal volume were reduced among children with maltreatment exposure and were negatively associated with SCR to the CS+ during early conditioning in the total sample, although these associations were negative only among non-maltreated children and were positive among maltreated children. The association of maltreatment with externalizing psychopathology was mediated by this perturbed pattern of fear conditioning. Child maltreatment is associated with failure to discriminate between threat and safety cues during fear conditioning in children. Poor threat-safety discrimination might reflect either enhanced fear generalization or a deficit in associative learning, which may in turn represent a central mechanism underlying the development of maltreatment-related externalizing psychopathology in children.
Maltreatment Exposure, Brain Structure, and Fear Conditioning in Children and Adolescents

PubMed Central

McLaughlin, Katie A; Sheridan, Margaret A; Gold, Andrea L; Duys, Andrea; Lambert, Hilary K; Peverill, Matthew; Heleniak, Charlotte; Shechner, Tomer; Wojcieszak, Zuzanna; Pine, Daniel S

2016-01-01

Alterations in learning processes and the neural circuitry that supports fear conditioning and extinction represent mechanisms through which trauma exposure might influence risk for psychopathology. Few studies examine how trauma or neural structure relates to fear conditioning in children. Children (n=94) aged 6–18 years, 40.4% (n=38) with exposure to maltreatment (physical abuse, sexual abuse, or domestic violence), completed a fear conditioning paradigm utilizing blue and yellow bells as conditioned stimuli (CS+/CS−) and an aversive alarm noise as the unconditioned stimulus. Skin conductance responses (SCR) and self-reported fear were acquired. Magnetic resonance imaging data were acquired from 60 children. Children without maltreatment exposure exhibited strong differential conditioning to the CS+ vs CS−, based on SCR and self-reported fear. In contrast, maltreated children exhibited blunted SCR to the CS+ and failed to exhibit differential SCR to the CS+ vs CS− during early conditioning. Amygdala and hippocampal volume were reduced among children with maltreatment exposure and were negatively associated with SCR to the CS+ during early conditioning in the total sample, although these associations were negative only among non-maltreated children and were positive among maltreated children. The association of maltreatment with externalizing psychopathology was mediated by this perturbed pattern of fear conditioning. Child maltreatment is associated with failure to discriminate between threat and safety cues during fear conditioning in children. Poor threat–safety discrimination might reflect either enhanced fear generalization or a deficit in associative learning, which may in turn represent a central mechanism underlying the development of maltreatment-related externalizing psychopathology in children. PMID:26677946
IMPAIRED FEAR EXTINCTION ASSOCIATED WITH PTSD INCREASES WITH HOURS-SINCE-WAKING.

PubMed

Zuj, Daniel V; Palmer, Matthew A; Hsu, Chia-Ming K; Nicholson, Emma L; Cushing, Pippa J; Gray, Kate E; Felmingham, Kim L

2016-03-01

Prior research has demonstrated that time-of-day may play an important role in the extinction of conditioned fear, with extinction better learned earlier in the day rather than later. Impaired fear extinction memory is widely considered a key mechanism of posttraumatic stress disorder (PTSD). The relationship between fear extinction and PTSD symptoms may be moderated by hours-since-waking. In the present experiment, we examined whether hours-since-waking would moderate fear extinction learning ability in a clinical PTSD sample (n = 15), compared to trauma-exposed (n = 33) and nonexposed controls (n = 22). Participants completed a standardized differential fear conditioning and extinction paradigm, providing skin conductance response measures to quantify conditioned responding. Mixed-model analysis of variance revealed a PTSD-specific impairment in extinction learning ability in the late extinction phase. A moderation analysis showed that hours-since-waking was a significant moderator of the relationship between impaired late extinction and PTSD symptoms. Specifically, we found that participants with higher PTSD symptoms demonstrated poorer fear extinction learning ability as they were awake for longer. The results of the current study add to a growing literature indicating deficits in fear extinction learning in PTSD samples, compared to trauma-exposed and nonexposed controls. These results support previous findings that fear extinction is impaired later in the day, and extends this to a clinical sample, suggesting that exposure-therapy may be optimized by scheduling sessions in the morning. © 2016 Wiley Periodicals, Inc.
Endogenous cortisol reactivity moderates the relationship between fear inhibition to safety signals and posttraumatic stress disorder symptoms.

PubMed

Zuj, Daniel V; Palmer, Matthew A; Malhi, Gin S; Bryant, Richard A; Felmingham, Kim L

2017-04-01

Posttraumatic stress symptoms (PTSS) are commonly associated with impairments in extinguishing fear to signals previously associated with danger, and also with inhibiting fear to safety signals. Previous studies indicate that PTSS are associated with low cortisol activity, and cortisol is shown to facilitate fear extinction. Few studies have examined the influence of cortisol reactivity on fear extinction in PTSS. We used a standardized fear conditioning and extinction paradigm to investigate the relationship between fear extinction and endogenous salivary cortisol activity in participants with high PTSS (n=18), trauma-exposed controls (n=33), and non-trauma-exposed controls (n=27). Skin conductance response (SCR) was used as an index of conditioned responding. Saliva samples were collected at baseline, and 20min post-fear acquisition for basal and reactive cortisol levels, respectively. PTSS participants demonstrated a slower rate of extinction learning during the early extinction phase. A moderation analysis revealed that cortisol reactivity was a significant moderator between fear inhibition to the safety signal (CS-) during early extinction and PTSS, but not to the threat signal (CS+). Specifically, this interaction was significant in two ways: (1) participants with elevated cortisol reactivity showed lower PTSS as fear inhibition improved; and (2) participants with low cortisol reactivity showed higher PTSS as fear inhibition improved. The findings of the present study show that the relationship between fear inhibition and cortisol reactivity is complex, and suggest that cortisol reactivity shapes safety signal learning in PTSS. Copyright © 2017 Elsevier Ltd. All rights reserved.
Conceptual Similarity Promotes Generalization of Higher Order Fear Learning

ERIC Educational Resources Information Center

Dunsmoor, Joseph E.; White, Allison J.; LaBar, Kevin S.

2011-01-01

We tested the hypothesis that conceptual similarity promotes generalization of conditioned fear. Using a sensory preconditioning procedure, three groups of subjects learned an association between two cues that were conceptually similar, unrelated, or mismatched. Next, one of the cues was paired with a shock. The other cue was then reintroduced to…
Encoding of Discriminative Fear Memory by Input-Specific LTP in the Amygdala.

PubMed

Kim, Woong Bin; Cho, Jun-Hyeong

2017-08-30

In auditory fear conditioning, experimental subjects learn to associate an auditory conditioned stimulus (CS) with an aversive unconditioned stimulus. With sufficient training, animals fear conditioned to an auditory CS show fear response to the CS, but not to irrelevant auditory stimuli. Although long-term potentiation (LTP) in the lateral amygdala (LA) plays an essential role in auditory fear conditioning, it is unknown whether LTP is induced selectively in the neural pathways conveying specific CS information to the LA in discriminative fear learning. Here, we show that postsynaptically expressed LTP is induced selectively in the CS-specific auditory pathways to the LA in a mouse model of auditory discriminative fear conditioning. Moreover, optogenetically induced depotentiation of the CS-specific auditory pathways to the LA suppressed conditioned fear responses to the CS. Our results suggest that input-specific LTP in the LA contributes to fear memory specificity, enabling adaptive fear responses only to the relevant sensory cue. VIDEO ABSTRACT. Copyright © 2017 Elsevier Inc. All rights reserved.
Ecologically relevant neurobehavioral assessment of the development of threat learning

PubMed Central

Mouly, Anne-Marie

2016-01-01

As altricial infants gradually transition to adults, their proximate environment changes. In three short weeks, pups transition from a small world with the caregiver and siblings to a complex milieu rich in dangers as their environment expands. Such contrasting environments require different learning abilities and lead to distinct responses throughout development. Here, we will review some of the learned fear conditioned responses to threats in rats during their ontogeny, including behavioral and physiological measures that permit the assessment of learning and its supporting neurobiology from infancy through adulthood. In adulthood, odor–shock conditioning produces robust fear learning to the odor that depends upon the amygdala and related circuitry. Paradoxically, this conditioning in young pups fails to support fear learning and supports approach learning to the odor previously paired with shock. This approach learning is mediated by the infant attachment network that does not include the amygdala. During the age range when pups transition from the infant to the adult circuit (10–15 d old), pups have access to both networks: odor–shock conditioning in maternal presence uses the attachment circuit but the adult amygdala-dependent circuit when alone. However, throughout development (as young as 5 d old) the attachment associated learning can be overridden and amygdala-dependent fear learning supported, if the mother expresses fear in the presence of the pup. This social modulation of the fear permits the expression of defense reactions in life threatening situations informed by the caregiver but prevents the learning of the caregiver itself as a threat. PMID:27634146
Ecologically relevant neurobehavioral assessment of the development of threat learning.

PubMed

Boulanger Bertolus, Julie; Mouly, Anne-Marie; Sullivan, Regina M

2016-10-01

As altricial infants gradually transition to adults, their proximate environment changes. In three short weeks, pups transition from a small world with the caregiver and siblings to a complex milieu rich in dangers as their environment expands. Such contrasting environments require different learning abilities and lead to distinct responses throughout development. Here, we will review some of the learned fear conditioned responses to threats in rats during their ontogeny, including behavioral and physiological measures that permit the assessment of learning and its supporting neurobiology from infancy through adulthood. In adulthood, odor-shock conditioning produces robust fear learning to the odor that depends upon the amygdala and related circuitry. Paradoxically, this conditioning in young pups fails to support fear learning and supports approach learning to the odor previously paired with shock. This approach learning is mediated by the infant attachment network that does not include the amygdala. During the age range when pups transition from the infant to the adult circuit (10-15 d old), pups have access to both networks: odor-shock conditioning in maternal presence uses the attachment circuit but the adult amygdala-dependent circuit when alone. However, throughout development (as young as 5 d old) the attachment associated learning can be overridden and amygdala-dependent fear learning supported, if the mother expresses fear in the presence of the pup. This social modulation of the fear permits the expression of defense reactions in life threatening situations informed by the caregiver but prevents the learning of the caregiver itself as a threat. © 2016 Boulanger Bertolus et al.; Published by Cold Spring Harbor Laboratory Press.
Different role of the ventral medial prefrontal cortex on modulation of innate and associative learned fear.

PubMed

Lisboa, S F; Stecchini, M F; Corrêa, F M A; Guimarães, F S; Resstel, L B M

2010-12-15

Reversible inactivation of the ventral portion of medial prefrontal cortex (vMPFC) of the rat brain has been shown to induce anxiolytic-like effects in animal models based on associative learning. The role of this brain region in situations involving innate fear, however, is still poorly understood, with several contradictory results in the literature. The objective of the present work was to verify in male Wistar rats the effects of vMPFC administration of cobalt chloride (CoCl(2)), a selective inhibitor of synaptic activity, in rats submitted to two models based on innate fear, the elevated plus-maze (EPM) and light-dark box (LDB), comparing the results with those obtained in two models involving associative learning, the contextual fear conditioning (CFC) and Vogel conflict (VCT) tests. The results showed that, whereas CoCl(2) induced anxiolytic-like effects in the CFC and VCT tests, it enhanced anxiety in rats submitted to the EPM and LDB. Together these results indicate that the vMPFC plays an important but complex role in the modulation of defensive-related behaviors, which seems to depend on the nature of the anxiety/fear inducing stimuli. Copyright © 2010 IBRO. Published by Elsevier Ltd. All rights reserved.
Fear Conditioning Selectively Disrupts Noradrenergic Facilitation of GABAergic Inhibition in the Basolateral Amygdala

PubMed Central

Skelly, M. J.; Ariwodola, O. J.; Weiner, J. L.

2016-01-01

Inappropriate fear memory formation is symptomatic of many psychopathologies, and delineating the neurobiology of non-pathological fear learning may provide critical insight into treating these disorders. Fear memory formation is associated with decreased inhibitory signaling in the basolateral amygdala (BLA), and disrupted noradrenergic signaling may contribute to this decrease. BLA noradrenergic neurotransmission has been implicated in fear memory formation, and distinct adrenoreceptor (AR) subtypes modulate excitatory and inhibitory neurotransmission in this region. For example, α1-ARs promote GABA release from local inhibitory interneurons, while β3-ARs potentiate neurotransmission at lateral paracapsular (LPC) GABAergic synapses. Conversely, β1/2-ARs amplify excitatory signaling at glutamatergic synapses in the BLA. As increased BLA excitability promotes fear memory formation, we hypothesized that fear learning shifts the balanced regional effects of noradrenergic signaling toward excitation. To test this hypothesis, we used the fear-potentiated startle paradigm in combination with whole cell patch clamp electrophysiology to examine the effects of AR activation on BLA synaptic transmission following fear conditioning in male Long-Evans rats. We first demonstrated that inhibitory neurotransmission is decreased at both local and LPC synapses following fear conditioning. We next measured noradrenergic facilitation of BLA inhibitory signaling at local and LPC synapses using α1- and β3-AR agonists (1μM A61603 and 10μM BRL37344), and found that the ability of these agents to facilitate inhibitory neurotransmission is disrupted following fear conditioning. Conversely, we found that fear learning does not disrupt noradrenergic modulation of glutamatergic signaling via a β1/2-AR agonist (1μM isoproterenol). Taken together, these studies suggest that fear learning increases BLA excitability by selectively disrupting the inhibitory effects of noradrenaline. PMID:27720769
Fear conditioning selectively disrupts noradrenergic facilitation of GABAergic inhibition in the basolateral amygdala.

PubMed

Skelly, M J; Ariwodola, O J; Weiner, J L

2017-02-01

Inappropriate fear memory formation is symptomatic of many psychopathologies, and delineating the neurobiology of non-pathological fear learning may provide critical insight into treating these disorders. Fear memory formation is associated with decreased inhibitory signaling in the basolateral amygdala (BLA), and disrupted noradrenergic signaling may contribute to this decrease. BLA noradrenergic neurotransmission has been implicated in fear memory formation, and distinct adrenoreceptor (AR) subtypes modulate excitatory and inhibitory neurotransmission in this region. For example, α1-ARs promote GABA release from local inhibitory interneurons, while β3-ARs potentiate neurotransmission at lateral paracapsular (LPC) GABAergic synapses. Conversely, β1/2-ARs amplify excitatory signaling at glutamatergic synapses in the BLA. As increased BLA excitability promotes fear memory formation, we hypothesized that fear learning shifts the balanced regional effects of noradrenergic signaling toward excitation. To test this hypothesis, we used the fear-potentiated startle paradigm in combination with whole cell patch clamp electrophysiology to examine the effects of AR activation on BLA synaptic transmission following fear conditioning in male Long-Evans rats. We first demonstrated that inhibitory neurotransmission is decreased at both local and LPC synapses following fear conditioning. We next measured noradrenergic facilitation of BLA inhibitory signaling at local and LPC synapses using α1-and β3-AR agonists (1 μM A61603 and 10 μM BRL37344), and found that the ability of these agents to facilitate inhibitory neurotransmission is disrupted following fear conditioning. Conversely, we found that fear learning does not disrupt noradrenergic modulation of glutamatergic signaling via a β1/2-AR agonist (1 μM isoproterenol). Taken together, these studies suggest that fear learning increases BLA excitability by selectively disrupting the inhibitory effects of noradrenaline. Copyright Â© 2016 Elsevier Ltd. All rights reserved.
Stress enables reinforcement-elicited serotonergic consolidation of fear memory

PubMed Central

Baratta, Michael V.; Kodandaramaiah, Suhasa B.; Monahan, Patrick E.; Yao, Junmei; Weber, Michael D.; Lin, Pei-Ann; Gisabella, Barbara; Petrossian, Natalie; Amat, Jose; Kim, Kyungman; Yang, Aimei; Forest, Craig R.; Boyden, Edward S.; Goosens, Ki A.

2015-01-01

Background Prior exposure to stress is a risk factor for developing post-traumatic stress disorder (PTSD) in response to trauma, yet the mechanisms by which this occurs are unclear. Using a rodent model of stress-based susceptibility to PTSD, we investigated the role of serotonin in this phenomenon. Methods Adult mice were exposed to repeated immobilization stress or handling, and the role of serotonin in subsequent fear learning was assessed using pharmacological manipulation and western blot detection of serotonin receptors, measurements of serotonin, high-speed optogenetic silencing, and behavior. Results Both dorsal raphe serotonergic activity during aversive reinforcement and amygdala serotonin 2c receptor (5-HT2CR) activity during memory consolidation are necessary for stress enhancement of fear memory, but neither process affects fear memory in unstressed mice. Additionally, prior stress increases amygdala sensitivity to serotonin by promoting surface expression of 5-HT2CR without affecting tissue levels of serotonin in the amygdala. We also show that the serotonin that drives stress enhancement of associative cued fear memory can arise from paired or unpaired footshock, an effect not predicted by theoretical models of associative learning. Conclusion Stress bolsters the consequences of aversive reinforcement, not by simply enhancing the neurobiological signals used to encode fear in unstressed animals, but rather by engaging distinct mechanistic pathways. These results reveal that predictions from classical associative learning models do not always hold for stressed animals, and suggest that 5-HT2CR blockade may represent a promising therapeutic target for psychiatric disorders characterized by excessive fear responses such as that observed in PTSD. PMID:26248536
Cannabinoid facilitation of fear extinction memory recall in humans

PubMed Central

Rabinak, Christine A.; Angstadt, Mike; Sripada, Chandra S.; Abelson, James L.; Liberzon, Israel; Milad, Mohammed R.; Phan, K. Luan

2012-01-01

A first-line approach to treat anxiety disorders is exposure-based therapy, which relies on extinction processes such as repeatedly exposing the patient to stimuli (conditioned stimuli; CS) associated with the traumatic, fear-related memory. However, a significant number of patients fail to maintain their gains, partly attributed to the fact that this inhibitory learning and its maintenance is temporary and conditioned fear responses can return. Animal studies have shown that activation of the cannabinoid system during extinction learning enhances fear extinction and its retention. Specifically, CB1 receptor agonists, such as Δ9-tetrahydrocannibinol (THC), can facilitate extinction recall by preventing recovery of extinguished fear in rats. However, this phenomenon has not been investigated in humans. We conducted a study using a randomized, double-blind, placebo-controlled, between-subjects design, coupling a standard Pavlovian fear extinction paradigm and simultaneous skin conductance response (SCR) recording with an acute pharmacological challenge with oral dronabinol (synthetic THC) or placebo (PBO) 2 hours prior to extinction learning in 29 healthy adult volunteers (THC = 14; PBO = 15) and tested extinction retention 24 hours after extinction learning. Compared to subjects that received PBO, subjects that received THC showed low SCR to a previously extinguished CS when extinction memory recall was tested 24 hours after extinction learning, suggesting that THC prevented the recovery of fear. These results provide the first evidence that pharmacological enhancement of extinction learning is feasible in humans using cannabinoid system modulators, which may thus warrant further development and clinical testing. PMID:22796109
Fear Conditioning in an Abdominal Pain Model: Neural Responses during Associative Learning and Extinction in Healthy Subjects

PubMed Central

Kattoor, Joswin; Gizewski, Elke R.; Kotsis, Vassilios; Benson, Sven; Gramsch, Carolin; Theysohn, Nina; Maderwald, Stefan; Forsting, Michael; Schedlowski, Manfred; Elsenbruch, Sigrid

2013-01-01

Fear conditioning is relevant for elucidating the pathophysiology of anxiety, but may also be useful in the context of chronic pain syndromes which often overlap with anxiety. Thus far, no fear conditioning studies have employed aversive visceral stimuli from the lower gastrointestinal tract. Therefore, we implemented a fear conditioning paradigm to analyze the conditioned response to rectal pain stimuli using fMRI during associative learning, extinction and reinstatement. In N = 21 healthy humans, visual conditioned stimuli (CS+) were paired with painful rectal distensions as unconditioned stimuli (US), while different visual stimuli (CS−) were presented without US. During extinction, all CSs were presented without US, whereas during reinstatement, a single, unpaired US was presented. In region-of-interest analyses, conditioned anticipatory neural activation was assessed along with perceived CS-US contingency and CS unpleasantness. Fear conditioning resulted in significant contingency awareness and valence change, i.e., learned unpleasantness of a previously neutral stimulus. This was paralleled by anticipatory activation of the anterior cingulate cortex, the somatosensory cortex and precuneus (all during early acquisition) and the amygdala (late acquisition) in response to the CS+. During extinction, anticipatory activation of the dorsolateral prefrontal cortex to the CS− was observed. In the reinstatement phase, a tendency for parahippocampal activation was found. Fear conditioning with rectal pain stimuli is feasible and leads to learned unpleasantness of previously neutral stimuli. Within the brain, conditioned anticipatory activations are seen in core areas of the central fear network including the amygdala and the anterior cingulate cortex. During extinction, conditioned responses quickly disappear, and learning of new predictive cue properties is paralleled by prefrontal activation. A tendency for parahippocampal activation during reinstatement could indicate a reactivation of the old memory trace. Together, these findings contribute to our understanding of aversive visceral learning and memory processes relevant to the pathophysiology of chronic abdominal pain. PMID:23468832
Neural correlates of appetitive-aversive interactions in Pavlovian fear conditioning.

PubMed

Nasser, Helen M; McNally, Gavan P

2013-03-19

We used Pavlovian counterconditioning in rats to identify the neural mechanisms for appetitive-aversive motivational interactions. In Stage I, rats were trained on conditioned stimulus (CS)-food (unconditioned stimulus [US]) pairings. In Stage II, this appetitive CS was transformed into a fear CS via pairings with footshock. The development of fear responses was retarded in rats that had received Stage I appetitive training. This counterconditioning was associated with increased levels of phosphorylated mitogen activated protein kinase immunoreactivity (pMAPK-IR) in several brain regions, including midline thalamus, rostral agranular insular cortex (RAIC), lateral amygdala, and nucleus accumbens core and shell, but decreased expression in the ventrolateral quadrant of the midbrain periaqueductal gray. These brain regions showing differential pMAPK-IR have previously been identified as part of the fear prediction error circuit. We then examined the causal role of RAIC MAPK in fear learning and showed that Stage II fear learning was prevented by RAIC infusions of the MEK inhibitor PD098059 (0.5 µg/hemisphere). Taken together, these results show that there are opponent interactions between the appetitive and aversive motivational systems during fear learning and that the transformation of a reward CS into a fear CS is linked to heightened activity in the fear prediction error circuit.

The Role of the Medial Prefrontal Cortex in Trace Fear Extinction

ERIC Educational Resources Information Center

Kwapis, Janine L.; Jarome, Timothy J.; Helmstetter, Fred J.

2015-01-01

The extinction of delay fear conditioning relies on a neural circuit that has received much attention and is relatively well defined. Whether this established circuit also supports the extinction of more complex associations, however, is unclear. Trace fear conditioning is a better model of complex relational learning, yet the circuit that…
Fear conditioning and extinction across development: Evidence from human studies and animal models☆

PubMed Central

Shechner, Tomer; Hong, Melanie; Britton, Jennifer C.; Pine, Daniel S.; Fox, Nathan A.

2015-01-01

The ability to differentiate danger and safety through associative processes emerges early in life. Understanding the mechanisms underlying associative learning of threat and safety can clarify the processes that shape development of normative fears and pathological anxiety. Considerable research has used fear conditioning and extinction paradigms to delineate underlying mechanisms in animals and human adults; however, little is known about these mechanisms in children and adolescents. The current paper summarizes the empirical data on the development of fear conditioning and extinction. It reviews methodological considerations and future directions for research on fear conditioning and extinction in pediatric populations. PMID:24746848
Pharmacogenetic excitation of dorsomedial prefrontal cortex restores fear prediction error.

PubMed

Yau, Joanna Oi-Yue; McNally, Gavan P

2015-01-07

Pavlovian conditioning involves encoding the predictive relationship between a conditioned stimulus (CS) and an unconditioned stimulus, so that synaptic plasticity and learning is instructed by prediction error. Here we used pharmacogenetic techniques to show a causal relation between activity of rat dorsomedial prefrontal cortex (dmPFC) neurons and fear prediction error. We expressed the excitatory hM3Dq designer receptor exclusively activated by a designer drug (DREADD) in dmPFC and isolated actions of prediction error by using an associative blocking design. Rats were trained to fear the visual CS (CSA) in stage I via pairings with footshock. Then in stage II, rats received compound presentations of visual CSA and auditory CS (CSB) with footshock. This prior fear conditioning of CSA reduced the prediction error during stage II to block fear learning to CSB. The group of rats that received AAV-hSYN-eYFP vector that was treated with clozapine-N-oxide (CNO; 3 mg/kg, i.p.) before stage II showed blocking when tested in the absence of CNO the next day. In contrast, the groups that received AAV-hSYN-hM3Dq and AAV-CaMKIIα-hM3Dq that were treated with CNO before stage II training did not show blocking; learning toward CSB was restored. This restoration of prediction error and fear learning was specific to the injection of CNO because groups that received AAV-hSYN-hM3Dq and AAV-CaMKIIα-hM3Dq that were injected with vehicle before stage II training did show blocking. These effects were not attributable to the DREADD manipulation enhancing learning or arousal, increasing fear memory strength or asymptotic levels of fear learning, or altering fear memory retrieval. Together, these results identify a causal role for dmPFC in a signature of adaptive behavior: using the past to predict future danger and learning from errors in these predictions. Copyright © 2015 the authors 0270-6474/15/350074-10$15.00/0.
Contingency learning in human fear conditioning involves the ventral striatum.

PubMed

Klucken, Tim; Tabbert, Katharina; Schweckendiek, Jan; Merz, Christian Josef; Kagerer, Sabine; Vaitl, Dieter; Stark, Rudolf

2009-11-01

The ability to detect and learn contingencies between fearful stimuli and their predictive cues is an important capacity to cope with the environment. Contingency awareness refers to the ability to verbalize the relationships between conditioned and unconditioned stimuli. Although there is a heated debate about the influence of contingency awareness on conditioned fear responses, neural correlates behind the formation process of contingency awareness have gained only little attention in human fear conditioning. Recent animal studies indicate that the ventral striatum (VS) could be involved in this process, but in human studies the VS is mostly associated with positive emotions. To examine this question, we reanalyzed four recently published classical fear conditioning studies (n = 117) with respect to the VS at three distinct levels of contingency awareness: subjects, who did not learn the contingencies (unaware), subjects, who learned the contingencies during the experiment (learned aware) and subjects, who were informed about the contingencies in advance (instructed aware). The results showed significantly increased activations in the left and right VS in learned aware compared to unaware subjects. Interestingly, this activation pattern was only found in learned but not in instructed aware subjects. We assume that the VS is not involved when contingency awareness does not develop during conditioning or when contingency awareness is unambiguously induced already prior to conditioning. VS involvement seems to be important for the transition from a contingency unaware to a contingency aware state. Implications for fear conditioning models as well as for the contingency awareness debate are discussed.
Hormonal Regulation of Extinction: Implication for Mechanisms of Gender Difference in PTSD

DTIC Science & Technology

2009-09-01

role of gonadal hormones in the regulation of Pavlovian fear conditioning and its extinction. Pavlovian fear conditioning and its extinction serve...learning in Pavlovian fear conditioning involves training with the presentation of an innocuous stimulus (the conditioned stimulus – CS) that is associated...GD, Schlinger BA, Fanselow MS (1998) Testicular hormones do not regulate sexually dimorphic Pavlovian fear conditioning or perforant- path long-term
The role of the medial prefrontal cortex in trace fear extinction

PubMed Central

Kwapis, Janine L.; Jarome, Timothy J.

2015-01-01

The extinction of delay fear conditioning relies on a neural circuit that has received much attention and is relatively well defined. Whether this established circuit also supports the extinction of more complex associations, however, is unclear. Trace fear conditioning is a better model of complex relational learning, yet the circuit that supports extinction of this memory has received very little attention. Recent research has indicated that trace fear extinction requires a different neural circuit than delay extinction; trace extinction requires the participation of the retrosplenial cortex, but not the amygdala, as noted in a previous study. Here, we tested the roles of the prelimbic and infralimbic regions of the medial prefrontal cortex in trace and delay fear extinction by blocking NMDA receptors during extinction learning. We found that the prelimbic cortex is necessary for trace, but not for delay fear extinction, whereas the infralimbic cortex is involved in both types of extinction. These results are consistent with the idea that trace fear associations require plasticity in multiple cortical areas for successful extinction. Further, the infralimbic cortex appears to play a role in extinction regardless of whether the animal was initially trained in trace or delay conditioning. Together, our results provide new information about how the neural circuits supporting trace and delay fear extinction differ. PMID:25512576
Regulation of Fear Extinction in the Basolateral Amygdala by Dopamine D2 Receptors Accompanied by Altered GluR1, GluR1-Ser845 and NR2B Levels.

PubMed

Shi, Yan-Wei; Fan, Bu-Fang; Xue, Li; Wen, Jia-Ling; Zhao, Hu

2017-01-01

The amygdala, a critical structure for both Pavlovian fear conditioning and fear extinction, receives sparse but comprehensive dopamine innervation and contains dopamine D1 and D2 receptors. Fear extinction, which involves learning to suppress the expression of a previously learned fear, appears to require the dopaminergic system. The specific roles of D2 receptors in mediating associative learning underlying fear extinction require further study. Intra-basolateral amygdala (BLA) infusions of a D2 receptor agonist, quinpirole, and a D2 receptor antagonist, sulpiride, prior to fear extinction and extinction retention were tested 24 h after fear extinction training for long-term memory (LTM). LTM was facilitated by quinpirole and attenuated by sulpiride. In addition, A-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor glutamate receptor 1 (GluR1) subunit, GluR1 phospho-Ser845, and N -methyl-D-aspartic acid receptor NR2B subunit levels in the BLA were generally increased by quinpirole and down-regulated by sulpiride. The present study suggests that activation of D2 receptors facilitates fear extinction and that blockade of D2 receptors impairs fear extinction, accompanied by changes in GluR1, GluR1-Ser845 and NR2B levels in the amygdala.
Instructed fear learning, extinction, and recall: additive effects of cognitive information on emotional learning of fear.

PubMed

Javanbakht, Arash; Duval, Elizabeth R; Cisneros, Maria E; Taylor, Stephan F; Kessler, Daniel; Liberzon, Israel

2017-08-01

The effects of instruction on learning of fear and safety are rarely studied. We aimed to examine the effects of cognitive information and experience on fear learning. Fourty healthy participants, randomly assigned to three groups, went through fear conditioning, extinction learning, and extinction recall with two conditioned stimuli (CS+). Information was presented about the presence or absence of conditioned stimulus-unconditioned stimulus (CS-US) contingency at different stages of the experiment. Information about the CS-US contingency prior to fear conditioning enhanced fear response and reduced extinction recall. Information about the absence of CS-US contingency promoted extinction learning and recall, while omission of this information prior to recall resulted in fear renewal. These findings indicate that contingency information can facilitate fear expression during fear learning, and can facilitate extinction learning and recall. Information seems to function as an element of the larger context in which conditioning occurs.
HDAC I inhibition in the dorsal and ventral hippocampus differentially modulates predator-odor fear learning and generalization.

PubMed

Yuan, Robin K; Hebert, Jenna C; Thomas, Arthur S; Wann, Ellen G; Muzzio, Isabel A

2015-01-01

Although predator odors are ethologically relevant stimuli for rodents, the molecular pathways and contribution of some brain regions involved in predator odor conditioning remain elusive. Inhibition of histone deacetylases (HDACs) in the dorsal hippocampus has been shown to enhance shock-induced contextual fear learning, but it is unknown if HDACs have differential effects along the dorso-ventral hippocampal axis during predator odor fear learning. We injected MS-275, a class I HDAC inhibitor, bilaterally in the dorsal or ventral hippocampus of mice and found that it had no effects on innate anxiety in either region. We then assessed the effects of MS-275 at different stages of fear learning along the longitudinal hippocampal axis. Animals were injected with MS-275 or vehicle after context pre-exposure (pre-conditioning injections), when a representation of the context is first formed, or after exposure to coyote urine (post-conditioning injections), when the context becomes associated with predator odor. When MS-275 was administered after context pre-exposure, dorsally injected animals showed enhanced fear in the training context but were able to discriminate it from a neutral environment. Conversely, ventrally injected animals did not display enhanced learning in the training context but generalized the fear response to a neutral context. However, when MS-275 was administered after conditioning, there were no differences between the MS-275 and vehicle control groups in either the dorsal or ventral hippocampus. Surprisingly, all groups displayed generalization to a neutral context, suggesting that predator odor exposure followed by a mild stressor such as restraint leads to fear generalization. These results may elucidate distinct functions of the dorsal and ventral hippocampus in predator odor-induced fear conditioning as well as some of the molecular mechanisms underlying fear generalization.
Stimulus fear relevance and the speed, magnitude, and robustness of vicariously learned fear.

PubMed

Dunne, Güler; Reynolds, Gemma; Askew, Chris

2017-08-01

Superior learning for fear-relevant stimuli is typically indicated in the laboratory by faster acquisition of fear responses, greater learned fear, and enhanced resistance to extinction. Three experiments investigated the speed, magnitude, and robustness of UK children's (6-10 years; N = 290; 122 boys, 168 girls) vicariously learned fear responses for three types of stimuli. In two experiments, children were presented with pictures of novel animals (Australian marsupials) and flowers (fear-irrelevant stimuli) alone (control) or together with faces expressing fear or happiness. To determine learning speed the number of stimulus-face pairings seen by children was varied (1, 10, or 30 trials). Robustness of learning was examined via repeated extinction procedures over 3 weeks. A third experiment compared the magnitude and robustness of vicarious fear learning for snakes and marsupials. Significant increases in fear responses were found for snakes, marsupials and flowers. There was no indication that vicarious learning for marsupials was faster than for flowers. Moreover, vicariously learned fear was neither greater nor more robust for snakes compared to marsupials, or for marsupials compared to flowers. These findings suggest that for this age group stimulus fear relevance may have little influence on vicarious fear learning. Copyright © 2017 Elsevier Ltd. All rights reserved.
Transformative learning theory: facilitating mammography screening in rural women.

PubMed

Purtzer, Mary Anne; Overstreet, Lindsey

2014-03-01

To use transformative learning to investigate what experiences serve as catalysts for mammography screening, the cognitive and affective responses that result from the catalyst, and how screening behavior is impacted. A descriptive qualitative study. Southeastern Wyoming. 25 low-income, rural women aged 40 years and older. Four focus group interviews. Cancer experiences triggered universal responses of fear by screeners and nonscreeners. The manner in which that fear response was interpreted was a critical factor in the facilitation of, or impedance to, screening. Dichotomous interpretations of fear responses provided the context for screening behavior. Immobilizing and isolating experiences were associated with nonscreening behavior, whereas motivation and self-efficacy were associated with screening behavior. Transformative learning theory is a useful framework from which to explain differences in mammography screening behavior. Creating opportunities that facilitate dialogue and critical reflection hold the potential to change immobilizing and isolating frames of reference in nonscreening women. To help women transcend their fear and become self-efficacious, nurses can assess how cancer and the screening experience is viewed and, if indicated, move beyond standard education and offer opportunities for dialogue and critical reflection.
Neurogenetic Approaches to Stress and Fear in Humans as Pathophysiological Mechanisms for Posttraumatic Stress Disorder.

PubMed

Nees, Frauke; Witt, Stephanie H; Flor, Herta

2018-05-15

In this review article, genetic variation associated with brain responses related to acute and chronic stress reactivity and fear learning in humans is presented as an important mechanism underlying posttraumatic stress disorder. We report that genes related to the regulation of the hypothalamic-pituitary-adrenal axis, as well as genes that modulate serotonergic, dopaminergic, and neuropeptidergic functions or plasticity, play a role in this context. The strong overlap of the genetic targets involved in stress and fear learning suggests that a dimensional and mechanistic model of the development of posttraumatic stress disorder based on these constructs is promising. Genome-wide genetic analyses on fear and stress mechanisms are scarce. So far, reliable replication is still lacking for most of the molecular genetic findings, and the proportion of explained variance is rather small. Further analysis of neurogenetic stress and fear learning needs to integrate data from animal and human studies. Copyright © 2018 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
ASIC-dependent LTP at multiple glutamatergic synapses in amygdala network is required for fear memory

PubMed Central

Chiang, Po-Han; Chien, Ta-Chun; Chen, Chih-Cheng; Yanagawa, Yuchio; Lien, Cheng-Chang

2015-01-01

Genetic variants in the human ortholog of acid-sensing ion channel-1a subunit (ASIC1a) gene are associated with panic disorder and amygdala dysfunction. Both fear learning and activity-induced long-term potentiation (LTP) of cortico-basolateral amygdala (BLA) synapses are impaired in ASIC1a-null mice, suggesting a critical role of ASICs in fear memory formation. In this study, we found that ASICs were differentially expressed within the amygdala neuronal population, and the extent of LTP at various glutamatergic synapses correlated with the level of ASIC expression in postsynaptic neurons. Importantly, selective deletion of ASIC1a in GABAergic cells, including amygdala output neurons, eliminated LTP in these cells and reduced fear learning to the same extent as that found when ASIC1a was selectively abolished in BLA glutamatergic neurons. Thus, fear learning requires ASIC-dependent LTP at multiple amygdala synapses, including both cortico-BLA input synapses and intra-amygdala synapses on output neurons. PMID:25988357
The role of sleep and sleep deprivation in consolidating fear memories.

PubMed

Menz, M M; Rihm, J S; Salari, N; Born, J; Kalisch, R; Pape, H C; Marshall, L; Büchel, C

2013-07-15

Sleep, in particular REM sleep, has been shown to improve the consolidation of emotional memories. Here, we investigated the role of sleep and sleep deprivation on the consolidation of fear memories and underlying neuronal mechanisms. We employed a Pavlovian fear conditioning paradigm either followed by a night of polysomnographically monitored sleep, or wakefulness in forty healthy participants. Recall of learned fear was better after sleep, as indicated by stronger explicitly perceived anxiety and autonomous nervous responses. These effects were positively correlated with the preceding time spent in REM sleep and paralleled by activation of the basolateral amygdala. These findings suggest REM sleep-associated consolidation of fear memory in the human amygdala. In view of the critical participation of fear learning mechanisms in the etiology of anxiety and post-traumatic stress disorder, deprivation of REM sleep after exposure to distressing events is an interesting target for further investigation. Copyright © 2013 Elsevier Inc. All rights reserved.
Neuronal Nitric-Oxide Synthase Deficiency Impairs the Long-Term Memory of Olfactory Fear Learning and Increases Odor Generalization

ERIC Educational Resources Information Center

Pavesi, Eloisa; Heldt, Scott A.; Fletcher, Max L.

2013-01-01

Experience-induced changes associated with odor learning are mediated by a number of signaling molecules, including nitric oxide (NO), which is predominantly synthesized by neuronal nitric oxide synthase (nNOS) in the brain. In the current study, we investigated the role of nNOS in the acquisition and retention of conditioned olfactory fear. Mice…
Reversal Learning and Associative Memory Impairments in a BACHD Rat Model for Huntington Disease

PubMed Central

Abada, Yah-se K.; Nguyen, Huu Phuc; Ellenbroek, Bart; Schreiber, Rudy

2013-01-01

Chorea and psychiatric symptoms are hallmarks of Huntington disease (HD), a neurodegenerative disorder, genetically characterized by the presence of expanded CAG repeats (>35) in the HUNTINGTIN (HTT) gene. HD patients present psychiatric symptoms prior to the onset of motor symptoms and we recently found a similar emergence of non motor and motor deficits in BACHD rats carrying the human full length mutated HTT (97 CAG-CAA repeats). We evaluated cognitive performance in reversal learning and associative memory tests in different age cohorts of BACHD rats. Male wild type (WT) and transgenic (TG) rats between 2 and 12 months of age were tested. Learning and strategy shifting were assessed in a cross-maze test. Associative memory was evaluated in different fear conditioning paradigms (context, delay and trace). The possible confound of a fear conditioning phenotype by altered sensitivity to a ‘painful’ stimulus was assessed in a flinch-jump test. In the cross maze, 6 months old TG rats showed a mild impairment in reversal learning. In the fear conditioning tasks, 4, 6 and 12 months old TG rats showed a marked reduction in contextual fear conditioning. In addition, TG rats showed impaired delay conditioning (9 months) and trace fear conditioning (3 months). This phenotype was unlikely to be affected by a change in ‘pain’ sensitivity as WT and TG rats showed no difference in their threshold response in the flinch-jump test. Our results suggest that BACHD rats have a profound associative memory deficit and, possibly, a deficit in reversal learning as assessed in a cross maze task. The time course for the emergence of these symptoms (i.e., before the occurrence of motor symptoms) in this rat model for HD appears similar to the time course in patients. These data suggest that BACHD rats may be a useful model for preclinical drug discovery. PMID:24223692
One-trial overshadowing: Evidence for fast specific fear learning in humans.

PubMed

Haesen, Kim; Beckers, Tom; Baeyens, Frank; Vervliet, Bram

2017-03-01

Adaptive defensive actions necessitate a fear learning system that is both fast and specific. Fast learning serves to minimize the number of threat confrontations, while specific learning ensures that the acquired fears are tied to threat-relevant cues only. In Pavlovian fear conditioning, fear acquisition is typically studied via repetitive pairings of a single cue with an aversive experience, which is not optimal for the examination of fast specific fear learning. In this study, we adopted the one-trial overshadowing procedure from basic learning research, in which a combination of two visual cues is presented once and paired with an aversive electrical stimulation. Using on-line shock expectancy ratings, skin conductance reactivity and startle reflex modulation as indices of fear learning, we found evidence of strong fear after a single conditioning trial (fast learning) as well as attenuated fear responding when only half of the trained stimulus combination was presented (specific learning). Moreover, specificity of fear responding tended to correlate with levels of state and trait anxiety. These results suggest that one-trial overshadowing can be used as a model to study fast specific fear learning in humans and individual differences therein. Copyright © 2016 Elsevier Ltd. All rights reserved.
Matrix Metalloproteinase (MMP) 9 Transcription in Mouse Brain Induced by Fear Learning*

PubMed Central

Ganguly, Krishnendu; Rejmak, Emilia; Mikosz, Marta; Nikolaev, Evgeni; Knapska, Ewelina; Kaczmarek, Leszek

2013-01-01

Memory formation requires learning-based molecular and structural changes in neurons, whereas matrix metalloproteinase (MMP) 9 is involved in the synaptic plasticity by cleaving extracellular matrix proteins and, thus, is associated with learning processes in the mammalian brain. Because the mechanisms of MMP-9 transcription in the brain are poorly understood, this study aimed to elucidate regulation of MMP-9 gene expression in the mouse brain after fear learning. We show here that contextual fear conditioning markedly increases MMP-9 transcription, followed by enhanced enzymatic levels in the three major brain structures implicated in fear learning, i.e. the amygdala, hippocampus, and prefrontal cortex. To reveal the role of AP-1 transcription factor in MMP-9 gene expression, we have used reporter gene constructs with specifically mutated AP-1 gene promoter sites. The constructs were introduced into the medial prefrontal cortex of neonatal mouse pups by electroporation, and the regulation of MMP-9 transcription was studied after contextual fear conditioning in the adult animals. Specifically, −42/-50- and −478/-486-bp AP-1 binding motifs of the mouse MMP-9 promoter sequence have been found to play a major role in MMP-9 gene activation. Furthermore, increases in MMP-9 gene promoter binding by the AP-1 transcription factor proteins c-Fos and c-Jun have been demonstrated in all three brain structures under investigation. Hence, our results suggest that AP-1 acts as a positive regulator of MMP-9 transcription in the brain following fear learning. PMID:23720741
Matrix metalloproteinase (MMP) 9 transcription in mouse brain induced by fear learning.

PubMed

Ganguly, Krishnendu; Rejmak, Emilia; Mikosz, Marta; Nikolaev, Evgeni; Knapska, Ewelina; Kaczmarek, Leszek

2013-07-19

Memory formation requires learning-based molecular and structural changes in neurons, whereas matrix metalloproteinase (MMP) 9 is involved in the synaptic plasticity by cleaving extracellular matrix proteins and, thus, is associated with learning processes in the mammalian brain. Because the mechanisms of MMP-9 transcription in the brain are poorly understood, this study aimed to elucidate regulation of MMP-9 gene expression in the mouse brain after fear learning. We show here that contextual fear conditioning markedly increases MMP-9 transcription, followed by enhanced enzymatic levels in the three major brain structures implicated in fear learning, i.e. the amygdala, hippocampus, and prefrontal cortex. To reveal the role of AP-1 transcription factor in MMP-9 gene expression, we have used reporter gene constructs with specifically mutated AP-1 gene promoter sites. The constructs were introduced into the medial prefrontal cortex of neonatal mouse pups by electroporation, and the regulation of MMP-9 transcription was studied after contextual fear conditioning in the adult animals. Specifically, -42/-50- and -478/-486-bp AP-1 binding motifs of the mouse MMP-9 promoter sequence have been found to play a major role in MMP-9 gene activation. Furthermore, increases in MMP-9 gene promoter binding by the AP-1 transcription factor proteins c-Fos and c-Jun have been demonstrated in all three brain structures under investigation. Hence, our results suggest that AP-1 acts as a positive regulator of MMP-9 transcription in the brain following fear learning.
Fear conditioning and extinction across development: evidence from human studies and animal models.

PubMed

Shechner, Tomer; Hong, Melanie; Britton, Jennifer C; Pine, Daniel S; Fox, Nathan A

2014-07-01

The ability to differentiate danger and safety through associative processes emerges early in life. Understanding the mechanisms underlying associative learning of threat and safety can clarify the processes that shape development of normative fears and pathological anxiety. Considerable research has used fear conditioning and extinction paradigms to delineate underlying mechanisms in animals and human adults; however, little is known about these mechanisms in children and adolescents. The current paper summarizes the empirical data on the development of fear conditioning and extinction. It reviews methodological considerations and future directions for research on fear conditioning and extinction in pediatric populations. Copyright © 2014 Elsevier B.V. All rights reserved.

Altered Pain Perception and Fear-Learning Deficits in Subjects With Posttraumatic Stress Disorder.

PubMed

Jenewein, Josef; Erni, Jeannine; Moergeli, Hanspeter; Grillon, Christian; Schumacher, Sonja; Mueller-Pfeiffer, Christoph; Hassanpour, Katayun; Seiler, Annina; Wittmann, Lutz; Schnyder, Ulrich; Hasler, Gregor

2016-12-01

There is growing evidence that fear-learning abnormalities are involved in the development of posttraumatic stress disorder (PTSD) and chronic pain. More than 50% of PTSD patients suffer from chronic pain. This study aimed to examine the role of fear-learning deficits in the link between pain perception and PTSD. We included 19 subjects with PTSD and 21 age- and sex-matched healthy control subjects in a fear-conditioning experiment. The conditioned stimulus (CS) consisted of visual signs flashed upon a screen in front of each subject. The unconditioned stimulus was either a low or high temperature impulse delivered through a thermal contact thermode on the subjects' hand. A designation of 'CS-' was assigned to CS always followed by nonpainful low-temperature stimuli; a designation of 'CS+' was given to CS that were randomly followed by either a low or a more painful high temperature. Skin conductance was used as a physiological marker of fear. In healthy control subjects, CS+ induced more fear than CS-, and a low-temperature stimulus induced less subjective pain after CS- than after CS+. PTSD subjects failed to demonstrate such adaptive conditioning. Fear ratings after CS presentation were significantly higher in the PTSD group than in the control group. There were significant interaction effects between group and the type of CS on fear and pain ratings. Fear-learning deficits are a potentially promising, specific psychopathological factor in altered pain perception associated with PTSD. Deficits in safety learning may increase fear and, consequently, pain sensations. These findings may contribute to elucidating the pathogenesis behind the highly prevalent comorbidity that exists between PTSD and pain disorders, and to developing new treatments. This study provides new insights into the pathogenesis of chronic pain in patients with PTSD. The findings may help to develop new treatment strategies for this highly prevalent comorbidity in PTSD. Copyright Â© 2016 American Pain Society. All rights reserved.
Medial prefrontal cortex activity during the extinction of conditioned fear: an investigation using functional near-infrared spectroscopy.

PubMed

Guhn, Anne; Dresler, Thomas; Hahn, Tim; Mühlberger, Andreas; Ströhle, Andreas; Deckert, Jürgen; Herrmann, Martin J

2012-06-01

The majority of fear conditioning studies in humans have focused on fear acquisition rather than fear extinction. For this reason only a few functional imaging studies on fear extinction are available. A large number of animal studies indicate the medial prefrontal cortex (mPFC) as neuronal substrate of extinction. We therefore determined mPFC contribution during extinction learning after a discriminative fear conditioning in 34 healthy human subjects by using functional near-infrared spectroscopy. During the extinction training, a previously conditioned neutral face (conditioned stimulus, CS+) no longer predicted an aversive scream (unconditioned stimulus, UCS). Considering differential valence and arousal ratings as well as skin conductance responses during the acquisition phase, we found a CS+ related increase in oxygenated haemoglobin concentration changes within the mPFC over the time course of extinction. Late CS+ trials further revealed higher activation than CS- trials in a cluster of probe set channels covering the mPFC. These results are in line with previous findings on extinction and further emphasize the mPFC as significant for associative learning processes. During extinction, the diminished fear association between a former CS+ and a UCS is inversely correlated with mPFC activity--a process presumably dysfunctional in anxiety disorders. Copyright © 2012 S. Karger AG, Basel.
Inhibition of amygdaloid dopamine D2 receptors impairs emotional learning measured with fear-potentiated startle.

PubMed

Greba, Q; Gifkins, A; Kokkinidis, L

2001-04-27

Considerable advances have been made in understanding the neurocircuitry underlying the acquisition and expression of Pavlovian conditioned fear responses. Within the complex cellular and molecular processes mediating fearfulness, amygdaloid dopamine (DA), originating from cells in the ventral tegmental area (VTA) of the midbrain, is thought to contribute to fear-motivated responding. Considering that blockade of DA D(2) receptors is a common mechanism of action for antipsychotic agents, we hypothesized that inhibition of D(2) receptors in the amygdala may be involved in the antiparanoid effects of these drugs. To assess the role of amygdaloid DA D(2) receptors in aversive emotionality, the D(2) receptor antagonist raclopride was infused into the amygdala prior to Pavlovian fear conditioning. Potentiated startle was used as a behavioral indicator of fear and anxiety. Classical fear conditioning and acoustic startle testing were conducted in a single session allowing for the concomitant assessment of shock reactivity with startle enhancement. Depending on dose, the results found conditioned fear acquisition and retention to be impaired following administration of raclopride into the amygdala. Additionally, the learning deficit was dissociated from shock detection and from fear expression assessed with the shock sensitization of acoustic startle. These findings further refine the known neural mechanisms of amygdala-based emotional learning and memory and were interpreted to suggest that, along with D(1) receptors, D(2) receptors in the amygdala may mediate the formation and the retention of newly-acquired fear associations.
Effects of chemogenetic excitation or inhibition of the ventrolateral periaqueductal gray on the acquisition and extinction of Pavlovian fear conditioning.

PubMed

Arico, Carolyn; Bagley, Elena E; Carrive, Pascal; Assareh, Neda; McNally, Gavan P

2017-10-01

The midbrain periaqueductal gray (PAG) has been implicated in the generation and transmission of a prediction error signal that instructs amygdala-based fear and extinction learning. However, the PAG also plays a key role in the expression of conditioned fear responses. The evidence for a role of the PAG in fear learning and extinction learning has been obtained almost exclusively using PAG-dependent fear responses. It is less clear whether the PAG regulates fear learning when other measures of learned fear are used. Here we combined a chemogenetic approach, permitting excitation or inhibition of neurons in the ventrolateral PAG (VLPAG), with conditioned suppression as the measure of learned fear to assess the role of VLPAG in the acquisition and extinction of fear learning. We show that chemogenetic excitation of VLPAG (with some encroachment on lateral PAG [LPAG]) impairs acquisition of fear and, conversely, chemogenetic inhibition impairs extinction of fear. These effects on fear and extinction learning were specific to the combination of DREADD expression and injection of CNO because they were observed relative to both eYFP controls injected with CNO as well as DREADD expressing controls injected with vehicle. Taken together, these results show that activity of L/VLPAG neurons regulates both the acquisition and extinction of Pavlovian fear learning. Copyright © 2017 Elsevier Inc. All rights reserved.
Nonassociative Learning Processes Determine Expression and Extinction of Conditioned Fear in Mice

ERIC Educational Resources Information Center

Kamprath, Kornelia; Wotjak, Carsten T.

2004-01-01

Freezing to a tone following auditory fear conditioning is commonly considered as a measure of the strength of the tone-shock association. The decrease in freezing on repeated nonreinforced tone presentation following conditioning, in turn, is attributed to the formation of an inhibitory association between tone and shock that leads to a…
Vicarious Learning and Reduction of Fear in Children via Adult and Child Models.

PubMed

Dunne, Güler; Askew, Chris

2017-06-01

Children can learn to fear stimuli vicariously, by observing adults' or peers' responses to them. Given that much of school-age children's time is typically spent with their peers, it is important to establish whether fear learning from peers is as effective or robust as learning from adults, and also whether peers can be successful positive models for reducing fear. During a vicarious fear learning procedure, children (6 to 10 years; N = 60) were shown images of novel animals together with images of adult or peer faces expressing fear. Later they saw their fear-paired animal again together with positive emotional adult or peer faces. Children's fear beliefs and avoidance for the animals increased following vicarious fear learning and decreased following positive vicarious counterconditioning. There was little evidence of differences in learning from adults and peers, demonstrating that for this age group peer models are effective models for both fear acquisition and reduction. (PsycINFO Database Record (c) 2017 APA, all rights reserved).
Rats with ventral hippocampal damage are impaired at various forms of learning including conditioned inhibition, spatial navigation, and discriminative fear conditioning to similar contexts.

PubMed

McDonald, Robert J; Balog, R J; Lee, Justin Q; Stuart, Emily E; Carrels, Brianna B; Hong, Nancy S

2018-10-01

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. Copyright © 2018 Elsevier B.V. All rights reserved.
RNA sequencing from neural ensembles activated during fear conditioning in the mouse temporal association cortex

PubMed Central

Cho, Jin-Hyung; Huang, Ben S.; Gray, Jesse M.

2016-01-01

The stable formation of remote fear memories is thought to require neuronal gene induction in cortical ensembles that are activated during learning. However, the set of genes expressed specifically in these activated ensembles is not known; knowledge of such transcriptional profiles may offer insights into the molecular program underlying stable memory formation. Here we use RNA-Seq to identify genes whose expression is enriched in activated cortical ensembles labeled during associative fear learning. We first establish that mouse temporal association cortex (TeA) is required for remote recall of auditory fear memories. We then perform RNA-Seq in TeA neurons that are labeled by the activity reporter Arc-dVenus during learning. We identify 944 genes with enriched expression in Arc-dVenus+ neurons. These genes include markers of L2/3, L5b, and L6 excitatory neurons but not glial or inhibitory markers, confirming Arc-dVenus to be an excitatory neuron-specific but non-layer-specific activity reporter. Cross comparisons to other transcriptional profiles show that 125 of the enriched genes are also activity-regulated in vitro or induced by visual stimulus in the visual cortex, suggesting that they may be induced generally in the cortex in an experience-dependent fashion. Prominent among the enriched genes are those encoding potassium channels that down-regulate neuronal activity, suggesting the possibility that part of the molecular program induced by fear conditioning may initiate homeostatic plasticity. PMID:27557751
What Can Ethobehavioral Studies Tell Us About The Brain’s Fear System?

PubMed Central

Pellman, Blake A.; Kim, Jeansok J.

2016-01-01

Foraging-associated predation risk is a natural problem all prey must face. Fear evolved due to its protective functions, guiding and shaping behaviors that help animals adapt to various ecological challenges. Despite the breadth of risky situations in nature that demand diversity in fear behaviors, contemporary neurobiological models of fear stem largely from Pavlovian fear conditioning studies that focus on how a particular cue becomes capable of eliciting learned fear responses, thus oversimplifying the brain’s fear system. Here we review fear from functional, mechanistic, and phylogenetic perspectives where environmental threats cause animals to alter their foraging strategies in terms of spatial and temporal navigation, and discuss whether the inferences we draw from fear conditioning studies operate in the natural world. PMID:27130660
Generalization of Pain-Related Fear Based on Conceptual Knowledge.

PubMed

Meulders, Ann; Vandael, Kristof; Vlaeyen, Johan W S

2017-05-01

Increasing evidence suggests that pain-related fear is key to the transition from acute to chronic pain. Previous research has shown that perceptual similarity with a pain-associated movement fosters the generalization of fear to novel movements. Perceptual generalization of pain-related fear is adaptive as it enables individuals to extrapolate the threat value of one movement to another without the necessity to learn anew. However, excessive spreading of fear to safe movements may become maladaptive and may lead to sustained anxiety, dysfunctional avoidance behaviors, and severe disability. A hallmark of human cognition is the ability to extract conceptual knowledge from a learning episode as well. Although this conceptual pathway may be important to understand fear generalization in chronic pain, research on this topic is lacking. We investigated acquisition and generalization of concept-based pain-related fear. During acquisition, unique exemplars of one action category (CS+; e.g., opening boxes) were followed by pain, whereas exemplars of another action category (CS-; e.g., closing boxes) were not. Subsequently, spreading of pain-related fear to novel exemplars of both action categories was tested. Participants learned to expect the pain to occur and reported more pain-related fear to the exemplars of the CS+ category compared with those of the CS- category. During generalization, fear and expectancy generalized to novel exemplars of the CS+ category, but not to the CS- category. This pattern was not corroborated in the eyeblink startle measures. This is the first study that demonstrates that pain-related fear can be acquired and generalized based on conceptual knowledge. Copyright © 2016. Published by Elsevier Ltd.
BDNFval66met affects neural activation pattern during fear conditioning and 24 h delayed fear recall.

PubMed

Lonsdorf, Tina B; Golkar, Armita; Lindström, Kara M; Haaker, Jan; Öhman, Arne; Schalling, Martin; Ingvar, Martin

2015-05-01

Brain-derived neurotrophic factor (BDNF), the most abundant neutrophin in the mammalian central nervous system, is critically involved in synaptic plasticity. In both rodents and humans, BDNF has been implicated in hippocampus- and amygdala-dependent learning and memory and has more recently been linked to fear extinction processes. Fifty-nine healthy participants, genotyped for the functional BDNFval66met polymorphism, underwent a fear conditioning and 24h-delayed extinction protocol while skin conductance and blood oxygenation level dependent (BOLD) responses (functional magnetic resonance imaging) were acquired. We present the first report of neural activation pattern during fear acquisition 'and' extinction for the BDNFval66met polymorphism using a differential conditioned stimulus (CS)+ > CS- comparison. During conditioning, we observed heightened allele dose-dependent responses in the amygdala and reduced responses in the subgenual anterior cingulate cortex in BDNFval66met met-carriers. During early extinction, 24h later, we again observed heightened responses in several regions ascribed to the fear network in met-carriers as opposed to val-carriers (insula, amygdala, hippocampus), which likely reflects fear memory recall. No differences were observed during late extinction, which likely reflects learned extinction. Our data thus support previous associations of the BDNFval66met polymorphism with neural activation in the fear and extinction network, but speak against a specific association with fear extinction processes. © The Author (2014). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.
Amygdala-ventral striatum circuit activation decreases long-term fear

PubMed Central

Correia, Susana S; McGrath, Anna G; Lee, Allison; Graybiel, Ann M; Goosens, Ki A

2016-01-01

In humans, activation of the ventral striatum, a region associated with reward processing, is associated with the extinction of fear, a goal in the treatment of fear-related disorders. This evidence suggests that extinction of aversive memories engages reward-related circuits, but a causal relationship between activity in a reward circuit and fear extinction has not been demonstrated. Here, we identify a basolateral amygdala (BLA)-ventral striatum (NAc) pathway that is activated by extinction training. Enhanced recruitment of this circuit during extinction learning, either by pairing reward with fear extinction training or by optogenetic stimulation of this circuit during fear extinction, reduces the return of fear that normally follows extinction training. Our findings thus identify a specific BLA-NAc reward circuit that can regulate the persistence of fear extinction and point toward a potential therapeutic target for disorders in which the return of fear following extinction therapy is an obstacle to treatment. DOI: http://dx.doi.org/10.7554/eLife.12669.001 PMID:27671733
The etiology of fear of heights and its relationship to severity and individual response patterns.

PubMed

Menzies, R G; Clarke, J C

1993-05-01

The acquisition of fear of heights in an undergraduate student sample was investigated. Height-fearful (n = 50) and non-fearful (n = 50) groups were formed on the basis of extreme scores to the heights item on the FSS-III (Wolpe & Lang, Behaviour Research and Therapy, 2, 27-30, 1964). Subjects were then assessed with a battery of measures including the Acrophobia Questionnaire (Cohen, Behaviour Therapy, 18, 17-23, 1977), self-rating of severity (Marks & Mathews, Behaviour Research and Therapy, 17, 263-267, 1979), global rating of severity (Michelson, Behaviour Research and Therapy, 24, 263-275, 1986), and a new comprehensive origins questionnaire constructed by the authors. Results obtained question the significance of simple associative-learning events in the acquisition of fear of heights. Only 18% of fearful Ss were classified as directly conditioned cases. Furthermore, no differences between groups were found in the proportion of Ss who knew other height-fearfuls, had experienced relevant associative-learning events, or the ages at which these events had occurred. Finally, no relationships between mode of acquisition and severity or individual response patterns were obtained. In general, the data were consistent with the non-associative, Darwinian accounts of fear acquisition that continue to attract theorists from a variety of backgrounds (e.g. Bowlby, Attachment and loss. London: Penguin, 1975; Clarke & Jackson, Hypnosis and behaviour therapy: The treatment of anxiety and phobias. New York: Springer, 1983; Marks, Fears, phobias and rituals: Panic anxiety and their disorders. New York, Oxford Univ. Press, 1987). Differences with previous studies in which classical conditioning has accounted for the majority of cases are discussed in terms of the methodological differences across studies.
Post-training gamma irradiation-enhanced contextual fear memory associated with reduced neuronal activation of the infralimbic cortex.

PubMed

Kugelman, Tara; Zuloaga, Damian G; Weber, Sydney; Raber, Jacob

2016-02-01

The brain might be exposed to irradiation under a variety of situations, including clinical treatments, nuclear accidents, dirty bomb scenarios, and military and space missions. Correctly recalling tasks learned prior to irradiation is important but little is known about post-learning effects of irradiation. It is not clear whether exposure to X-ray irradiation during memory consolidation, a few hours following training, is associated with altered contextual fear conditioning 24h after irradiation and which brain region(s) might be involved in these effects. Brain immunoreactivity patterns of the immediately early gene c-Fos, a marker of cellular activity was used to determine which brain areas might be altered in post-training irradiation memory retention tasks. In this study, we show that post-training gamma irradiation exposure (1 Gy) enhanced contextual fear memory 24h later and is associated with reduced cellular activation in the infralimbic cortex. Reduced GABA-ergic neurotransmission in parvalbumin-positive cells in the infralimbic cortex might play a role in this post-training radiation-enhanced contextual fear memory. Copyright © 2015 Elsevier B.V. All rights reserved.
Post-training gamma irradiation-enhanced contextual fear memory associated with reduced neuronal activation of the infralimbic cortex

PubMed Central

Kugelman, Tara; Zuloaga, Damian G.; Weber, Sydney; Raber, Jacob

2015-01-01

The brain might be exposed to irradiation under a variety of situations, including clinical treatments, nuclear accidents, dirty bomb scenarios, and military and space missions. Correctly recalling tasks learned prior to irradiation is important but little is known about post-learning effects of irradiation. It is not clear whether exposure to X-ray irradiation during memory consolidation, a few hours following training, is associated with altered contextual fear conditioning 24 hours after irradiation and which brain region(s) might be involved in these effects. Brain immunoreactivity patterns of the immediately early gene c-Fos, a marker of cellular activity was used to determine which brain areas might be altered in post-training irradiation memory retention tasks. In this study, we show that post-training gamma irradiation exposure (1 Gy) enhanced contextual fear memory 24 hours later and is associated with reduced cellular activation in the infralimbic cortex. Reduced GABA-ergic neurotransmission in parvalbumin-positive cells in the infralimbic cortex might play a role in this post-training radiation-enhanced contextual fear memory. PMID:26522840
Complementary roles for amygdala and periaqueductal gray in temporal-difference fear learning.

PubMed

Cole, Sindy; McNally, Gavan P

2009-01-01

Pavlovian fear conditioning is not a unitary process. At the neurobiological level multiple brain regions and neurotransmitters contribute to fear learning. At the behavioral level many variables contribute to fear learning including the physical salience of the events being learned about, the direction and magnitude of predictive error, and the rate at which these are learned about. These experiments used a serial compound conditioning design to determine the roles of basolateral amygdala (BLA) NMDA receptors and ventrolateral midbrain periaqueductal gray (vlPAG) mu-opioid receptors (MOR) in predictive fear learning. Rats received a three-stage design, which arranged for both positive and negative prediction errors producing bidirectional changes in fear learning within the same subjects during the test stage. Intra-BLA infusion of the NR2B receptor antagonist Ifenprodil prevented all learning. In contrast, intra-vlPAG infusion of the MOR antagonist CTAP enhanced learning in response to positive predictive error but impaired learning in response to negative predictive error--a pattern similar to Hebbian learning and an indication that fear learning had been divorced from predictive error. These findings identify complementary but dissociable roles for amygdala NMDA receptors and vlPAG MOR in temporal-difference predictive fear learning.
Animal Models of Fear Relapse

PubMed Central

Goode, Travis D.; Maren, Stephen

2014-01-01

Whereas fear memories are rapidly acquired and enduring over time, extinction memories are slow to form and are susceptible to disruption. Consequently, behavioral therapies that involve extinction learning (e.g., exposure therapy) often produce only temporary suppression of fear and anxiety. This review focuses on the factors that are known to influence the relapse of extinguished fear. Several phenomena associated with the return of fear after extinction are discussed, including renewal, spontaneous recovery, reacquisition, and reinstatement. Additionally, this review describes recent work, which has focused on the role of psychological stress in the relapse of extinguished fear. Recent developments in behavioral and pharmacological research are examined in light of treatment of pathological fear in humans. PMID:25225304
Easy to remember, difficult to forget: the development of fear regulation

PubMed Central

Johnson, D.C.; Casey, B.J.

2014-01-01

Fear extinction learning is a highly adaptive process that involves the integrity of frontolimbic circuitry. Its disruption has been associated with emotional dysregulation in stress and anxiety disorders. In this article we consider how age, genetics and experiences shape our capacity to regulate fear in cross-species studies. Evidence for adolescent-specific diminished fear extinction learning is presented in the context of immature frontolimbic circuitry. We also present evidence for less neural plasticity in fear regulation as a function of early life stress and by genotype, focusing on the common brain derived neurotrophin factor (BDNF) Val66Met polymorphism. Finally, we discuss this work in the context of exposure-based behavioral therapies for the treatment of anxiety and stress disorders that are based on principles of fear extinction. We conclude by speculating on how such therapies may be optimized for the individual based on the patient’s age, genetic profile and personal history to move from standard treatment of care to personalized and precision medicine. PMID:25238998
Cholinergic transmission in the dorsal hippocampus modulates trace but not delay fear conditioning.

PubMed

Pang, Min-Hee; Kim, Nam-Soo; Kim, Il-Hwan; Kim, Hyun; Kim, Hyun-Taek; Choi, June-Seek

2010-09-01

Although cholinergic mechanisms have been widely implicated in learning and memory processes, few studies have investigated the specific contribution of hippocampal cholinergic transmission during trace fear conditioning, a form of associative learning involving a temporal gap between two stimuli. Microinfusions of scopolamine, a muscarinic receptor antagonist, into the dorsal hippocampus (DH) produced dose-dependent impairment in the acquisition and expression of a conditioned response (CR) following trace fear conditioning with a tone conditioned stimulus (CS) and a footshock unconditioned stimulus (US) in rats. The same infusions, however, had no effect on delay conditioning, general activity, pain sensitivity or attentional modulation. Moreover, scopolamine infusions attenuated phosphorylation of extracellular signal-regulated kinase (ERK) in the amygdala, indicating that cholinergic signals in the DH are important for trace fear conditioning. Taken together, the current study provides evidence that cholinergic neurotransmission in the DH is essential for the cellular processing of CS-US association in the amygdala when the two stimuli are temporally disconnected. Copyright 2010 Elsevier Inc. All rights reserved.
Sleep deprivation affects fear memory consolidation: bi-stable amygdala connectivity with insula and ventromedial prefrontal cortex.

PubMed

Feng, Pan; Becker, Benjamin; Zheng, Yong; Feng, Tingyong

2018-02-01

Sleep plays an important role for successful fear memory consolidation. Growing evidence suggests that sleep disturbances might contribute to the development and the maintenance of posttraumatic stress disorder (PTSD), a disorders characterized by dysregulations in fear learning mechanisms, as well as exaggerated arousal and salience processing. Against this background, the present study examined the effects of sleep deprivation (SD) on the acquisition of fear and the subsequent neural consolidation. To this end, the present study assessed fear acquisition and associated changes in fMRI-based amygdala-functional connectivity following 24 h of SD. Relative to non-sleep deprived controls, SD subjects demonstrated increased fear ratings and skin conductance responses (SCR) during fear acquisition. During fear consolidation SD inhibited increased amygdala-ventromendial prefrontal cortex (vmPFC) connectivity and concomitantly increased changes in amygdala-insula connectivity. Importantly, whereas in controls fear indices during acquisition were negatively associated with amygdala-vmPFC connectivity during consolidation, fear indices were positively associated with amygdala-insula coupling following SD. Together the findings suggest that SD may interfere with vmPFC control of the amygdala and increase bottom-up arousal signaling in the amygdala-insula pathway during fear consolidation, which might mediate the negative impact of sleep disturbances on PSTD symptomatology.

Stimulation of the noradrenergic system during memory formation impairs extinction learning but not the disruption of reconsolidation.

PubMed

Soeter, Marieke; Kindt, Merel

2012-04-01

The noradrenergic system plays a critical role in the 'consolidation' of emotional memory. If we are to target 'reconsolidation' in patients with anxiety disorders, the noradrenergic strengthening of fear memory should not impair the disruption of reconsolidation. In Experiment I, we addressed this issue using a differential fear conditioning procedure allowing selective reactivation of one of two fear associations. First, we strengthened fear memory by administering an α(2)-adrenergic receptor antagonist (ie, yohimbine HCl; double-blind placebo-controlled study) 30 min before acquisition (time for peak value yohimbine HCl <1 h). Next, the reconsolidation of one of the fear associations was manipulated by administering a β-adrenergic receptor antagonist (ie, propranolol HCl) 90 min before its selective reactivation (time for peak value propranolol HCl <2 h). In Experiment II, we administered propranolol HCl after reactivation of the memory to rule out a possible effect of the pharmacological manipulation on the memory retrieval itself. The excessive release of noradrenaline during memory formation not only delayed the process of extinction 48 h later, but also triggered broader fear generalization. Yet, the β-adrenergic receptor blocker during reconsolidation selectively 'neutralized' the fear-arousing aspects of the noradrenergic-strengthened memory and undermined the generalization of fear. We observed a similar reduction in fear responding when propranolol HCl was administered after reactivation of the memory. The present findings demonstrate the involvement of noradrenergic modulation in the formation as well as generalization of human fear memory. Given that the noradrenergic strengthening of fear memory impaired extinction learning but not the disruption of reconsolidation, our findings may have implications for the treatment of anxiety disorders.
Comparing Electric Shock and a Fearful Screaming Face as Unconditioned Stimuli for Fear Learning

PubMed Central

Glenn, Catherine R.; Lieberman, Lynne; Hajcak, Greg

2012-01-01

The potency of an unconditioned stimulus (UCS) can impact the degree of fear learning. One of the most common and effective UCSs is an electric shock, which is inappropriate for certain populations (e.g., children). To address this need, a novel fear learning paradigm was recently developed that uses a fearful female face and scream as the UCS. The present study directly compared the efficacy of the screaming female UCS and a traditional shock UCS in two fear learning paradigms. Thirty-six young adults completed two fear learning tasks and a measure of trait anxiety; fear learning was indexed with fear-potentiated startle (FPS) and self-reported fear ratings. Results indicated comparable FPS across the two tasks. However, larger overall startle responses were exhibited in the shock task, and participants rated the shock UCS and overall task as more aversive than the screaming female. In addition, trait anxiety was only related to FPS in the fear learning task that employed a shock as the UCS. Taken together, results indicate that, although both UCS paradigms can be used for fear conditioning (i.e., to produce differences between CS+ and CS−), the shock UCS paradigm is more aversive and potentially more sensitive to individual differences in anxiety. PMID:23007035
Dispositional cognitive reappraisal modulates the neural correlates of fear acquisition and extinction.

PubMed

Hermann, Andrea; Keck, Tanja; Stark, Rudolf

2014-09-01

Adverse learning experiences play a significant role in the etiology of anxiety disorders. However, not all individuals experiencing negative events develop heightened anxiety. This is possibly due to individual differences in the regulation of negative emotions associated with these negative events. Cognitive reappraisal is defined as reinterpreting an emotion-eliciting situation in a way that changes its emotional impact. A more frequent use of cognitive reappraisal in daily life has been shown to be more adaptive. However, no study to date examined the association of dispositional cognitive reappraisal with emotional learning, in order to elucidate individual differences in negative emotional responses towards aversive events. The goal of this functional magnetic resonance imaging (fMRI) study was to investigate the association of dispositional cognitive reappraisal with subjective, electrodermal and neural correlates of fear acquisition and extinction. Data of 41 healthy individuals, who participated in a socially relevant differential conditioning paradigm (acquisition and extinction learning: day 1, extinction recall: day 2), were acquired. Dispositional cognitive reappraisal was negatively associated with right insula, and hippocampus activation during acquisition. Furthermore, the reduction of self-reported conditioned fear during extinction learning as well as reduced insula and enhanced rostral anterior cingulate cortex activation during extinction learning was related to cognitive reappraisal. In addition, reduced recovery of conditioned arousal, reduced anterior cingulate and dorsomedial prefrontal cortex activation and enhanced ventromedial prefrontal cortex activation during extinction recall was observed in individuals with higher cognitive reappraisal scores. The results indicate that dispositional cognitive reappraisal modulates subjective and neural correlates of fear conditioning, probably leading to reduced acquisition and stronger extinction learning and recall. These results point to the important role of dispositional cognitive reappraisal in the development and modification of conditioned emotional responses and might further improve our understanding of anxiety disorders. Copyright © 2014 Elsevier Inc. All rights reserved.
Learned together, extinguished apart: reducing fear to complex stimuli

PubMed Central

Jones, Carolyn E.; Ringuet, Stephanie; Monfils, Marie-H.

2013-01-01

Pairing a previously neutral conditioned stimulus (CS; e.g., a tone) to an aversive unconditioned stimulus (US; e.g., a footshock) leads to associative learning such that the tone alone comes to elicit a conditioned response (e.g., freezing). We have previously shown that an extinction session that occurs within the reconsolidation window attenuates fear responding and prevents the return of fear in pure tone Pavlovian fear conditioning. Here we sought to examine whether this effect also applies to a more complex fear memory. First, we show that after fear conditioning to the simultaneous presentation of a tone and a light (T+L) coterminating with a shock, the compound memory that ensues is more resistant to fear extinction than simple tone-shock pairings. Next, we demonstrate that the compound memory can be disrupted by interrupting the reconsolidation of the two individual components using a sequential retrieval+extinction paradigm, provided the stronger compound component is retrieved first. These findings provide insight into how compound memories are encoded, and could have important implications for PTSD treatment. PMID:24241750
Cholinergic regulation of fear learning and extinction.

PubMed

Wilson, Marlene A; Fadel, Jim R

2017-03-01

Cholinergic activation regulates cognitive function, particularly long-term memory consolidation. This Review presents an overview of the anatomical, neurochemical, and pharmacological evidence supporting the cholinergic regulation of Pavlovian contextual and cue-conditioned fear learning and extinction. Basal forebrain cholinergic neurons provide inputs to neocortical regions and subcortical limbic structures such as the hippocampus and amygdala. Pharmacological manipulations of muscarinic and nicotinic receptors support the role of cholinergic processes in the amygdala, hippocampus, and prefrontal cortex in modulating the learning and extinction of contexts or cues associated with threat. Additional evidence from lesion studies and analysis of in vivo acetylcholine release with microdialysis similarly support a critical role of cholinergic neurotransmission in corticoamygdalar or corticohippocampal circuits during acquisition of fear extinction. Although a few studies have suggested a complex role of cholinergic neurotransmission in the cellular plasticity essential for extinction learning, more work is required to elucidate the exact cholinergic mechanisms and physiological role of muscarinic and nicotinic receptors in these fear circuits. Such studies are important for elucidating the role of cholinergic neurotransmission in disorders such as posttraumatic stress disorder that involve deficits in extinction learning as well as for developing novel therapeutic approaches for such disorders. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.
Pituitary adenylate cyclase-activating polypeptide (PACAP) signaling in the prefrontal cortex modulates cued fear learning, but not spatial working memory, in female rats.

PubMed

Kirry, Adam J; Herbst, Matthew R; Poirier, Sarah E; Maskeri, Michelle M; Rothwell, Amy C; Twining, Robert C; Gilmartin, Marieke R

2018-05-01

A genetic polymorphism within the gene encoding the pituitary adenylate cyclase- activating polypeptide (PACAP) receptor type I (PAC1R) has recently been associated with hyper-reactivity to threat-related cues in women, but not men, with post-traumatic stress disorder (PTSD). PACAP is a highly conserved peptide, whose role in mediating adaptive physiological stress responses is well established. Far less is understood about the contribution of PACAP signaling in emotional learning and memory, particularly the encoding of fear to discrete cues. Moreover, a neurobiological substrate that may account for the observed link between PAC1R and PTSD in women, but not men, has yet to be identified. Sex differences in PACAP signaling during emotional learning could provide novel targets for the treatment of PTSD. Here we investigated the contribution of PAC1R signaling within the prefrontal cortex to the acquisition of cued fear in female and male rats. We used a variant of fear conditioning called trace fear conditioning, which requires sustained attention to fear cues and depends on working-memory like neuronal activity within the prefrontal cortex. We found that cued fear learning, but not spatial working memory, was impaired by administration of a PAC1R antagonist directly into the prelimbic area of the prefrontal cortex. This effect was specific to females. We also found that levels of mRNA for the PAC1R receptor in the prelimbic cortex were greater in females compared with males, and were highest during and immediately following the proestrus stage of the estrous cycle. Together, these results demonstrate a sex-specific role of PAC1R signaling in learning about threat-related cues. Copyright © 2018 Elsevier Ltd. All rights reserved.
Calcineurin inhibition blocks within-, but not between-session fear extinction in mice

PubMed Central

Moulin, Thiago C.; Carneiro, Clarissa F. D.; Gonçalves, Marina M. C.; Junqueira, Lara S.; Amaral, Olavo B.

2015-01-01

Memory extinction involves the formation of a new associative memory that inhibits a previously conditioned association. Nonetheless, it could also depend on weakening of the original memory trace if extinction is assumed to have multiple components. The phosphatase calcineurin (CaN) has been described as being involved in extinction but not in the initial consolidation of fear learning. With this in mind, we set to study whether CaN could have different roles in distinct components of extinction. Systemic treatment with the CaN inhibitors cyclosporin A (CsA) or FK-506, as well as i.c.v. administration of CsA, blocked within-session, but not between-session extinction or initial learning of contextual fear conditioning. Similar effects were found in multiple-session extinction of contextual fear conditioning and in auditory fear conditioning, indicating that CaN is involved in different types of short-term extinction. Meanwhile, inhibition of protein synthesis by cycloheximide (CHX) treatment did not affect within-session extinction, but disrupted fear acquisition and slightly impaired between-session extinction. Our results point to a dissociation of within- and between-session extinction of fear conditioning, with the former being more dependent on CaN activity and the latter on protein synthesis. Moreover, the modulation of within-session extinction did not affect between-session extinction, suggesting that these components are at least partially independent. PMID:25691516
More than just noise: Inter-individual differences in fear acquisition, extinction and return of fear in humans - Biological, experiential, temperamental factors, and methodological pitfalls.

PubMed

Lonsdorf, Tina B; Merz, Christian J

2017-09-01

Why do only some individuals develop pathological anxiety following adverse events? Fear acquisition, extinction and return of fear paradigms serve as experimental learning models for the development, treatment and relapse of anxiety. Individual differences in experimental performance were however mostly regarded as 'noise' by researchers interested in basic associative learning principles. Our work for the first time presents a comprehensive literature overview and methodological discussion on inter-individual differences in fear acquisition, extinction and return of fear. We tell a story from noise that steadily develops into a meaningful tune and converges to a model of mechanisms contributing to individual risk/resilience with respect to fear and anxiety-related behavior. Furthermore, in light of the present 'replicability crisis' we identify methodological pitfalls and provide suggestions for study design and analyses tailored to individual difference research in fear conditioning. Ultimately, synergistic transdisciplinary and collaborative efforts hold promise to not only improve our mechanistic understanding but can also be expected to contribute to the development of specifically tailored ('individualized') intervention and targeted prevention programs in the future. Copyright © 2017 Elsevier Ltd. All rights reserved.
Enhancing dopaminergic signaling and histone acetylation promotes long-term rescue of deficient fear extinction.

PubMed

Whittle, N; Maurer, V; Murphy, C; Rainer, J; Bindreither, D; Hauschild, M; Scharinger, A; Oberhauser, M; Keil, T; Brehm, C; Valovka, T; Striessnig, J; Singewald, N

2016-12-06

Extinction-based exposure therapy is used to treat anxiety- and trauma-related disorders; however, there is the need to improve its limited efficacy in individuals with impaired fear extinction learning and to promote greater protection against return-of-fear phenomena. Here, using 129S1/SvImJ mice, which display impaired fear extinction acquisition and extinction consolidation, we revealed that persistent and context-independent rescue of deficient fear extinction in these mice was associated with enhanced expression of dopamine-related genes, such as dopamine D1 (Drd1a) and -D2 (Drd2) receptor genes in the medial prefrontal cortex (mPFC) and amygdala, but not hippocampus. Moreover, enhanced histone acetylation was observed in the promoter of the extinction-regulated Drd2 gene in the mPFC, revealing a potential gene-regulatory mechanism. Although enhancing histone acetylation, via administering the histone deacetylase (HDAC) inhibitor MS-275, does not induce fear reduction during extinction training, it promoted enduring and context-independent rescue of deficient fear extinction consolidation/retrieval once extinction learning was initiated as shown following a mild conditioning protocol. This was associated with enhanced histone acetylation in neurons of the mPFC and amygdala. Finally, as a proof-of-principle, mimicking enhanced dopaminergic signaling by L-dopa treatment rescued deficient fear extinction and co-administration of MS-275 rendered this effect enduring and context-independent. In summary, current data reveal that combining dopaminergic and epigenetic mechanisms is a promising strategy to improve exposure-based behavior therapy in extinction-impaired individuals by initiating the formation of an enduring and context-independent fear-inhibitory memory.
Selective synaptic remodeling of amygdalocortical connections associated with fear memory.

PubMed

Yang, Yang; Liu, Dan-Qian; Huang, Wei; Deng, Juan; Sun, Yangang; Zuo, Yi; Poo, Mu-Ming

2016-10-01

Neural circuits underlying auditory fear conditioning have been extensively studied. Here we identified a previously unexplored pathway from the lateral amygdala (LA) to the auditory cortex (ACx) and found that selective silencing of this pathway using chemo- and optogenetic approaches impaired fear memory retrieval. Dual-color in vivo two-photon imaging of mouse ACx showed pathway-specific increases in the formation of LA axon boutons, dendritic spines of ACx layer 5 pyramidal cells, and putative LA-ACx synaptic pairs after auditory fear conditioning. Furthermore, joint imaging of pre- and postsynaptic structures showed that essentially all new synaptic contacts were made by adding new partners to existing synaptic elements. Together, these findings identify an amygdalocortical projection that is important to fear memory expression and is selectively modified by associative fear learning, and unravel a distinct architectural rule for synapse formation in the adult brain.
Activation of D1/5 Dopamine Receptors: A Common Mechanism for Enhancing Extinction of Fear and Reward-Seeking Behaviors.

PubMed

Abraham, Antony D; Neve, Kim A; Lattal, K Matthew

2016-07-01

Dopamine is critical for many processes that drive learning and memory, including motivation, prediction error, incentive salience, memory consolidation, and response output. Theories of dopamine's function in these processes have, for the most part, been developed from behavioral approaches that examine learning mechanisms in appetitive tasks. A parallel and growing literature indicates that dopamine signaling is involved in consolidation of memories into stable representations in aversive tasks such as fear conditioning. Relatively little is known about how dopamine may modulate memories that form during extinction, when organisms learn that the relation between previously associated events is severed. We investigated whether fear and reward extinction share common mechanisms that could be enhanced with dopamine D1/5 receptor activation. Pharmacological activation of dopamine D1/5 receptors (with SKF 81297) enhanced extinction of both cued and contextual fear. These effects also occurred in the extinction of cocaine-induced conditioned place preference, suggesting that the observed effects on extinction were not specific to a particular type of procedure (aversive or appetitive). A cAMP/PKA biased D1 agonist (SKF 83959) did not affect fear extinction, whereas a broadly efficacious D1 agonist (SKF 83822) promoted fear extinction. Together, these findings show that dopamine D1/5 receptor activation is a target for the enhancement of fear or reward extinction.
Effects of 7-nitroindazole, a selective neural nitric oxide synthase inhibitor, on context-shock associative learning in a two-process contextual fear conditioning paradigm.

PubMed

Chen, Weihai; Yan, Minmin; Wang, Yan; Wang, Xiaqing; Yuan, Jiajin; Li, Ming

2016-10-01

Nitric oxide (NO) is an important retrograde neuronal intracellular messenger which plays an important role in synaptic plasticity and is involved in learning and memory. However, evidence that NO is particularly important for the acquisition of contextual fear conditioning is mixed. Also, little is known about at which stages of the contextual fear conditioning does NO make its contribution. In the present study, we used 7-nitroindazole to temporarily inhibit neural nitric oxide synthase at either the pre-exposure stage or conditioning stage in a two-process paradigm and examined the potential contribution that NO makes to the contextually conditioned fear. Results showed that the expression of contextual fear memory was significantly impaired in rats treated with 7-nitroindazole (30mg/kg, i.p.) prior to the pairing of context-shock (p=0.034, n=8), but not after the conditioning phase (p=0.846, n=8). In addition, the expression of contextual fear memory and reconsolidation was not significantly impaired by 7-nitroindazole administered prior to the context pre-exposure stage or prior to another context-shock learning. These findings suggest that NO is specifically involved in the acquisition but not the consolidation, retrieval or reconsolidation of contextual fear memory. Copyright © 2016 Elsevier Inc. All rights reserved.
A cross species study of heterogeneity in fear extinction learning in relation to FKBP5 variation and expression: Implications for the acute treatment of posttraumatic stress disorder.

PubMed

Galatzer-Levy, Isaac R; Andero, Raül; Sawamura, Takehito; Jovanovic, Tanja; Papini, Santiago; Ressler, Kerry J; Norrholm, Seth Davin

2017-04-01

Deficits in fear extinction learning are hypothesized to underlie the development of posttraumatic stress disorder (PTSD). Such deficits may, in part, be due to genetic and epigenetic variation in the stress related gene FKBP5. Conversely, altering FKBP5 epigenetic responses during memory consolidation may rescue extinction deficits making it a target for acute intervention to prevent the development of PTSD. Study 1 (Humans) examines if FKBP5 single nucleotide polymorphisms (SNPs) and PTSD symptom domains (re-experiencing, avoidance/numbing, hyperarousal) are associated with abnormal fear extinction phenotypes identified using latent growth mixture modeling (LGMM). Study 2 (Mice) tests if increasing doses of dexamethasone administered prior to extinction alters Fkbp5 mRNA production in the amygdala after extinction and recall and prevents the development of abnormal extinction phenotypes. In humans, abnormal extinction was associated with the TT homozygous genotype of FKBP5 SNPs RS9470080 and RS1360780, and hyperarousal symptoms. In mice, dexamethasone 300 μg/kg was associated with increased amygdala Fkbp5 mRNA following extinction and robust extinction learning while lower doses were not associated with amygdala Fkbp5 mRNA or differences in extinction learning. Further, mice that extinguished on dexamethasone 300 μg/kg maintained low levels of freezing behavior during recall training while mRNA levels were no longer elevated. Together, findings indicate that FKBP5 confers risk for fear extinction deficits. However, this risk may be ameliorated by increasing fkbp5 mRNA expression in the amygdala during memory consolidation making this mechanism a plausible point of acute intervention to prevent the development of PTSD. Copyright © 2016 Elsevier Ltd. All rights reserved.
Complementary Roles for Amygdala and Periaqueductal Gray in Temporal-Difference Fear Learning

ERIC Educational Resources Information Center

Cole, Sindy; McNally, Gavan P.

2009-01-01

Pavlovian fear conditioning is not a unitary process. At the neurobiological level multiple brain regions and neurotransmitters contribute to fear learning. At the behavioral level many variables contribute to fear learning including the physical salience of the events being learned about, the direction and magnitude of predictive error, and the…
Modeling startle eyeblink electromyogram to assess fear learning.

PubMed

Khemka, Saurabh; Tzovara, Athina; Gerster, Samuel; Quednow, Boris B; Bach, Dominik R

2017-02-01

Pavlovian fear conditioning is widely used as a laboratory model of associative learning in human and nonhuman species. In this model, an organism is trained to predict an aversive unconditioned stimulus from initially neutral events (conditioned stimuli, CS). In humans, fear memory is typically measured via conditioned autonomic responses or fear-potentiated startle. For the latter, various analysis approaches have been developed, but a systematic comparison of competing methodologies is lacking. Here, we investigate the suitability of a model-based approach to startle eyeblink analysis for assessment of fear memory, and compare this to extant analysis strategies. First, we build a psychophysiological model (PsPM) on a generic startle response. Then, we optimize and validate this PsPM on three independent fear-conditioning data sets. We demonstrate that our model can robustly distinguish aversive (CS+) from nonaversive stimuli (CS-, i.e., has high predictive validity). Importantly, our model-based approach captures fear-potentiated startle during fear retention as well as fear acquisition. Our results establish a PsPM-based approach to assessment of fear-potentiated startle, and qualify previous peak-scoring methods. Our proposed model represents a generic startle response and can potentially be used beyond fear conditioning, for example, to quantify affective startle modulation or prepulse inhibition of the acoustic startle response. © 2016 The Authors. Psychophysiology published by Wiley Periodicals, Inc. on behalf of Society for Psychophysiological Research.
Dissociating response systems: erasing fear from memory.

PubMed

Soeter, Marieke; Kindt, Merel

2010-07-01

In addition to the extensive evidence in animals, we previously showed that disrupting reconsolidation by noradrenergic blockade produced amnesia for the original fear response in humans. Interestingly, the declarative memory for the fear association remained intact. These results asked for a solid replication. Moreover, given the constructive nature of memories, the intact recollection of the fear association could eventually 'rebuild' the fear memory, resulting in the spontaneous recovery of the fear response. Yet, perseverance of the amnesic effects would have substantial clinical implications, as even the most effective treatments for psychiatric disorders display high percentages of relapse. Using a differential fear conditioning procedure in humans, we replicated our previous findings by showing that administering propranolol (40mg) prior to memory reactivation eliminated the startle fear response 24h later. But most importantly, this effect persisted at one month follow-up. Notably, the propranolol manipulation not only left the declarative memory for the acquired contingency untouched, but also skin conductance discrimination. In addition, a close association between declarative knowledge and skin conductance responses was found. These findings are in line with the supposed double dissociation of fear conditioning and declarative knowledge relative to the amygdala and hippocampus in humans. They support the view that skin conductance conditioning primarily reflects contingency learning, whereas the startle response is a rather specific measure of fear. Furthermore, the results indicate the absence of a causal link between the actual knowledge of a fear association and its fear response, even though they often operate in parallel. Interventions targeting the amygdalar fear memory may be essential in specifically and persistently dampening the emotional impact of fear. From a clinical and ethical perspective, disrupting reconsolidation points to promising interventions persistently erasing fear responses from trauma memory without affecting the actual recollection.
Early life programming of innate fear and fear learning in adult female rats.

PubMed

Stevenson, Carl W; Meredith, John P; Spicer, Clare H; Mason, Rob; Marsden, Charles A

2009-03-02

The early rearing environment can impact on emotional reactivity and learning later in life. In this study the effects of neonatal maternal separation (MS) on innate fear and fear learning were assessed in the adult female rat. Pups were subjected to MS (360 min), brief handling (H; 15 min), or animal facility rearing (AFR) on post-natal days 2-14. In the first experiment, innate fear was tested in the open field. No differences between the early rearing groups were observed in unconditioned fear. In the second experiment, separate cohorts were used in a 3-day fear learning paradigm which tested the acquisition (Day 1), expression and extinction (both Day 2) of conditioning to an auditory cue; extinction recall was determined as well (Day 3). Contextual fear conditioning was also assessed prior to cue presentations on Days 2 and 3. Whereas MS attenuated the acquisition and expression of fear conditioning to the cue, H potentiated extinction learning. Cue-induced fear was reduced on Day 3, compared to Day 2, indicating that the recall of extinction learning was evident; however, no early rearing group differences in extinction recall were observed. Similarly, while contextual fear was decreased on Day 3, compared to Day 2, there were no differences between the early rearing groups on either day tested. The present findings of altered cue-conditioned fear learning, in the absence of innate fear changes, lend further support for the important role of the early rearing environment in mediating cognition in adulthood.
Opposite effects of fear conditioning and extinction on dendritic spine remodelling.

PubMed

Lai, Cora Sau Wan; Franke, Thomas F; Gan, Wen-Biao

2012-02-19

It is generally believed that fear extinction is a form of new learning that inhibits rather than erases previously acquired fear memories. Although this view has gained much support from behavioural and electrophysiological studies, the hypothesis that extinction causes the partial erasure of fear memories remains viable. Using transcranial two-photon microscopy, we investigated how neural circuits are modified by fear learning and extinction by examining the formation and elimination of postsynaptic dendritic spines of layer-V pyramidal neurons in the mouse frontal association cortex. Here we show that fear conditioning by pairing an auditory cue with a footshock increases the rate of spine elimination. By contrast, fear extinction by repeated presentation of the same auditory cue without a footshock increases the rate of spine formation. The degrees of spine remodelling induced by fear conditioning and extinction strongly correlate with the expression and extinction of conditioned fear responses, respectively. Notably, spine elimination and formation induced by fear conditioning and extinction occur on the same dendritic branches in a cue- and location-specific manner: cue-specific extinction causes formation of dendritic spines within a distance of two micrometres from spines that were eliminated after fear conditioning. Furthermore, reconditioning preferentially induces elimination of dendritic spines that were formed after extinction. Thus, within vastly complex neuronal networks, fear conditioning, extinction and reconditioning lead to opposing changes at the level of individual synapses. These findings also suggest that fear memory traces are partially erased after extinction.
Using facial expressions as CSs and fearsome and disgusting pictures as UCSs: affective responding and evaluative learning of fear and disgust in blood-injection-injury phobia.

PubMed

Olatunji, Bunmi O; Lohr, Jeffrey M; Sawchuk, Craig N; Westendorf, David H

2005-01-01

Two experiments examine use of an evaluative conditioning (EC) paradigm in the acquisition of fear and disgust responding to neutral facial expressions. In Experiment 1, 60 participants were randomly assigned to one of three evaluative learning conditions in which neutral facial expressions were paired with fearsome, disgusting, or neutral pictures. No statistically significant differences were detected between the three conditions. However, significant differences emerged within subjects as post-exposure of fear and disgust ratings were higher among expressions that were paired with pictorial stimuli. Experiment 2 sought to examine if an analogue sample of BII phobics would be more susceptible than nonphobic controls to fear and disgust EC utilizing a similar experimental design, given the co-occurrence of fear and disgust in BII-phobic responding. Results failed to demonstrate an EC effect specific to the analogue phobic group, although both groups showed an evaluative shift toward disgust for those facial expressions paired with BII-relevant pictures. Consistent with previous findings, examination of picture rating data suggested that analogue BII phobics rated the BII pictures as significantly more disgusting than fearful. The role of EC processes and a priori expectancy biases in the associative learning of disgust in BII phobia is discussed.
Optogenetic stimulation of a hippocampal engram activates fear memory recall.

PubMed

Liu, Xu; Ramirez, Steve; Pang, Petti T; Puryear, Corey B; Govindarajan, Arvind; Deisseroth, Karl; Tonegawa, Susumu

2012-03-22

A specific memory is thought to be encoded by a sparse population of neurons. These neurons can be tagged during learning for subsequent identification and manipulation. Moreover, their ablation or inactivation results in reduced memory expression, suggesting their necessity in mnemonic processes. However, the question of sufficiency remains: it is unclear whether it is possible to elicit the behavioural output of a specific memory by directly activating a population of neurons that was active during learning. Here we show in mice that optogenetic reactivation of hippocampal neurons activated during fear conditioning is sufficient to induce freezing behaviour. We labelled a population of hippocampal dentate gyrus neurons activated during fear learning with channelrhodopsin-2 (ChR2) and later optically reactivated these neurons in a different context. The mice showed increased freezing only upon light stimulation, indicating light-induced fear memory recall. This freezing was not detected in non-fear-conditioned mice expressing ChR2 in a similar proportion of cells, nor in fear-conditioned mice with cells labelled by enhanced yellow fluorescent protein instead of ChR2. Finally, activation of cells labelled in a context not associated with fear did not evoke freezing in mice that were previously fear conditioned in a different context, suggesting that light-induced fear memory recall is context specific. Together, our findings indicate that activating a sparse but specific ensemble of hippocampal neurons that contribute to a memory engram is sufficient for the recall of that memory. Moreover, our experimental approach offers a general method of mapping cellular populations bearing memory engrams.

Optogenetic stimulation of a hippocampal engram activates fear memory recall

PubMed Central

Liu, Xu; Ramirez, Steve; Pang, Petti T.; Puryear, Corey B.; Govindarajan, Arvind; Deisseroth, Karl; Tonegawa, Susumu

2012-01-01

A specific memory is thought to be encoded by a sparse population of neurons1,2. These neurons can be tagged during learning for subsequent identification3 and manipulation4,5,6. Moreover, their ablation or inactivation results in reduced memory expression, suggesting their necessity in mnemonic processes. However, a critical question of sufficiency remains: can one elicit the behavioral output of a specific memory by directly activating a population of neurons that was active during learning? Here we show that optogenetic reactivation of hippocampal neurons activated during fear conditioning is sufficient to induce freezing behavior. We labeled a population of hippocampal dentate gyrus neurons activated during fear learning with channelrhodopsin-2 (ChR2)7,8 and later optically reactivated these neurons in a different context. The mice showed increased freezing only upon light stimulation, indicating light-induced fear memory recall. This freezing was not detected in non-fear conditioned mice expressing ChR2 in a similar proportion of cells, nor in fear conditioned mice with cells labeled by EYFP instead of ChR2. Finally, activation of cells labeled in a context not associated with fear did not evoke freezing in mice that were previously fear conditioned in a different context, suggesting that light-induced fear memory recall is context-specific. Together, our findings indicate that activating a sparse but specific ensemble of hippocampal neurons that contribute to a memory engram is sufficient for the recall of that memory. Moreover, our experimental approach offers a general method of mapping cellular populations bearing memory engrams. PMID:22441246
Learning and Judgment Can Be Affected by Predisposed Fearfulness in Laying Hens

PubMed Central

de Haas, Elske N.; Lee, Caroline; Rodenburg, T. Bas

2017-01-01

High fearfulness could disrupt learning and likely affects judgment in animals, especially when it is part of an animals’ personality, i.e., trait anxiety. Here, we tested whether high fearfulness affects discrimination learning and judgment bias (JB) in laying hens. Based on the response to an open field at 5 weeks of age, birds were categorized as fearful (FC) by showing no walking or vocalizing or non-fearful (NFC) by showing walking and vocalizing. At adult age, birds (n = 24) were trained in a go–go task to discriminate two cues (white or black) with a small or large reward. Birds that reached training criteria were exposed to three unrewarded ambiguous cues (25, 50, and 75% black) to assess JB. Task acquisition took longer for FC birds than for NFC birds, due to a left side bias, and more sessions were needed to unlearn this side bias. Changes in trial setup increased response latencies for FC birds but not for NFC birds. A larger number of FC birds than NFC birds chose optimistically in the last ambiguous trial (25% black). FC birds had a longer latency to choose in the ambiguous trial (75% black) compared to NFC birds. Prior choice in ambiguous trials and a preceding large or small trial affected latencies and choices for both types of birds. Our study showed that fearfulness was associated with differences in discrimination learning ability and JB. It appeared that FC birds used a rigid response strategy during early learning phases by choosing a specific side repeatedly irrespective of success. FC birds were more affected by changes in the setup of the trials in comparison to NFC birds. We speculate that FC birds are more sensitive to changes in environmental cues and reward expectancy. These factors could explain how high fearfulness affects learning. PMID:28798918
Cannabidiol regulation of emotion and emotional memory processing: relevance for treating anxiety-related and substance abuse disorders.

PubMed

Lee, Jonathan L C; Bertoglio, Leandro J; Guimarães, Francisco S; Stevenson, Carl W

2017-10-01

Learning to associate cues or contexts with potential threats or rewards is adaptive and enhances survival. Both aversive and appetitive memories are therefore powerful drivers of behaviour, but the inappropriate expression of conditioned responding to fear- and drug-related stimuli can develop into anxiety-related and substance abuse disorders respectively. These disorders are associated with abnormally persistent emotional memories and inadequate treatment, often leading to symptom relapse. Studies show that cannabidiol, the main non-psychotomimetic phytocannabinoid found in Cannabis sativa, reduces anxiety via 5-HT 1A and (indirect) cannabinoid receptor activation in paradigms assessing innate responses to threat. There is also accumulating evidence from animal studies investigating the effects of cannabidiol on fear memory processing indicating that it reduces learned fear in paradigms that are translationally relevant to phobias and post-traumatic stress disorder. Cannabidiol does so by reducing fear expression acutely and by disrupting fear memory reconsolidation and enhancing fear extinction, both of which can result in a lasting reduction of learned fear. Recent studies have also begun to elucidate the effects of cannabidiol on drug memory expression using paradigms with translational relevance to addiction. The findings suggest that cannabidiol reduces the expression of drug memories acutely and by disrupting their reconsolidation. Here, we review the literature demonstrating the anxiolytic effects of cannabidiol before focusing on studies investigating its effects on various fear and drug memory processes. Understanding how cannabidiol regulates emotion and emotional memory processing may eventually lead to its use as a treatment for anxiety-related and substance abuse disorders. Linked Articles This article is part of a themed section on Pharmacology of Cognition: a Panacea for Neuropsychiatric Disease? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.19/issuetoc. © 2017 The British Pharmacological Society.
Implications of memory modulation for post-traumatic stress and fear disorders

PubMed Central

Parsons, Ryan G; Ressler, Kerry J

2013-01-01

Post-traumatic stress disorder, panic disorder and phobia manifest in ways that are consistent with an uncontrollable state of fear. Their development involves heredity, previous sensitizing experiences, association of aversive events with previous neutral stimuli, and inability to inhibit or extinguish fear after it is chronic and disabling. We highlight recent progress in fear learning and memory, differential susceptibility to disorders of fear, and how these findings are being applied to the understanding, treatment and possible prevention of fear disorders. Promising advances are being translated from basic science to the clinic, including approaches to distinguish risk versus resilience before trauma exposure, methods to interfere with fear development during memory consolidation after a trauma, and techniques to inhibit fear reconsolidation and to enhance extinction of chronic fear. It is hoped that this new knowledge will translate to more successful, neuroscientifically informed and rationally designed approaches to disorders of fear regulation. PMID:23354388
5-HT2C receptors in the BNST are necessary for the enhancement of fear learning by selective serotonin reuptake inhibitors.

PubMed

Pelrine, Eliza; Pasik, Sara Diana; Bayat, Leyla; Goldschmiedt, Debora; Bauer, Elizabeth P

2016-12-01

Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed to treat anxiety and depression, yet they paradoxically increase anxiety during initial treatment. Acute administration of these drugs prior to learning can also enhance Pavlovian cued fear conditioning. This potentiation has been previously reported to depend upon the bed nucleus of the stria terminalis (BNST). Here, using temporary inactivation, we confirmed that the BNST is not necessary for the acquisition of cued or contextual fear memory. Systemic administration of the SSRI citalopram prior to fear conditioning led to an upregulation of the immediate early gene Arc (activity-regulated cytoskeleton-associated protein) in the oval nucleus of the BNST, and a majority of these neurons expressed the 5-HT2C receptor. Finally, local infusions of a 5-HT2C receptor antagonist directly into the oval nucleus of the BNST prevented the fear memory-enhancing effects of citalopram. These findings highlight the ability of the BNST circuitry to be recruited into gating fear and anxiety-like behaviors. Copyright Â© 2016 Elsevier Inc. All rights reserved.
The centrality of fear extinction in linking risk factors to PTSD: A narrative review.

PubMed

Zuj, Daniel V; Palmer, Matthew A; Lommen, Miriam J J; Felmingham, Kim L

2016-10-01

Recent prospective studies in emergency services have identified impaired fear extinction learning and memory to be a significant predictor of Posttraumatic Stress Disorder (PTSD), complementing a wealth of cross-sectional evidence of extinction deficits associated with the disorder. Additional fields of research show specific risk factors and biomarkers of the disorder, including candidate genotypes, stress and sex hormones, cognitive factors, and sleep disturbances. Studies in mostly nonclinical populations also reveal that the aforementioned factors are involved in fear extinction learning and memory. Here, we provide a comprehensive narrative review of the literature linking PTSD to these risk factors, and linking these risk factors to impaired fear extinction. On balance, the evidence suggests that fear extinction may play a role in the relationship between risk factors and PTSD. Should this notion hold true, this review carries important implications for the improvement of exposure-based treatments, as well as strategies for the implementation of treatment. Copyright © 2016 Elsevier Ltd. All rights reserved.
Attentional Bias for Uncertain Cues of Shock in Human Fear Conditioning: Evidence for Attentional Learning Theory

PubMed Central

Koenig, Stephan; Uengoer, Metin; Lachnit, Harald

2017-01-01

We conducted a human fear conditioning experiment in which three different color cues were followed by an aversive electric shock on 0, 50, and 100% of the trials, and thus induced low (L), partial (P), and high (H) shock expectancy, respectively. The cues differed with respect to the strength of their shock association (L < P < H) and the uncertainty of their prediction (L < P > H). During conditioning we measured pupil dilation and ocular fixations to index differences in the attentional processing of the cues. After conditioning, the shock-associated colors were introduced as irrelevant distracters during visual search for a shape target while shocks were no longer administered and we analyzed the cues’ potential to capture and hold overt attention automatically. Our findings suggest that fear conditioning creates an automatic attention bias for the conditioned cues that depends on their correlation with the aversive outcome. This bias was exclusively linked to the strength of the cues’ shock association for the early attentional processing of cues in the visual periphery, but additionally was influenced by the uncertainty of the shock prediction after participants fixated on the cues. These findings are in accord with attentional learning theories that formalize how associative learning shapes automatic attention. PMID:28588466
Individual differences in recovery from traumatic fear

PubMed Central

Holmes, Andrew; Singewald, Nicolas

2013-01-01

Although exposure to major psychological trauma is unfortunately common, risk for related neuropsychiatric conditions, such as post-traumatic stress disorder (PTSD), varies greatly among individuals. Fear extinction offers a tractable and translatable behavioral readout of individual differences in learned recovery from trauma. Studies in rodent substrains and subpopulations are providing new insights into neural system dysfunctions associated with impaired fear extinction. Rapid progress is also being made in identifying key molecular circuits, epigenetic mechanisms, and gene variants associated with differences in fear extinction. Here, we discuss how this research is informing understanding of the etiology and pathophysiology of individual differences in risk for trauma-related anxiety disorders, and how future work can help identify novel diagnostic biomarkers and pharmacotherapeutics for these disorders. PMID:23260015
In the Blink of an Eye: Investigating the Role of Awareness in Fear Responding by Measuring the Latency of Startle Potentiation

PubMed Central

Åsli, Ole; Flaten, Magne A.

2012-01-01

The latency of startle reflex potentiation may shed light on the aware and unaware processes underlying associative learning, especially associative fear learning. We review research suggesting that single-cue delay classical conditioning is independent of awareness of the contingency between the conditioned stimulus (CS) and the unconditioned stimulus (US). Moreover, we discuss research that argues that conditioning independent of awareness has not been proven. Subsequently, three studies from our lab are presented that have investigated the role of awareness in classical conditioning, by measuring the minimum latency from CS onset to observed changes in reflexive behavior. In sum, research using this method shows that startle is potentiated 30 to 100 ms after CS onset following delay conditioning. Following trace fear conditioning, startle is potentiated 1500 ms after CS presentation. These results indicate that the process underlying delay conditioned responding is independent of awareness, and that trace fear conditioned responding is dependent on awareness. Finally, this method of investigating the role of awareness is discussed and future research possibilities are proposed. PMID:24962686
Enhancing dopaminergic signaling and histone acetylation promotes long-term rescue of deficient fear extinction

PubMed Central

Whittle, N; Maurer, V; Murphy, C; Rainer, J; Bindreither, D; Hauschild, M; Scharinger, A; Oberhauser, M; Keil, T; Brehm, C; Valovka, T; Striessnig, J; Singewald, N

2016-01-01

Extinction-based exposure therapy is used to treat anxiety- and trauma-related disorders; however, there is the need to improve its limited efficacy in individuals with impaired fear extinction learning and to promote greater protection against return-of-fear phenomena. Here, using 129S1/SvImJ mice, which display impaired fear extinction acquisition and extinction consolidation, we revealed that persistent and context-independent rescue of deficient fear extinction in these mice was associated with enhanced expression of dopamine-related genes, such as dopamine D1 (Drd1a) and -D2 (Drd2) receptor genes in the medial prefrontal cortex (mPFC) and amygdala, but not hippocampus. Moreover, enhanced histone acetylation was observed in the promoter of the extinction-regulated Drd2 gene in the mPFC, revealing a potential gene-regulatory mechanism. Although enhancing histone acetylation, via administering the histone deacetylase (HDAC) inhibitor MS-275, does not induce fear reduction during extinction training, it promoted enduring and context-independent rescue of deficient fear extinction consolidation/retrieval once extinction learning was initiated as shown following a mild conditioning protocol. This was associated with enhanced histone acetylation in neurons of the mPFC and amygdala. Finally, as a proof-of-principle, mimicking enhanced dopaminergic signaling by L-dopa treatment rescued deficient fear extinction and co-administration of MS-275 rendered this effect enduring and context-independent. In summary, current data reveal that combining dopaminergic and epigenetic mechanisms is a promising strategy to improve exposure-based behavior therapy in extinction-impaired individuals by initiating the formation of an enduring and context-independent fear-inhibitory memory. PMID:27922638
Strain-dependent Effects of Acute, Chronic, and Withdrawal from Chronic Nicotine on Fear Conditioning

PubMed Central

Portugal, George S.; Wilkinson, Derek S.; Kenney, Justin W.; Sullivan, Colleen

2013-01-01

The effects of nicotine on cognitive processes such as learning and memory may play an important role in the addictive liability of tobacco. However, it remains unknown whether genetic variability modulates the effects of nicotine on learning and memory. The present study characterized the effects of acute, chronic, and withdrawal from chronic nicotine administration on fear conditioning, somatic signs, and the elevated plus maze in 8 strains of inbred mice. Strain-dependent effects of acute nicotine and nicotine withdrawal on contextual fear conditioning, somatic signs, and the elevated plus maze were observed, but no association between the effects of acute nicotine and nicotine withdrawal on contextual fear conditioning were observed, suggesting that different genetic substrates may mediate these effects. The identification of genetic factors that may alter the effects of nicotine on cognition may lead to more efficacious treatments for nicotine addiction. PMID:21822688
Altered neural encoding of prediction errors in assault-related posttraumatic stress disorder.

PubMed

Ross, Marisa C; Lenow, Jennifer K; Kilts, Clinton D; Cisler, Josh M

2018-05-12

Posttraumatic stress disorder (PTSD) is widely associated with deficits in extinguishing learned fear responses, which relies on mechanisms of reinforcement learning (e.g., updating expectations based on prediction errors). However, the degree to which PTSD is associated with impairments in general reinforcement learning (i.e., outside of the context of fear stimuli) remains poorly understood. Here, we investigate brain and behavioral differences in general reinforcement learning between adult women with and without a current diagnosis of PTSD. 29 adult females (15 PTSD with exposure to assaultive violence, 14 controls) underwent a neutral reinforcement-learning task (i.e., two arm bandit task) during fMRI. We modeled participant behavior using different adaptations of the Rescorla-Wagner (RW) model and used Independent Component Analysis to identify timecourses for large-scale a priori brain networks. We found that an anticorrelated and risk sensitive RW model best fit participant behavior, with no differences in computational parameters between groups. Women in the PTSD group demonstrated significantly less neural encoding of prediction errors in both a ventral striatum/mPFC and anterior insula network compared to healthy controls. Weakened encoding of prediction errors in the ventral striatum/mPFC and anterior insula during a general reinforcement learning task, outside of the context of fear stimuli, suggests the possibility of a broader conceptualization of learning differences in PTSD than currently proposed in current neurocircuitry models of PTSD. Copyright © 2018 Elsevier Ltd. All rights reserved.
The hypocretin/orexin system mediates the extinction of fear memories.

PubMed

Flores, África; Valls-Comamala, Victòria; Costa, Giulia; Saravia, Rocío; Maldonado, Rafael; Berrendero, Fernando

2014-11-01

Anxiety disorders are often associated with an inability to extinguish learned fear responses. The hypocretin/orexin system is involved in the regulation of emotional states and could also participate in the consolidation and extinction of aversive memories. Using hypocretin receptor-1 and hypocretin receptor-2 antagonists, hypocretin-1 and hypocretin-2 peptides, and hypocretin receptor-1 knockout mice, we investigated the role of the hypocretin system in cue- and context-dependent fear conditioning and extinction. Hypocretins were crucial for the consolidation of fear conditioning, and this effect was mainly observed in memories with a high emotional component. Notably, after the acquisition of fear memory, hypocretin receptor-1 blockade facilitated fear extinction, whereas hypocretin-1 administration impaired this extinction process. The extinction-facilitating effects of the hypocretin receptor-1 antagonist SB334867 were associated with increased expression of cFos in the basolateral amygdala and the infralimbic cortex. Intra-amygdala, but neither intra-infralimbic prefrontal cortex nor intra-dorsohippocampal infusion of SB334867 enhanced fear extinction. These results reveal a key role for hypocretins in the extinction of aversive memories and suggest that hypocretin receptor-1 blockade could represent a novel therapeutic target for the treatment of diseases associated with inappropriate retention of fear, such as post-traumatic stress disorder and phobias.
The Hypocretin/Orexin System Mediates the Extinction of Fear Memories

PubMed Central

Flores, África; Valls-Comamala, Victòria; Costa, Giulia; Saravia, Rocío; Maldonado, Rafael; Berrendero, Fernando

2014-01-01

Anxiety disorders are often associated with an inability to extinguish learned fear responses. The hypocretin/orexin system is involved in the regulation of emotional states and could also participate in the consolidation and extinction of aversive memories. Using hypocretin receptor-1 and hypocretin receptor-2 antagonists, hypocretin-1 and hypocretin-2 peptides, and hypocretin receptor-1 knockout mice, we investigated the role of the hypocretin system in cue- and context-dependent fear conditioning and extinction. Hypocretins were crucial for the consolidation of fear conditioning, and this effect was mainly observed in memories with a high emotional component. Notably, after the acquisition of fear memory, hypocretin receptor-1 blockade facilitated fear extinction, whereas hypocretin-1 administration impaired this extinction process. The extinction-facilitating effects of the hypocretin receptor-1 antagonist SB334867 were associated with increased expression of cFos in the basolateral amygdala and the infralimbic cortex. Intra-amygdala, but neither intra-infralimbic prefrontal cortex nor intra-dorsohippocampal infusion of SB334867 enhanced fear extinction. These results reveal a key role for hypocretins in the extinction of aversive memories and suggest that hypocretin receptor-1 blockade could represent a novel therapeutic target for the treatment of diseases associated with inappropriate retention of fear, such as post-traumatic stress disorder and phobias. PMID:24930888
Gene networks associated with conditional fear in mice identified using a systems genetics approach

PubMed Central

2011-01-01

Background Our understanding of the genetic basis of learning and memory remains shrouded in mystery. To explore the genetic networks governing the biology of conditional fear, we used a systems genetics approach to analyze a hybrid mouse diversity panel (HMDP) with high mapping resolution. Results A total of 27 behavioral quantitative trait loci were mapped with a false discovery rate of 5%. By integrating fear phenotypes, transcript profiling data from hippocampus and striatum and also genotype information, two gene co-expression networks correlated with context-dependent immobility were identified. We prioritized the key markers and genes in these pathways using intramodular connectivity measures and structural equation modeling. Highly connected genes in the context fear modules included Psmd6, Ube2a and Usp33, suggesting an important role for ubiquitination in learning and memory. In addition, we surveyed the architecture of brain transcript regulation and demonstrated preservation of gene co-expression modules in hippocampus and striatum, while also highlighting important differences. Rps15a, Kif3a, Stard7, 6330503K22RIK, and Plvap were among the individual genes whose transcript abundance were strongly associated with fear phenotypes. Conclusion Application of our multi-faceted mapping strategy permits an increasingly detailed characterization of the genetic networks underlying behavior. PMID:21410935
Fear Conditioning is Disrupted by Damage to the Postsubiculum

PubMed Central

Robinson, Siobhan; Bucci, David J.

2011-01-01

The hippocampus plays a central role in spatial and contextual learning and memory, however relatively little is known about the specific contributions of parahippocampal structures that interface with the hippocampus. The postsubiculum (PoSub) is reciprocally connected with a number of hippocampal, parahippocampal and subcortical structures that are involved in spatial learning and memory. In addition, behavioral data suggest that PoSub is needed for optimal performance during tests of spatial memory. Together, these data suggest that PoSub plays a prominent role in spatial navigation. Currently it is unknown whether the PoSub is needed for other forms of learning and memory that also require the formation of associations among multiple environmental stimuli. To address this gap in the literature we investigated the role of PoSub in Pavlovian fear conditioning. In Experiment 1 male rats received either lesions of PoSub or Sham surgery prior to training in a classical fear conditioning procedure. On the training day a tone was paired with foot shock three times. Conditioned fear to the training context was evaluated 24 hr later by placing rats back into the conditioning chamber without presenting any tones or shocks. Auditory fear was assessed on the third day by presenting the auditory stimulus in a novel environment (no shock). PoSub-lesioned rats exhibited impaired acquisition of the conditioned fear response as well as impaired expression of contextual and auditory fear conditioning. In Experiment 2, PoSub lesions were made 1 day after training to specifically assess the role of PoSub in fear memory. No deficits in the expression of contextual fear were observed, but freezing to the tone was significantly reduced in PoSub-lesioned rats compared to shams. Together, these results indicate that PoSub is necessary for normal acquisition of conditioned fear, and that PoSub contributes to the expression of auditory but not contextual fear memory. PMID:22076971
Associations between feeling and judging the emotions of happiness and fear: findings from a large-scale field experiment.

PubMed

Buchanan, Tony W; Bibas, David; Adolphs, Ralph

2010-05-14

How do we recognize emotions from other people? One possibility is that our own emotional experiences guide us in the online recognition of emotion in others. A distinct but related possibility is that emotion experience helps us to learn how to recognize emotions in childhood. We explored these ideas in a large sample of people (N = 4,608) ranging from 5 to over 50 years old. Participants were asked to rate the intensity of emotional experience in their own lives, as well as to perform a task of facial emotion recognition. Those who reported more intense experience of fear and happiness were significantly more accurate (closer to prototypical) in recognizing facial expressions of fear and happiness, respectively, and intense experience of fear was associated also with more accurate recognition of surprised and happy facial expressions. The associations held across all age groups. These results suggest that the intensity of one's own emotional experience of fear and happiness correlates with the ability to recognize these emotions in others, and demonstrate such an association as early as age 5.
Stress hormones are associated with the neuronal correlates of instructed fear conditioning.

PubMed

Merz, Christian Josef; Stark, Rudolf; Vaitl, Dieter; Tabbert, Katharina; Wolf, Oliver Tobias

2013-01-01

The effects of sex and stress hormones on classical fear conditioning have been subject of recent experimental studies. A correlation approach between basal cortisol concentrations and neuronal activation in fear-related structures seems to be a promising alternative approach in order to foster our understanding of how cortisol influences emotional learning. In this functional magnetic resonance imaging study, participants with varying sex hormone status (20 men, 15 women taking oral contraceptives, 15 women tested in the luteal phase) underwent an instructed fear conditioning protocol with geometrical figures as conditioned stimuli and an electrical stimulation as unconditioned stimulus. Salivary cortisol concentrations were measured and afterwards correlated with fear conditioned brain responses. Results revealed a positive correlation between basal cortisol levels and differential activation in the amygdala in men and OC women only. These results suggest that elevated endogenous cortisol levels are associated with enhanced fear anticipation depending on current sex hormone availability. Copyright © 2012 Elsevier B.V. All rights reserved.
Fear learning circuitry is biased toward generalization of fear associations in posttraumatic stress disorder

PubMed Central

Morey, R A; Dunsmoor, J E; Haswell, C C; Brown, V M; Vora, A; Weiner, J; Stjepanovic, D; Wagner, H R; Brancu, Mira; Marx, Christine E; Naylor, Jennifer C; Van Voorhees, Elizabeth; Taber, Katherine H; Beckham, Jean C; Calhoun, Patrick S; Fairbank, John A; Szabo, Steven T; LaBar, K S

2015-01-01

Fear conditioning is an established model for investigating posttraumatic stress disorder (PTSD). However, symptom triggers may vaguely resemble the initial traumatic event, differing on a variety of sensory and affective dimensions. We extended the fear-conditioning model to assess generalization of conditioned fear on fear processing neurocircuitry in PTSD. Military veterans (n=67) consisting of PTSD (n=32) and trauma-exposed comparison (n=35) groups underwent functional magnetic resonance imaging during fear conditioning to a low fear-expressing face while a neutral face was explicitly unreinforced. Stimuli that varied along a neutral-to-fearful continuum were presented before conditioning to assess baseline responses, and after conditioning to assess experience-dependent changes in neural activity. Compared with trauma-exposed controls, PTSD patients exhibited greater post-study memory distortion of the fear-conditioned stimulus toward the stimulus expressing the highest fear intensity. PTSD patients exhibited biased neural activation toward high-intensity stimuli in fusiform gyrus (P<0.02), insula (P<0.001), primary visual cortex (P<0.05), locus coeruleus (P<0.04), thalamus (P<0.01), and at the trend level in inferior frontal gyrus (P=0.07). All regions except fusiform were moderated by childhood trauma. Amygdala–calcarine (P=0.01) and amygdala–thalamus (P=0.06) functional connectivity selectively increased in PTSD patients for high-intensity stimuli after conditioning. In contrast, amygdala–ventromedial prefrontal cortex (P=0.04) connectivity selectively increased in trauma-exposed controls compared with PTSD patients for low-intensity stimuli after conditioning, representing safety learning. In summary, fear generalization in PTSD is biased toward stimuli with higher emotional intensity than the original conditioned-fear stimulus. Functional brain differences provide a putative neurobiological model for fear generalization whereby PTSD symptoms are triggered by threat cues that merely resemble the index trauma. PMID:26670285
Persistent Prelimbic Cortex Activity Contributes to Enhanced Learned Fear Expression in Females

ERIC Educational Resources Information Center

Fenton, Georgina E.; Pollard, Amelia K.; Halliday, David M.; Mason, Rob; Bredy, Timothy W.; Stevenson, Carl W.

2014-01-01

Anxiety disorders, such as post-traumatic stress, are more prevalent in women and are characterized by impaired inhibition of learned fear and medial prefrontal cortex (mPFC) dysfunction. Here we examined sex differences in fear extinction and mPFC activity in rats. Females showed more learned fear expression during extinction and its recall, but…

Impairment of contextual fear extinction by chronic nicotine and withdrawal from chronic nicotine is associated with hippocampal nAChR upregulation

PubMed Central

Kutlu, Munir Gunes; Oliver, Chicora; Huang, Peng; Liu-Chen, Lee-Yuan; Gould, Thomas J.

2017-01-01

Chronic nicotine and withdrawal from chronic nicotine have been shown to be major modulators of fear learning behavior. Moreover, recent studies from our laboratory have shown that acute nicotine impaired fear extinction and safety learning in mice. However, the effects of chronic nicotine and withdrawal on fear extinction are unknown. Therefore, the current experiments were conducted to investigate the effects of chronic nicotine as well as withdrawal from chronic nicotine on contextual fear extinction in mice. C57BL6/J mice were given contextual fear conditioning training and retention testing during chronic nicotine administration. Mice then received contextual fear extinction either during chronic nicotine or during withdrawal from chronic nicotine. Our results showed that contextual fear extinction was impaired both during chronic nicotine administration and subsequent withdrawal. However, it was also observed that the effects of prior chronic nicotine disappeared after 72 h in withdrawal, a timeline that closely matches with the timing of the chronic nicotine-induced upregulation of hippocampal nicotinic acetylcholine receptor (nAChR) density. Additional experiments found that 4 days, but not 1 day, of continuous nicotine administration upregulated hippocampal nAChRs and impaired contextual fear extinction. These effects disappeared following 72 h withdrawal. Overall, these experiments provide a potential link between nicotine-induced upregulation of hippocampal nAChRs and fear extinction deficits observed in patients with anxiety disorders, which may lead to advancements in the pharmacological treatment methods for this disorder. PMID:27378334
Animal models of fear relapse.

PubMed

Goode, Travis D; Maren, Stephen

2014-01-01

Whereas fear memories are rapidly acquired and enduring over time, extinction memories are slow to form and are susceptible to disruption. Consequently, behavioral therapies that involve extinction learning (e.g., exposure therapy) often produce only temporary suppression of fear and anxiety. This review focuses on the factors that are known to influence the relapse of extinguished fear. Several phenomena associated with the return of fear after extinction are discussed, including renewal, spontaneous recovery, reacquisition, and reinstatement. Additionally, this review describes recent work, which has focused on the role of psychological stress in the relapse of extinguished fear. Recent developments in behavioral and pharmacological research are examined in light of treatment of pathological fear in humans. © The Author 2014. Published by Oxford University Press on behalf of the Institute for Laboratory Animal Research. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
Reduced autobiographical memory specificity is associated with impaired discrimination learning in anxiety disorder patients

PubMed Central

Lenaert, Bert; Boddez, Yannick; Vervliet, Bram; Schruers, Koen; Hermans, Dirk

2015-01-01

Associative learning plays an important role in the development of anxiety disorders, but a thorough understanding of the variables that impact such learning is still lacking. We investigated whether individual differences in autobiographical memory specificity are related to discrimination learning and generalization. In an associative learning task, participants learned the association between two pictures of female faces and a non-aversive outcome. Subsequently, six morphed pictures functioning as generalization stimuli (GSs) were introduced. In a sample of healthy participants (Study 1), we did not find evidence for differences in discrimination learning as a function of memory specificity. In a sample of anxiety disorder patients (Study 2), individuals who were characterized by low memory specificity showed deficient discrimination learning relative to high specific individuals. In contrast to previous findings, results revealed no effect of memory specificity on generalization. These results indicate that impaired discrimination learning, previously shown in patients suffering from an anxiety disorder, may be—in part—due to limited memory specificity. Together, these studies emphasize the importance of incorporating cognitive variables in associative learning theories and their implications for the development of anxiety disorders. In addition, re-analyses of the data (Study 3) showed that patients suffering from panic disorder showed higher outcome expectancies in the presence of the stimulus that was never followed by an outcome during discrimination training, relative to patients suffering from other anxiety disorders and healthy participants. Because we used a neutral, non-aversive outcome (i.e., drawing of a lightning bolt), these data suggest that learning abnormalities in panic disorder may not be restricted to fear learning, but rather reflect a more general associative learning deficit that also manifests in fear irrelevant contexts. PMID:26191015
Infralimbic EphB2 Modulates Fear Extinction in Adolescent Rats

PubMed Central

Cruz, Emmanuel; Soler-Cedeño, Omar; Negrón, Geovanny; Criado-Marrero, Marangelie; Chompré, Gladys

2015-01-01

Adolescent rats are prone to impaired fear extinction, suggesting that mechanistic differences in extinction could exist in adolescent and adult rats. Since the infralimbic cortex (IL) is critical for fear extinction, we used PCR array technology to identify gene expression changes in IL induced by fear extinction in adolescent rats. Interestingly, the ephrin type B receptor 2 (EphB2), a tyrosine kinase receptor associated with synaptic development, was downregulated in IL after fear extinction. Consistent with the PCR array results, EphB2 levels of mRNA and protein were reduced in IL after fear extinction compared with fear conditioning, suggesting that EphB2 signaling in IL regulates fear extinction memory in adolescents. Finally, reducing EphB2 synthesis in IL with shRNA accelerated fear extinction learning in adolescent rats, but not in adult rats. These findings identify EphB2 in IL as a key regulator of fear extinction during adolescence, perhaps due to the increase in synaptic remodeling occurring during this developmental phase. PMID:26354908
Fear conditioning to subliminal fear relevant and non fear relevant stimuli.

PubMed

Lipp, Ottmar V; Kempnich, Clare; Jee, Sang Hoon; Arnold, Derek H

2014-01-01

A growing body of evidence suggests that conscious visual awareness is not a prerequisite for human fear learning. For instance, humans can learn to be fearful of subliminal fear relevant images--images depicting stimuli thought to have been fear relevant in our evolutionary context, such as snakes, spiders, and angry human faces. Such stimuli could have a privileged status in relation to manipulations used to suppress usually salient images from awareness, possibly due to the existence of a designated sub-cortical 'fear module'. Here we assess this proposition, and find it wanting. We use binocular masking to suppress awareness of images of snakes and wallabies (particularly cute, non-threatening marsupials). We find that subliminal presentations of both classes of image can induce differential fear conditioning. These data show that learning, as indexed by fear conditioning, is neither contingent on conscious visual awareness nor on subliminal conditional stimuli being fear relevant.
Have we met before? Neural correlates of emotional learning in women with social phobia.

PubMed

Laeger, Inga; Keuper, Kati; Heitmann, Carina; Kugel, Harald; Dobel, Christian; Eden, Annuschka; Arolt, Volker; Zwitserlood, Pienie; Dannlowski, Udo; Zwanzger, Peter

2014-05-01

Altered memory processes are thought to be a key mechanism in the etiology of anxiety disorders, but little is known about the neural correlates of fear learning and memory biases in patients with social phobia. The present study therefore examined whether patients with social phobia exhibit different patterns of neural activation when confronted with recently acquired emotional stimuli. Patients with social phobia and a group of healthy controls learned to associate pseudonames with pictures of persons displaying either a fearful or a neutral expression. The next day, participants read the pseudonames in the magnetic resonance imaging scanner. Afterwards, 2 memory tests were carried out. We enrolled 21 patients and 21 controls in our study. There were no group differences for learning performance, and results of the memory tests were mixed. On a neural level, patients showed weaker amygdala activation than controls for the contrast of names previously associated with fearful versus neutral faces. Social phobia severity was negatively related to amygdala activation. Moreover, a detailed psychophysiological interaction analysis revealed an inverse correlation between disorder severity and frontolimbic connectivity for the emotional > neutral pseudonames contrast. Our sample included only women. Our results support the theory of a disturbed cortico limbic interplay, even for recently learned emotional stimuli. We discuss the findings with regard to the vigilance-avoidance theory and contrast them to results indicating an oversensitive limbic system in patients with social phobia.
A ghrelin-growth hormone axis drives stress-induced vulnerability to enhanced fear

PubMed Central

Meyer, Retsina M.; Burgos-Robles, Anthony; Liu, Elizabeth; Correia, Susana S.; Goosens, Ki A.

2014-01-01

Hormones in the hypothalamus-pituitary-adrenal (HPA) axis mediate many of the bodily responses to stressors, yet there is not a clear relationship between the levels of these hormones and stress-associated mental illnesses such as post-traumatic stress disorder (PTSD). Therefore, other hormones are likely to be involved in this effect of stress. Here we used a rodent model of PTSD in which rats repeatedly exposed to a stressor display heightened fear learning following auditory Pavlovian fear conditioning. Our results show that stress-related increases in circulating ghrelin, a peptide hormone, are necessary and sufficient for stress-associated vulnerability to exacerbated fear learning and these actions of ghrelin occur in the amygdala. Importantly, these actions are also independent of the classic HPA stress axis. Repeated systemic administration of a ghrelin receptor agonist enhanced fear memory but did not increase either corticotropin releasing factor (CRF) or corticosterone. Repeated intra-amygdala infusion of a ghrelin receptor agonist produced a similar enhancement of fear memory. Ghrelin receptor antagonism during repeated stress abolished stress-related enhancement of fear memory without blunting stress-induced corticosterone release. We also examined links between ghrelin and growth hormone (GH), a major downstream effector of the ghrelin receptor. GH protein was upregulated in the amygdala following chronic stress, and its release from amygdala neurons was increased by ghrelin receptor stimulation. Virus-mediated overexpression of GH in the amygdala was also sufficient to increase fear. Finally, virus-mediated overexpression of a GH receptor antagonist was sufficient to block the fear enhancing effects of repeated ghrelin receptor stimulation. Thus, ghrelin requires GH in the amygdala to exert fear-enhancing effects. These results suggest that ghrelin mediates a novel branch of the stress response and highlight a previously unrecognized role for ghrelin and growth hormone in maladaptive changes following prolonged stress. PMID:24126924
Caloric restriction enhances fear extinction learning in mice.

PubMed

Riddle, Megan C; McKenna, Morgan C; Yoon, Yone J; Pattwell, Siobhan S; Santos, Patricia Mae G; Casey, B J; Glatt, Charles E

2013-05-01

Fear extinction learning, the ability to reassess a learned cue of danger as safe when it no longer predicts aversive events, is often dysregulated in anxiety disorders. Selective serotonin reuptake inhibitors (SSRI's) enhance neural plasticity and their ability to enhance fear extinction learning may explain their anxiolytic properties. Caloric restriction (CR) has SSRI-like effects on neural plasticity and anxiety-related behavior. We implemented CR in mice to determine its effects on conditioned-fear responses. Wild type and serotonin transporter (SERT) knockout mice underwent CR for 7 days leading to significant weight loss. Mice were then tested for cued fear learning and anxiety-related behavior. CR markedly enhanced fear extinction learning and its retention in adolescent female mice, and adults of both sexes. These effects of CR were absent in SERT knockout mice. Moreover, CR phenocopied behavioral and molecular effects of chronic fluoxetine, but there was no additive effect of CR in fluoxetine-treated mice. These results demonstrate that CR enhances fear extinction learning through a SERT-dependent mechanism. These results may have implications for eating disorders such as anorexia nervosa (AN), in which there is a high prevalence of anxiety before the onset of dietary restriction and support proposals that in AN, CR is a motivated effort to control dysregulated fear responses and elevated anxiety.
A twin study of the genetics of fear conditioning.

PubMed

Hettema, John M; Annas, Peter; Neale, Michael C; Kendler, Kenneth S; Fredrikson, Mats

2003-07-01

Fear conditioning is a traditional model for the acquisition of fears and phobias. Studies of the genetic architecture of fear conditioning may inform gene-finding strategies for anxiety disorders. The objective of this study was to determine the genetic and environmental sources of individual differences in fear conditioning by means of a twin sample. Classic fear conditioning data were experimentally obtained from 173 same-sex twin pairs (90 monozygotic and 83 dizygotic). Sequences of evolutionary fear-relevant (snakes and spiders) and fear-irrelevant (circles and triangles) pictorial stimuli served as conditioned stimuli paired with a mild electric shock serving as the unconditioned stimulus. The outcome measure was the electrodermal skin conductance response. We applied structural equation modeling methods to the 3 conditioning phases of habituation, acquisition, and extinction to determine the extent to which genetic and environmental factors underlie individual variation in associative and nonassociative learning. All components of the fear conditioning process in humans demonstrated moderate heritability, in the range of 35% to 45%. Best-fitting multivariate models suggest that 2 sets of genes may underlie the trait of fear conditioning: one that most strongly affects nonassociative processes of habituation that also is shared with acquisition and extinction, and a second that appears related to associative fear conditioning processes. In addition, these data provide tentative evidence of differences in heritability based on the fear relevance of the stimuli. Genes represent a significant source of individual variation in the habituation, acquisition, and extinction of fears, and genetic effects specific to fear conditioning are involved.
Developmental regulation of fear learning and anxiety behavior by endocannabinoids

PubMed Central

Lee, Tiffany T.-Y.; Hill, Matthew N.; Lee, Francis S.

2015-01-01

The developing brain undergoes substantial maturation into adulthood and the development of specific neural structures occurs on differing timelines. Transient imbalances between developmental trajectories of corticolimbic structures, which are known to contribute to regulation over fear learning and anxiety, can leave an individual susceptible to mental illness, particularly anxiety disorders. There is a substantial body of literature indicating that the endocannabinoid system critically regulates stress responsivity and emotional behavior throughout the life span, making this system a novel therapeutic target for stress- and anxiety-related disorders. During early life and adolescence, corticolimbic endocannabinoid signaling changes dynamically and coincides with different sensitive periods of fear learning, suggesting that endocannabinoid signaling underlies age-specific fear learning responses. Moreover, perturbations to these normative fluctuations in corticolimbic endocannabinoid signaling, such as stress or cannabinoid exposure, could serve as a neural substrate contributing to alterations to the normative developmental trajectory of neural structures governing emotional behavior and fear learning. In this review, we first introduce the components of the endocannabinoid system and discuss clinical and rodent models demonstrating endocannabinoid regulation of fear learning and anxiety in adulthood. Next, we highlight distinct fear learning and regulation profiles throughout development and discuss the ontogeny of the endocannabinoid system in the central nervous system, and models of pharmacological augmentation of endocannabinoid signaling during development in the context of fear learning and anxiety. PMID:26419643
Enhancing exposure therapy for anxiety disorders with glucocorticoids: from basic mechanisms of emotional learning to clinical applications.

PubMed

Bentz, Dorothée; Michael, Tanja; de Quervain, Dominique J-F; Wilhelm, Frank H

2010-03-01

Current neurophysiological and psychological accounts view exposure therapy as the clinical analog of extinction learning that results in persistent modifications of the fear memory involved in the pathogenesis, symptomatology, and maintenance of anxiety disorders. Evidence from studies in animals and humans indicate that glucocorticoids have the potential to facilitate the processes that underlie extinction learning during exposure therapy. Particularly, glucocorticoids can restrict retrieval of previous aversive learning episodes and enhance consolidation of memory traces relating to non-fearful responding in feared situations. Thus, glucocorticoid treatment especially in combination with exposure therapy might be a promising approach to optimize treatment of anxiety disorders. This review examines the processes involved in aversive conditioning, fear learning and fear extinction, and how glucocorticoids might enhance restructuring of fear memories during therapy. Copyright 2009 Elsevier Ltd. All rights reserved.
Central Ghrelin Resistance Permits the Overconsolidation of Fear Memory.

PubMed

Harmatz, Elia S; Stone, Lauren; Lim, Seh Hong; Lee, Graham; McGrath, Anna; Gisabella, Barbara; Peng, Xiaoyu; Kosoy, Eliza; Yao, Junmei; Liu, Elizabeth; Machado, Nuno J; Weiner, Veronica S; Slocum, Warren; Cunha, Rodrigo A; Goosens, Ki A

2017-06-15

There are many contradictory findings about the role of the hormone ghrelin in aversive processing, with studies suggesting that ghrelin signaling can both inhibit and enhance aversion. Here, we characterize and reconcile the paradoxical role of ghrelin in the acquisition of fearful memories. We used enzyme-linked immunosorbent assay to measure endogenous acyl-ghrelin and corticosterone at time points surrounding auditory fear learning. We used pharmacological (systemic and intra-amygdala) manipulations of ghrelin signaling and examined several aversive and appetitive behaviors. We also used biotin-labeled ghrelin to visualize ghrelin binding sites in coronal brain sections of amygdala. All work was performed in rats. In unstressed rodents, endogenous peripheral acyl-ghrelin robustly inhibits fear memory consolidation through actions in the amygdala and accounts for virtually all interindividual variability in long-term fear memory strength. Higher levels of endogenous ghrelin after fear learning were associated with weaker long-term fear memories, and pharmacological agonism of the ghrelin receptor during the memory consolidation period reduced fear memory strength. These fear-inhibitory effects cannot be explained by changes in appetitive behavior. In contrast, we show that chronic stress, which increases both circulating endogenous acyl-ghrelin and fear memory formation, promotes profound loss of ghrelin binding sites in the amygdala and behavioral insensitivity to ghrelin receptor agonism. These studies provide a new link between stress, a novel type of metabolic resistance, and vulnerability to excessive fear memory formation and reveal that ghrelin can regulate negative emotionality in unstressed animals without altering appetite. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
Executive functions deficits impair extinction of generalization of fear of movement-related pain.

PubMed

Niederstrasser, N G; Meulders, A; Meulders, M; Struyf, D; Vlaeyen, J W

2017-05-01

Generalization of fear of movement-related pain across novel but similar movements can lead to fear responses to movements that are actually not associated with pain. The peak-shift effect describes a phenomenon whereby particular novel movements elicit even greater fear responses than the original pain-provoking movement (CS+), because they represent a more extreme version of the CS+. There is great variance in the propensity to generalize as well as the speed of extinction learning when these novel movements are not followed by pain. It can be argued that this variance may be associated with executive function capacity, as individuals may be unable to intentionally inhibit fear responses. This study examined whether executive function capacity contributes to generalization and extinction of generalization as well as peak-shift of conditioned fear of movement-related pain and expectancy. Healthy participants performed a proprioceptive fear conditioning task. Executive function tests assessing updating, switching, and inhibition were used to predict changes in (extinction of) fear of movement-related pain and pain expectancy generalization. Low inhibitory capacity was associated with slower extinction of generalized fear of movement-related pain and pain expectancy. Evidence was found in favor of an area-shift, rather than a peak-shift effect, which implies that the peak conditioned fear response extended to, but did not shift to a novel stimulus. Participants with low inhibitory capacity may have difficulties withholding fear responses, leading to a slower decrease of generalized fear over time. The findings may be relevant to inform treatments. Low inhibitory capacity is not associated with slower generalization, but extinction of fear generalization. Fear elicited by a novel safe movement, situated outside the CS+/- continuum on the CS+ side, can be as strong as to the original stimulus predicting the pain-onset. © 2017 European Pain Federation - EFIC®.
Posterior insular cortex is necessary for conditioned inhibition of fear

PubMed Central

Foilb, Allison R.; Flyer-Adams, Johanna G.; Maier, Steven F.; Christianson, John P.

2016-01-01

Veridical detection of safety versus danger is critical to survival. Learned signals for safety inhibit fear, and so when presented, reduce fear responses produced by danger signals. This phenomenon is termed conditioned inhibition of fear. Here, we report that CS+/CS− fear discrimination conditioning over 5 days in rats leads the CS− to become a conditioned inhibitor of fear, as measured by the classic tests of conditioned inhibition: summation and retardation of subsequent fear acquisition. We then show that NMDA-receptor antagonist AP5 injected to posterior insular cortex (IC) before training completely prevented the acquisition of a conditioned fear inhibitor, while intra-AP5 to anterior and medial IC had no effect. To determine if the IC contributes to the recall of learned fear inhibition, injections of the GABAA agonist muscimol were made to posterior IC before a summation test. This resulted in fear inhibition per se, which obscured inference to the effect of IC inactivation with recall of the safety cue. Control experiments sought to determine if the role of the IC in conditioned inhibition learning could be reduced to simpler fear discrimination function, but fear discrimination and recall were unaffected by AP5 or muscmiol, respectively, in the posterior IC. These data implicate a role of posterior IC in the learning of conditioned fear inhibitors. PMID:27523750
The strength of aversive and appetitive associations and maladaptive behaviors.

PubMed

Itzhak, Yossef; Perez-Lanza, Daniel; Liddie, Shervin

2014-08-01

Certain maladaptive behaviors are thought to be acquired through classical Pavlovian conditioning. Exaggerated fear response, which can develop through Pavlovian conditioning, is associated with acquired anxiety disorders such as post-traumatic stress disorders (PTSDs). Inflated reward-seeking behavior, which develops through Pavlovian conditioning, underlies some types of addictive behavior (e.g., addiction to drugs, food, and gambling). These maladaptive behaviors are dependent on associative learning and the development of long-term memory (LTM). In animal models, an aversive reinforcer (fear conditioning) encodes an aversive contextual and cued LTM. On the other hand, an appetitive reinforcer results in conditioned place preference (CPP) that encodes an appetitive contextual LTM. The literature on weak and strong associative learning pertaining to the development of aversive and appetitive LTM is relatively scarce; thus, this review is particularly focused on the strength of associative learning. The strength of associative learning is dependent on the valence of the reinforcer and the salience of the conditioned stimulus that ultimately sways the strength of the memory trace. Our studies suggest that labile (weak) aversive and appetitive LTM may share similar signaling pathways, whereas stable (strong) aversive and appetitive LTM is mediated through different pathways. In addition, we provide some evidence suggesting that extinction of aversive fear memory and appetitive drug memory is likely to be mediated through different signaling molecules. We put forward the importance of studies aimed to investigate the molecular mechanisms underlying the development of weak and strong memories (aversive and appetitive), which would ultimately help in the development of targeted pharmacotherapies for the management of maladaptive behaviors that arise from classical Pavlovian conditioning. © 2014 International Union of Biochemistry and Molecular Biology.
Passive avoidance is linked to impaired fear extinction in humans

PubMed Central

Cornwell, Brian R.; Overstreet, Cassie; Krimsky, Marissa; Grillon, Christian

2013-01-01

Conventional wisdom dictates we must face our fears to conquer them. This idea is embodied in exposure-based treatments for anxiety disorders, where the intent of exposure is to reverse a history of avoidant behavior that is thought to fuel a patient’s irrational fears. We tested in humans the relationship between fear and avoidance by combining Pavlovian differential fear conditioning with a novel task for quantifying spontaneous passive avoidant behavior. During self-guided navigation in virtual reality following de novo fear conditioning, we observed participants keeping their distance from the feared object. At the individual level, passive avoidant behavior was highly associated with maladaptive fear expression (fear-potentiated startle) during late extinction training, indicating that extinction learning was impaired following a brief episode of avoidance. Avoidant behavior, however, was not related to initial acquired fear, raising doubt about a straightforward link between physiological fear and behavioral avoidance. We conclude that a deeper understanding of what motivates avoidance may offer a target for early intervention, before fears transition from the rational to the irrational. PMID:23427168
The Physiology of Fear: Reconceptualizing the Role of the Central Amygdala in Fear Learning

PubMed Central

Keifer, Orion P.; Hurt, Robert C.; Ressler, Kerry J.

2015-01-01

The historically understood role of the central amygdala (CeA) in fear learning is to serve as a passive output station for processing and plasticity that occurs elsewhere in the brain. However, recent research has suggested that the CeA may play a more dynamic role in fear learning. In particular, there is growing evidence that the CeA is a site of plasticity and memory formation, and that its activity is subject to tight regulation. The following review examines the evidence for these three main roles of the CeA as they relate to fear learning. The classical role of the CeA as a routing station to fear effector brain structures like the periaqueductal gray, the lateral hypothalamus, and paraventricular nucleus of the hypothalamus will be briefly reviewed, but specific emphasis is placed on recent literature suggesting that the CeA 1) has an important role in the plasticity underlying fear learning, 2) is involved in regulation of other amygdala subnuclei, and 3) is itself regulated by intra- and extra-amygdalar input. Finally, we discuss the parallels of human and mouse CeA involvement in fear disorders and fear conditioning, respectively. PMID:26328883
Deficient inhibitory processing in trait anxiety: Evidence from context-dependent fear learning, extinction recall and renewal.

PubMed

Haaker, J; Lonsdorf, T B; Schümann, D; Menz, M; Brassen, S; Bunzeck, N; Gamer, M; Kalisch, R

2015-10-01

Impaired fear inhibition has been described as a hallmark of pathological anxiety. We aimed at further characterizing the relation between fear inhibition and anxiety by extending previous work to contextual safety stimuli as well as to dimensional scores of trait anxiety in a large sample. We employed a validated paradigm for context-dependent fear acquisition/extinction (day 1) and retrieval/expression (day 2) in 377 healthy individuals. This large sample size allowed the employment of a dimensional rather than binary approach with respect to individual differences in trait anxiety. We observed a positive correlation on day 1 between trait anxiety with all CSs that possess an inherent inhibitory component, conveyed either by reliable non-reinforcement of a specific CS in a dangerous context (safe cue) or by the context itself (i.e., safe context). No correlation however was observed for a CS that possesses excitatory (threatening) properties only. These results were observed during fear learning (day 1) for US expectancy and fear ratings but not for SCRs. No such pattern was evident during fear and extinction retrieval/expression (day 2). We provide further evidence that high trait anxiety is associated with the inability to take immediate advantage of environmental safety cues (cued and contextual), which might represent a promising trans-diagnostic marker for different anxiety disorders. Consequently, the incorporation of methods to optimize inhibitory learning in current cognitive behavioral therapy (CBT) treatments might open up a promising avenue for precision medicine in anxiety disorders. We did not include patients diagnosed with anxiety disorders. Copyright © 2015. Published by Elsevier B.V.
Brain-wide maps of Fos expression during fear learning and recall.

PubMed

Cho, Jin-Hyung; Rendall, Sam D; Gray, Jesse M

2017-04-01

Fos induction during learning labels neuronal ensembles in the hippocampus that encode a specific physical environment, revealing a memory trace. In the cortex and other regions, the extent to which Fos induction during learning reveals specific sensory representations is unknown. Here we generate high-quality brain-wide maps of Fos mRNA expression during auditory fear conditioning and recall in the setting of the home cage. These maps reveal a brain-wide pattern of Fos induction that is remarkably similar among fear conditioning, shock-only, tone-only, and fear recall conditions, casting doubt on the idea that Fos reveals auditory-specific sensory representations. Indeed, novel auditory tones lead to as much gene induction in visual as in auditory cortex, while familiar (nonconditioned) tones do not appreciably induce Fos anywhere in the brain. Fos expression levels do not correlate with physical activity, suggesting that they are not determined by behavioral activity-driven alterations in sensory experience. In the thalamus, Fos is induced more prominently in limbic than in sensory relay nuclei, suggesting that Fos may be most sensitive to emotional state. Thus, our data suggest that Fos expression during simple associative learning labels ensembles activated generally by arousal rather than specifically by a particular sensory cue. © 2017 Cho et al.; Published by Cold Spring Harbor Laboratory Press.
Neural signals of vicarious extinction learning

PubMed Central

Haaker, Jan; Selbing, Ida; Olsson, Andreas

2016-01-01

Social transmission of both threat and safety is ubiquitous, but little is known about the neural circuitry underlying vicarious safety learning. This is surprising given that these processes are critical to flexibly adapt to a changeable environment. To address how the expression of previously learned fears can be modified by the transmission of social information, two conditioned stimuli (CS + s) were paired with shock and the third was not. During extinction, we held constant the amount of direct, non-reinforced, exposure to the CSs (i.e. direct extinction), and critically varied whether another individual—acting as a demonstrator—experienced safety (CS + vic safety) or aversive reinforcement (CS + vic reinf). During extinction, ventromedial prefrontal cortex (vmPFC) responses to the CS + vic reinf increased but decreased to the CS + vic safety. This pattern of vmPFC activity was reversed during a subsequent fear reinstatement test, suggesting a temporal shift in the involvement of the vmPFC. Moreover, only the CS + vic reinf association recovered. Our data suggest that vicarious extinction prevents the return of conditioned fear responses, and that this efficacy is reflected by diminished vmPFC involvement during extinction learning. The present findings may have important implications for understanding how social information influences the persistence of fear memories in individuals suffering from emotional disorders. PMID:27278792

Brain-wide maps of Fos expression during fear learning and recall

PubMed Central

Cho, Jin-Hyung; Rendall, Sam D.; Gray, Jesse M.

2017-01-01

Fos induction during learning labels neuronal ensembles in the hippocampus that encode a specific physical environment, revealing a memory trace. In the cortex and other regions, the extent to which Fos induction during learning reveals specific sensory representations is unknown. Here we generate high-quality brain-wide maps of Fos mRNA expression during auditory fear conditioning and recall in the setting of the home cage. These maps reveal a brain-wide pattern of Fos induction that is remarkably similar among fear conditioning, shock-only, tone-only, and fear recall conditions, casting doubt on the idea that Fos reveals auditory-specific sensory representations. Indeed, novel auditory tones lead to as much gene induction in visual as in auditory cortex, while familiar (nonconditioned) tones do not appreciably induce Fos anywhere in the brain. Fos expression levels do not correlate with physical activity, suggesting that they are not determined by behavioral activity-driven alterations in sensory experience. In the thalamus, Fos is induced more prominently in limbic than in sensory relay nuclei, suggesting that Fos may be most sensitive to emotional state. Thus, our data suggest that Fos expression during simple associative learning labels ensembles activated generally by arousal rather than specifically by a particular sensory cue. PMID:28331016
Amygdala kindling-resistant (SLOW) or -prone (FAST) rat strains show differential fear responses.

PubMed

Mohapel, P; McIntyre, D C

1998-12-01

The authors compared two rat strains, selectively bred for their susceptibility to amygdala kindling, with respect to their performance on various behavioral and learning tasks that are associated with fear and anxiety. The two rat strains differed significantly in measurements of exploration of novel and familiar environments, as well as in reactivity to footshock and fear-based learning. The kindling-resistant (SLOW) strain exhibited a lower ratio of open- to closed-arm entries in the elevated plus-maze, less activity over days in the open field, greater behavioral suppression in the open-field if previously footshocked, greater freezing in the inhibitory avoidance task, and slower acquisition and poorer retention in the one-way avoidance task than did the kindling-prone (FAST) strain. These experiments suggest that the SLOW rats are more expressively fearful than the FAST rats, particularly with respect to environmentally triggered freezing or immobility. Further, these observations imply that the relatively constrained excitability of the amygdala network in the SLOW rats might mediate their relatively greater expression of fear and anxiety compared with the FAST rats.
Developmental Effects of Acute, Chronic, and Withdrawal from Chronic Nicotine on Fear Conditioning

PubMed Central

Portugal, George S.; Wilkinson, Derek S.; Turner, Jill R.; Blendy, Julie A.; Gould, Thomas J.

2012-01-01

Pre-adolescence and adolescence are developmental periods associated with increased vulnerability for tobacco addiction, and exposure to tobacco during these periods may lead to long-lasting changes in behavioral and neuronal plasticity. The present study examined the short- and long-term effects of nicotine and nicotine withdrawal on fear conditioning in pre-adolescent, adolescent, and adult mice, and potential underlying substrates that may mediate the developmental effects of nicotine, such as changes in nicotinic acetylcholine receptor (nAChR) binding, CREB expression, and nicotine metabolism. Age-related differences existed in sensitivity to the effects of acute nicotine, chronic nicotine and nicotine withdrawal on contextual fear conditioning (no changes in cued fear conditioning were seen); younger mice were more sensitive to the acute effects and less sensitive to the effects of nicotine withdrawal 24 hours post treatment cessation. Developmental differences in nAChR binding were associated with the effects of nicotine withdrawal on contextual learning. Developmental differences in nicotine metabolism and CREB expression were also observed, but were not related to the effects of nicotine withdrawal on contextual learning 24 hours post treatment. Chronic nicotine exposure during pre-adolescence or adolescence, however, produced long-lasting impairments in contextual learning that were observed during adulthood, whereas adult chronic nicotine exposure did not. These developmental effects could be related to changes in CREB. Overall, there is a developmental shift in the effects of nicotine on hippocampus-dependent learning and developmental exposure to nicotine results in adult cognitive deficits; these changes in cognition may play an important role in the development and maintenance of nicotine addiction. PMID:22521799
Hippocampal interleukin-1 mediates stress-enhanced fear learning: A potential role for astrocyte-derived interleukin-1β.

PubMed

Jones, Meghan E; Lebonville, Christina L; Paniccia, Jacqueline E; Balentine, Megan E; Reissner, Kathryn J; Lysle, Donald T

2018-01-01

Post-traumatic stress disorder (PTSD) is associated with immune dysregulation. We have previously shown that severe stress exposure in a preclinical animal model of the disorder, stress-enhanced fear learning (SEFL), is associated with an increase in hippocampal interleukin-1β (IL-1β) and that blocking central IL-1 after the severe stress prevents the development of SEFL. Here, we tested whether blocking hippocampal IL-1 signaling is sufficient to prevent enhanced fear learning and identified the cellular source of stress-induced IL-1β in this region. Experiment 1 tested whether intra-dorsal hippocampal (DH) infusions of interleukin-1 receptor antagonist (IL-1RA, 1.25µg per hemisphere) 24 and 48h after stress exposure prevents the development of enhanced fear learning. Experiment 2 used triple fluorescence immunohistochemistry to examine hippocampal alterations in IL-1β, glial fibrillary acidic protein (GFAP), an astrocyte-specific marker, and ionized calcium binding adaptor molecule -1 (Iba-1), a microglial-specific marker, 48h after exposure to the severe stressor of the SEFL paradigm. Intra-DH IL-1RA prevented SEFL and stress-induced IL-1β was primarily colocalized with astrocytes in the hippocampus. Further, hippocampal GFAP immunoreactivity was not altered, whereas hippocampal Iba-1 immunoreactivity was significantly attenuated following severe stress. These data suggest that hippocampal IL-1 signaling is critical to the development of SEFL and that astrocytes are a predominant source of stress-induced IL-1β. Copyright © 2017 Elsevier Inc. All rights reserved.
Dissociable Learning Processes Underlie Human Pain Conditioning

PubMed Central

Zhang, Suyi; Mano, Hiroaki; Ganesh, Gowrishankar; Robbins, Trevor; Seymour, Ben

2016-01-01

Summary Pavlovian conditioning underlies many aspects of pain behavior, including fear and threat detection [1], escape and avoidance learning [2], and endogenous analgesia [3]. Although a central role for the amygdala is well established [4], both human and animal studies implicate other brain regions in learning, notably ventral striatum and cerebellum [5]. It remains unclear whether these regions make different contributions to a single aversive learning process or represent independent learning mechanisms that interact to generate the expression of pain-related behavior. We designed a human parallel aversive conditioning paradigm in which different Pavlovian visual cues probabilistically predicted thermal pain primarily to either the left or right arm and studied the acquisition of conditioned Pavlovian responses using combined physiological recordings and fMRI. Using computational modeling based on reinforcement learning theory, we found that conditioning involves two distinct types of learning process. First, a non-specific “preparatory” system learns aversive facial expressions and autonomic responses such as skin conductance. The associated learning signals—the learned associability and prediction error—were correlated with fMRI brain responses in amygdala-striatal regions, corresponding to the classic aversive (fear) learning circuit. Second, a specific lateralized system learns “consummatory” limb-withdrawal responses, detectable with electromyography of the arm to which pain is predicted. Its related learned associability was correlated with responses in ipsilateral cerebellar cortex, suggesting a novel computational role for the cerebellum in pain. In conclusion, our results show that the overall phenotype of conditioned pain behavior depends on two dissociable reinforcement learning circuits. PMID:26711494
Cornering the fear engram: long-term synaptic changes in the lateral nucleus of the amygdala after fear conditioning.

PubMed

Kwon, Jeong-Tae; Choi, June-Seek

2009-08-05

Use-dependent synaptic modifications in the lateral nucleus of the amygdala (LA) have been suggested to be the cellular analog of memory trace after pavlovian fear conditioning. However, whether neurophysiological changes in the LA are produced as a direct consequence of associative learning awaits additional proof. Using microstimulation of the medial geniculate nucleus of the thalamus as the conditioned stimulus (CS), we demonstrated that contingent pairings of the brain-stimulation CS and a footshock unconditioned stimulus lead to enhanced synaptic efficacy in the thalamic input to the LA, supporting the hypothesis that localized synaptic alterations underlie fear memory formation.
Hippocampal Processing of Ambiguity Enhances Fear Memory

PubMed Central

Amadi, Ugwechi; Lim, Seh Hong; Liu, Elizabeth; Baratta, Michael V.; Goosens, Ki Ann

2016-01-01

Despite the ubiquitous use of Pavlovian fear conditioning as a model for fear learning, the highly predictable conditions used in the laboratory do not resemble real-world conditions, where dangerous situations can lead to unpleasant outcomes in unpredictable ways. Here we varied the timing of aversive events following predictive cues in rodents and discovered that temporal ambiguity of aversive events greatly enhances fear. During fear conditioning with unpredictably timed aversive events, pharmacological inactivation of the dorsal hippocampus or optogenetic silencing of CA1 cells during aversive negative prediction errors prevented this enhancement of fear without impacting fear learning for predictable events. Dorsal hippocampal inactivation also prevented ambiguity-related enhancement of fear during auditory fear conditioning under a partial reinforcement schedule. These results reveal that information about the timing and occurrence of aversive events is rapidly acquired and that unexpectedly timed or omitted aversive events generate hippocampal signals to enhance fear learning. PMID:28182526
Hippocampal Processing of Ambiguity Enhances Fear Memory.

PubMed

Amadi, Ugwechi; Lim, Seh Hong; Liu, Elizabeth; Baratta, Michael V; Goosens, Ki A

2017-02-01

Despite the ubiquitous use of Pavlovian fear conditioning as a model for fear learning, the highly predictable conditions used in the laboratory do not resemble real-world conditions, in which dangerous situations can lead to unpleasant outcomes in unpredictable ways. In the current experiments, we varied the timing of aversive events after predictive cues in rodents and discovered that temporal ambiguity of aversive events greatly enhances fear. During fear conditioning with unpredictably timed aversive events, pharmacological inactivation of the dorsal hippocampus or optogenetic silencing of cornu ammonis 1 cells during aversive negative prediction errors prevented this enhancement of fear without affecting fear learning for predictable events. Dorsal hippocampal inactivation also prevented ambiguity-related enhancement of fear during auditory fear conditioning under a partial-reinforcement schedule. These results reveal that information about the timing and occurrence of aversive events is rapidly acquired and that unexpectedly timed or omitted aversive events generate hippocampal signals to enhance fear learning.
A test of the cognitive social learning model of type A behavior.

PubMed

Matteson, M T; Ivancevich, J M; Gamble, G O

1987-01-01

Portions of the cognitive social learning model proposed by Price as an explanation for the development and maintenance of Type A behavior were examined empirically. Specifically, the hypothesis that Type A behavior is fostered by various beliefs and fears and that these same beliefs and fears arise, in part, as the result of certain parental characteristics was investigated. A questionnaire assessing Type A behavior and the beliefs, fears, and parental characteristics proposed by Price was constructed and administered to a sample of males and females. The results indicated moderate associations between the variables examined for both males and females, with no significant gender differences in the pattern of relationships. The findings are congruent with relationships proposed by Price's model. Implications of the model are discussed in terms of additional research needed.
Neural circuits and mechanisms involved in Pavlovian fear conditioning: A critical review

PubMed Central

Kim, Jeansok J.; Jung, Min Whan

2015-01-01

Pavlovian or classical fear conditioning is recognized as a model system to investigate the neurobiological mechanisms of learning and memory in the mammalian brain and to understand the root of fear-related disorders in humans. In recent decades, important progress has been made in delineating the essential neural circuitry and cellular–molecular mechanisms of fear conditioning. Converging lines of evidence indicate that the amygdala is necessarily involved in the acquisition, storage and expression of conditioned fear memory, and long-term potentiation (LTP) in the lateral nucleus of the amygdala is often proposed as the underlying synaptic mechanism of associative fear memory. Recent studies further implicate the prefrontal cortex–amygdala interaction in the extinction (or inhibition) of conditioned fear. Despite these advances, there are unresolved issues and findings that challenge the validity and sufficiency of the current amygdalar LTP hypothesis of fear conditioning. The purpose of this review is to critically evaluate the strengths and weaknesses of evidence indicating that fear conditioning depend crucially upon the amygdalar circuit and plasticity. PMID:16120461
Vicarious extinction learning during reconsolidation neutralizes fear memory.

PubMed

Golkar, Armita; Tjaden, Cathelijn; Kindt, Merel

2017-05-01

Previous studies have suggested that fear memories can be updated when recalled, a process referred to as reconsolidation. Given the beneficial effects of model-based safety learning (i.e. vicarious extinction) in preventing the recovery of short-term fear memory, we examined whether consolidated long-term fear memories could be updated with safety learning accomplished through vicarious extinction learning initiated within the reconsolidation time-window. We assessed this in a final sample of 19 participants that underwent a three-day within-subject fear-conditioning design, using fear-potentiated startle as our primary index of fear learning. On day 1, two fear-relevant stimuli (reinforced CSs) were paired with shock (US) and a third stimulus served as a control (CS). On day 2, one of the two previously reinforced stimuli (the reminded CS) was presented once in order to reactivate the fear memory 10 min before vicarious extinction training was initiated for all CSs. The recovery of the fear memory was tested 24 h later. Vicarious extinction training conducted within the reconsolidation time window specifically prevented the recovery of the reactivated fear memory (p = 0.03), while leaving fear-potentiated startle responses to the non-reactivated cue intact (p = 0.62). These findings are relevant to both basic and clinical research, suggesting that a safe, non-invasive model-based exposure technique has the potential to enhance the efficiency and durability of anxiolytic therapies. Copyright © 2017 Elsevier Ltd. All rights reserved.
Forming Competing Fear Learning and Extinction Memories in Adolescence Makes Fear Difficult to Inhibit

ERIC Educational Resources Information Center

Baker, Kathryn D.; Richardson, Rick

2015-01-01

Fear inhibition is markedly impaired in adolescent rodents and humans. The present experiments investigated whether this impairment is critically determined by the animal's age at the time of fear learning or their age at fear extinction. Male rats (n = 170) were tested for extinction retention after conditioning and extinction at different ages.…
Do Learners Fear More than Fear Itself: The Role of Fear in Law Students Educational Experiences

ERIC Educational Resources Information Center

Perrin, Jeffrey; O'Neil, Jennifer; Grimes, Ashley; Bryson, Laura

2014-01-01

While previous research has examined the various relationships between fear and learning in K-12 academic settings, the relationship is surprisingly unexplored amongst law students. Using a descriptive qualitative approach, we examine the role fear plays in law students' learning experiences. Through a series of semi-structured interviews a few…
Sex differences in learned fear expression and extinction involve altered gamma oscillations in medial prefrontal cortex.

PubMed

Fenton, Georgina E; Halliday, David M; Mason, Rob; Bredy, Timothy W; Stevenson, Carl W

2016-11-01

Sex differences in learned fear expression and extinction involve the medial prefrontal cortex (mPFC). We recently demonstrated that enhanced learned fear expression during auditory fear extinction and its recall is linked to persistent theta activation in the prelimbic (PL) but not infralimbic (IL) cortex of female rats. Emerging evidence indicates that gamma oscillations in mPFC are also implicated in the expression and extinction of learned fear. Therefore we re-examined our in vivo electrophysiology data and found that females showed persistent PL gamma activation during extinction and a failure of IL gamma activation during extinction recall. Altered prefrontal gamma oscillations thus accompany sex differences in learned fear expression and its extinction. These findings are relevant for understanding the neural basis of post-traumatic stress disorder, which is more prevalent in women and involves impaired extinction and mPFC dysfunction. Copyright © 2016 Elsevier Inc. All rights reserved.
Temporal-difference prediction errors and Pavlovian fear conditioning: role of NMDA and opioid receptors.

PubMed

Cole, Sindy; McNally, Gavan P

2007-10-01

Three experiments studied temporal-difference (TD) prediction errors during Pavlovian fear conditioning. In Stage I, rats received conditioned stimulus A (CSA) paired with shock. In Stage II, they received pairings of CSA and CSB with shock that blocked learning to CSB. In Stage III, a serial overlapping compound, CSB --> CSA, was followed by shock. The change in intratrial durations supported fear learning to CSB but reduced fear of CSA, revealing the operation of TD prediction errors. N-methyl- D-aspartate (NMDA) receptor antagonism prior to Stage III prevented learning, whereas opioid receptor antagonism selectively affected predictive learning. These findings support a role for TD prediction errors in fear conditioning. They suggest that NMDA receptors contribute to fear learning by acting on the product of predictive error, whereas opioid receptors contribute to predictive error. (PsycINFO Database Record (c) 2007 APA, all rights reserved).
Immunization against social fear learning.

PubMed

Golkar, Armita; Olsson, Andreas

2016-06-01

Social fear learning offers an efficient way to transmit information about potential threats; little is known, however, about the learning processes that counteract the social transmission of fear. In three separate experiments, we found that safety information transmitted from another individual (i.e., demonstrator) during preexposure prevented subsequent observational fear learning (Experiments 1-3), and this effect was maintained in a new context involving direct threat confrontation (Experiment 3). This protection from observational fear learning was specific to conditions in which information about both safety and danger was transmitted from the same demonstrator (Experiments 2-3) and was unaffected by increasing the number of the safety demonstrators (Experiment 3). Collectively, these findings demonstrate that observational preexposure can limit social transmission of fear. Future research is needed to better understand the conditions under which such effects generalize across individual demonstrators. (PsycINFO Database Record (c) 2016 APA, all rights reserved).
Developmental emergence of fear/threat learning: neurobiology, associations and timing

PubMed Central

Tallot, L.; Doyère, V.; Sullivan, R. M.

2016-01-01

Pavlovian fear or threat conditioning, where a neutral stimulus takes on aversive properties through pairing with an aversive stimulus, has been an important tool for exploring the neurobiology of learning. In the past decades, this neurobehavioral approach has been expanded to include the developing infant. Indeed, protracted postnatal brain development permits the exploration of how incorporating the amygdala, prefrontal cortex and hippocampus into this learning system impacts the acquisition and expression of aversive conditioning. Here, we review the developmental trajectory of these key brain areas involved in aversive conditioning and relate it to pups’ transition to independence through weaning. Overall, the data suggests that adult-like features of threat learning emerge as the relevant brain areas become incorporated into this learning. Specifically, the developmental emergence of the amygdala permits cue learning and the emergence of the hippocampus permits context learning. We also describe unique features of learning in early life that block threat learning and enhance interaction with the mother or exploration of the environment. Finally, we describe the development of a sense of time within this learning and its involvement in creating associations. Together these data suggest that the development of threat learning is a useful tool for dissecting adult-like functioning of brain circuits, as well as providing unique insights into ecologically relevant developmental changes. PMID:26534899
The impact of cue learning, trait anxiety and genetic variation in the serotonin 1A receptor on contextual fear.

PubMed

Baas, Johanna M P; Heitland, Ivo

2015-12-01

In everyday life, aversive events are usually associated with certain predictive cues. Normally, the acquisition of these contingencies enables organisms to appropriately respond to threat. Presence of a threat cue clearly signals 'danger', whereas absence of such cues signals a period of 'safety'. Failure to identify threat cues may lead to chronic states of anxious apprehension in the context in which the threat has been imminent, which may be instrumental in the pathogenesis of anxiety disorders. In this study, existing data from 150 healthy volunteers in a cue and context virtual reality fear conditioning paradigm were reanalyzed. The aim was to further characterize the impact of cue acquisition and trait anxiety, and of a single nucleotide polymorphism in the serotonin 1A receptor gene (5-HTR1A, rs6295), on cued fear and contextual anxiety before and after fear contingencies were explicitly introduced. Fear conditioned responding was quantified with fear potentiation of the eyeblink startle reflex and subjective fear ratings. First, we replicated previous findings that the inability to identify danger cues during acquisition leads to heightened anxious apprehension in the threat context. Second, in subjects who did not identify the danger cue initially, contextual fear was associated with trait anxiety after the contingencies were explicitly instructed. Third, genetic variability within 5-HTR1A (rs6295) was associated with contextual fear independent of awareness or trait anxiety. These findings confirm that failure to acquire cue contingencies impacts contextual fear responding, in association with trait anxiety. The observed 5-HTR1A effect is in line with models of anxiety, but needs further replication. Copyright © 2014 Elsevier B.V. All rights reserved.
Fear learning and memory across adolescent development Hormones and Behavior Special Issue: Puberty and Adolescence

PubMed Central

Pattwell, Siobhan S.; Lee, Francis S.; Casey, B.J.

2013-01-01

Throughout the past several decades, studies have uncovered a wealth of information about the neural circuitry underlying fear learning and extinction that has helped to inform treatments for fear-related disorders such as post-traumatic stress and anxiety. Yet, up to 40 percent of people do not respond to such treatments. Adolescence, in particular, is a developmental stage during which anxiety disorders peak, yet little is known about the development of fear-related neural circuitry during this period. Moreover, pharmacological and behavioral therapies that have been developed are based on mature circuitry and function. Here, we review neural circuitry implicated in fear learning and data from adolescent mouse and human fear learning studies. In addition, we propose a developmental model of fear neural circuitry that may optimize current treatments and inform when, during development, specific treatments for anxiety may be most effective. PMID:23998679
Fear learning and memory across adolescent development: Hormones and Behavior Special Issue: Puberty and Adolescence.

PubMed

Pattwell, Siobhan S; Lee, Francis S; Casey, B J

2013-07-01

Throughout the past several decades, studies have uncovered a wealth of information about the neural circuitry underlying fear learning and extinction that has helped to inform treatments for fear-related disorders such as post-traumatic stress and anxiety. Yet, up to 40% of people do not respond to such treatments. Adolescence, in particular, is a developmental stage during which anxiety disorders peak, yet little is known about the development of fear-related neural circuitry during this period. Moreover, pharmacological and behavioral therapies that have been developed are based on mature circuitry and function. Here, we review neural circuitry implicated in fear learning and data from adolescent mouse and human fear learning studies. In addition, we propose a developmental model of fear neural circuitry that may optimize current treatments and inform when, during development, specific treatments for anxiety may be most effective. Copyright © 2013 Elsevier Inc. All rights reserved.

Developmental regulation of fear learning and anxiety behavior by endocannabinoids.

PubMed

Lee, T T-Y; Hill, M N; Lee, F S

2016-01-01

The developing brain undergoes substantial maturation into adulthood and the development of specific neural structures occurs on differing timelines. Transient imbalances between developmental trajectories of corticolimbic structures, which are known to contribute to regulation over fear learning and anxiety, can leave an individual susceptible to mental illness, particularly anxiety disorders. There is a substantial body of literature indicating that the endocannabinoid (eCB) system critically regulates stress responsivity and emotional behavior throughout the life span, making this system a novel therapeutic target for stress- and anxiety-related disorders. During early life and adolescence, corticolimbic eCB signaling changes dynamically and coincides with different sensitive periods of fear learning, suggesting that eCB signaling underlies age-specific fear learning responses. Moreover, perturbations to these normative fluctuations in corticolimbic eCB signaling, such as stress or cannabinoid exposure, could serve as a neural substrate contributing to alterations to the normative developmental trajectory of neural structures governing emotional behavior and fear learning. In this review, we first introduce the components of the eCB system and discuss clinical and rodent models showing eCB regulation of fear learning and anxiety in adulthood. Next, we highlight distinct fear learning and regulation profiles throughout development and discuss the ontogeny of the eCB system in the central nervous system, and models of pharmacological augmentation of eCB signaling during development in the context of fear learning and anxiety. © 2015 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.
Abnormal fear circuitry in Attention Deficit Hyperactivity Disorder: A controlled magnetic resonance imaging study.

PubMed

Spencer, Andrea E; Marin, Marie-France; Milad, Mohammed R; Spencer, Thomas J; Bogucki, Olivia E; Pope, Amanda L; Plasencia, Natalie; Hughes, Brittany; Pace-Schott, Edward F; Fitzgerald, Maura; Uchida, Mai; Biederman, Joseph

2017-04-30

We examined whether non-traumatized subjects with Attention Deficit Hyperactivity Disorder (ADHD) have dysfunctional activation in brain structures mediating fear extinction, possibly explaining the statistical association between ADHD and other disorders characterized by aberrant fear processing such as PTSD. Medication naïve, non-traumatized young adult subjects with (N=27) and without (N=20) ADHD underwent a 2-day fear conditioning and extinction protocol in a 3T functional magnetic resonance imaging (fMRI) scanner. Skin conductance response (SCR) was recorded as a measure of conditioned response. Compared to healthy controls, ADHD subjects had significantly greater insular cortex activation during early extinction, lesser dorsal anterior cingulate cortex (dACC) activation during late extinction, lesser ventromedial prefrontal cortex (vmPFC) activation during late extinction learning and extinction recall, and greater hippocampal activation during extinction recall. Hippocampal and vmPFC deficits were similar to those documented in PTSD subjects compared to traumatized controls without PTSD. Non-traumatized, medication naive adults with ADHD had abnormalities in fear circuits during extinction learning and extinction recall, and some findings were consistent with those previously documented in subjects with PTSD compared to traumatized controls without PTSD. These findings could explain the significant association between ADHD and PTSD as well as impaired emotion regulation in ADHD. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.
Individual Differences in Discriminatory Fear Learning under Conditions of Ambiguity: A Vulnerability Factor for Anxiety Disorders?

PubMed Central

Arnaudova, Inna; Krypotos, Angelos-Miltiadis; Effting, Marieke; Boddez, Yannick; Kindt, Merel; Beckers, Tom

2013-01-01

Complex fear learning procedures might be better suited than the common differential fear-conditioning paradigm for detecting individual differences related to vulnerability for anxiety disorders. Two such procedures are the blocking procedure and the protection-from-overshadowing procedure. Their comparison allows for the examination of discriminatory fear learning under conditions of ambiguity. The present study examined the role of individual differences in such discriminatory fear learning. We hypothesized that heightened trait anxiety would be related to a deficit in discriminatory fear learning. Participants gave US-expectancy ratings as an index for the threat value of individual CSs following blocking and protection-from-overshadowing training. The difference in threat value at test between the protected-from-overshadowing conditioned stimulus (CS) and the blocked CS was negatively correlated with scores on a self-report tension-stress scale that approximates facets of generalized anxiety disorder (GAD), the Depression Anxiety Stress Scale-Stress (DASS-S), but not with other individual difference variables. In addition, a behavioral test showed that only participants scoring high on the DASS-S avoided the protected-from-overshadowing CS. This observed deficit in discriminatory fear learning for participants with high levels of tension-stress might be an underlying mechanism for fear overgeneralization in diffuse anxiety disorders such as GAD. PMID:23755030
Impairment of contextual fear extinction by chronic nicotine and withdrawal from chronic nicotine is associated with hippocampal nAChR upregulation.

PubMed

Kutlu, Munir Gunes; Oliver, Chicora; Huang, Peng; Liu-Chen, Lee-Yuan; Gould, Thomas J

2016-10-01

Chronic nicotine and withdrawal from chronic nicotine have been shown to be major modulators of fear learning behavior. Moreover, recent studies from our laboratory have shown that acute nicotine impaired fear extinction and safety learning in mice. However, the effects of chronic nicotine and withdrawal on fear extinction are unknown. Therefore, the current experiments were conducted to investigate the effects of chronic nicotine as well as withdrawal from chronic nicotine on contextual fear extinction in mice. C57BL6/J mice were given contextual fear conditioning training and retention testing during chronic nicotine administration. Mice then received contextual fear extinction either during chronic nicotine or during withdrawal from chronic nicotine. Our results showed that contextual fear extinction was impaired both during chronic nicotine administration and subsequent withdrawal. However, it was also observed that the effects of prior chronic nicotine disappeared after 72 h in withdrawal, a timeline that closely matches with the timing of the chronic nicotine-induced upregulation of hippocampal nicotinic acetylcholine receptor (nAChR) density. Additional experiments found that 4 days, but not 1 day, of continuous nicotine administration upregulated hippocampal nAChRs and impaired contextual fear extinction. These effects disappeared following 72 h withdrawal. Overall, these experiments provide a potential link between nicotine-induced upregulation of hippocampal nAChRs and fear extinction deficits observed in patients with anxiety disorders, which may lead to advancements in the pharmacological treatment methods for this disorder. Copyright © 2016 Elsevier Ltd. All rights reserved.
Posterior insular cortex is necessary for conditioned inhibition of fear.

PubMed

Foilb, Allison R; Flyer-Adams, Johanna G; Maier, Steven F; Christianson, John P

2016-10-01

Veridical detection of safety versus danger is critical to survival. Learned signals for safety inhibit fear, and so when presented, reduce fear responses produced by danger signals. This phenomenon is termed conditioned inhibition of fear. Here, we report that CS+/CS- fear discrimination conditioning over 5 days in rats leads the CS- to become a conditioned inhibitor of fear, as measured by the classic tests of conditioned inhibition: summation and retardation of subsequent fear acquisition. We then show that NMDA-receptor antagonist AP5 injected to posterior insular cortex (IC) before training completely prevented the acquisition of a conditioned fear inhibitor, while intra-AP5 to anterior and medial IC had no effect. To determine if the IC contributes to the recall of learned fear inhibition, injections of the GABAA agonist muscimol were made to posterior IC before a summation test. This resulted in fear inhibition per se, which obscured inference to the effect of IC inactivation with recall of the safety cue. Control experiments sought to determine if the role of the IC in conditioned inhibition learning could be reduced to simpler fear discrimination function, but fear discrimination and recall were unaffected by AP5 or muscimol, respectively, in the posterior IC. These data implicate a role of posterior IC in the learning of conditioned fear inhibitors. Copyright © 2016 Elsevier Inc. All rights reserved.
AX+, BX- Discrimination Learning in the Fear-Potentiated Startle Paradigm: Possible Relevance to Inhibitory Fear Learning in Extinction

ERIC Educational Resources Information Center

Myers, Karyn M.; Davis, Michael

2004-01-01

The neural mechanisms of fear suppression most commonly are studied through the use of extinction, a behavioral procedure in which a feared stimulus (i.e., one previously paired with shock) is nonreinforced repeatedly, leading to a reduction or elimination of the fear response. Although extinction is perhaps the most convenient index of fear…
Beta-catenin is required for memory consolidation.

PubMed

Maguschak, Kimberly A; Ressler, Kerry J

2008-11-01

beta-catenin has been implicated in neuronal synapse regulation and remodeling. Here we have examined beta-catenin expression in the adult mouse brain and its role in amygdala-dependent learning and memory. We found alterations in beta-catenin mRNA and protein phosphorylation during fear-memory consolidation. Such alterations correlated with a change in the association of beta-catenin with cadherin. Pharmacologically, this consolidation was enhanced by lithium-mediated facilitation of beta-catenin. Genetically, the role of beta-catenin was confirmed with site-specific deletions of loxP-flanked Ctnnb1 (encoding beta-catenin) in the amygdala. Baseline locomotion, anxiety-related behaviors and acquisition or expression of conditioned fear were normal. However, amygdala-specific deletion of Ctnnb1 prevented the normal transfer of newly formed fear learning into long-term memory. Thus, beta-catenin may be required in the amygdala for the normal consolidation, but not acquisition, of fear memory. This suggests a general role for beta-catenin in the synaptic remodeling and stabilization underlying long-term memory in adults.
Neurobiology of fear and specific phobias.

PubMed

Garcia, René

2017-09-01

Fear, which can be expressed innately or after conditioning, is triggered when a danger or a stimulus predicting immediate danger is perceived. Its role is to prepare the body to face this danger. However, dysfunction in fear processing can lead to psychiatric disorders in which fear outweighs the danger or possibility of harm. Although recognized as highly debilitating, pathological fear remains insufficiently treated, indicating the importance of research on fear processing. The neurobiological basis of normal and pathological fear reactions is reviewed in this article. Innate and learned fear mechanisms, particularly those involving the amygdala, are considered. These fear mechanisms are also distinguished in specific phobias, which can indeed be nonexperiential (implicating innate, learning-independent mechanisms) or experiential (implicating learning-dependent mechanisms). Poor habituation and poor extinction are presented as dysfunctional mechanisms contributing to persistence of nonexperiential and experiential phobias, respectively. © 2017 Garcia; Published by Cold Spring Harbor Laboratory Press.
The Physiology of Fear: Reconceptualizing the Role of the Central Amygdala in Fear Learning.

PubMed

Keifer, Orion P; Hurt, Robert C; Ressler, Kerry J; Marvar, Paul J

2015-09-01

The historically understood role of the central amygdala (CeA) in fear learning is to serve as a passive output station for processing and plasticity that occurs elsewhere in the brain. However, recent research has suggested that the CeA may play a more dynamic role in fear learning. In particular, there is growing evidence that the CeA is a site of plasticity and memory formation, and that its activity is subject to tight regulation. The following review examines the evidence for these three main roles of the CeA as they relate to fear learning. The classical role of the CeA as a routing station to fear effector brain structures like the periaqueductal gray, the lateral hypothalamus, and paraventricular nucleus of the hypothalamus will be briefly reviewed, but specific emphasis is placed on recent literature suggesting that the CeA 1) has an important role in the plasticity underlying fear learning, 2) is involved in regulation of other amygdala subnuclei, and 3) is itself regulated by intra- and extra-amygdalar input. Finally, we discuss the parallels of human and mouse CeA involvement in fear disorders and fear conditioning, respectively. ©2015 Int. Union Physiol. Sci./Am. Physiol. Soc.
Yohimbine Impairs Extinction of Cocaine-Conditioned Place Preference in an [alpha] [subscript 2]-Adrenergic Receptor Independent Process

ERIC Educational Resources Information Center

Davis, Adeola R.; Shields, Angela D.; Brigman, Jonathan L.; Norcross, Maxine; McElligott, Zoe A.; Holmes, Andrew; Winder, Danny G.

2008-01-01

Extinction, a form of learning that has the ability to reshape learned behavior based on new experiences, has been heavily studied utilizing fear learning paradigms. Mechanisms underlying extinction of positive-valence associations, such as drug self-administration and place preference, are poorly understood yet may have important relevance to…
Adolescent Transitions in Reflexive and Non-Reflexive Behavior: Review of Fear Conditioning and Impulse Control in Rodent Models

PubMed Central

Hunt, Pamela S.; Burk, Joshua A.; Barnet, Robert C.

2016-01-01

Adolescence is a time of critical brain changes that pave the way for adult learning processes. However, the extent to which learning in adolescence is best characterized as a transitional linear progression from childhood to adulthood, or represents a period that differs from earlier and later developmental stages, remains unclear. Here we examine behavioral literature on associative fear conditioning and complex choice behavior with rodent models. Many aspects of fear conditioning are intact by adolescence and do not differ from adult patterns. Sufficient evidence, however, suggests that adolescent learning cannot be characterized simply as an immature precursor to adulthood. Across different paradigms assessing choice behavior, literature suggests that adolescent animals typically display more impulsive patterns of responding compared to adults. The extent to which the development of basic conditioning processes serves as a scaffold for later adult decision making is an additional research area that is important for theory, but also has widespread applications for numerous psychological conditions. PMID:27339692
Reorganization of Learning-Associated Prefrontal Synaptic Plasticity between the Recall of Recent and Remote Fear Extinction Memory

ERIC Educational Resources Information Center

Hugues, Sandrine; Garcia, Rene

2007-01-01

We have previously shown that fear extinction is accompanied by an increase of synaptic efficacy in inputs from the ventral hippocampus (vHPC) and mediodorsal thalamus (MD) to the medial prefrontal cortex (mPFC) and that disrupting these changes to mPFC synaptic transmission compromises extinction processes. The aim of this study was to examine…
How Administration of the Beta-Blocker Propranolol Before Extinction can Prevent the Return of Fear

PubMed Central

Kroes, Marijn C W; Tona, Klodiana-Daphne; den Ouden, Hanneke E M; Vogel, Susanne; van Wingen, Guido A; Fernández, Guillén

2016-01-01

Combining beta-blockers with exposure therapy has been advocated to reduce fear, yet experimental studies combining beta-blockers with memory reactivation have had contradictory results. We explored how beta-blockade might affect the course of safety learning and the subsequent return of fear in a double-blind placebo-controlled functional magnetic resonance imaging study in humans (N=46). A single dose of propranolol before extinction learning caused a loss of conditioned fear responses, and prevented the subsequent return of fear and decreased explicit memory for the fearful events in the absence of drug. Fear-related neural responses were persistently attenuated in the dorsal medial prefrontal cortex (dmPFC), increased in the hippocampus 24 h later, and correlated with individual behavioral indices of fear. Prediction error-related responses in the ventral striatum persisted during beta-blockade. We suggest that this pattern of results is most consistent with a model where beta-blockade can prevent the return of fear by (i) reducing retrieval of fear memory, via the dmPFC and (ii) increasing contextual safety learning, via the hippocampus. Our findings suggest that retrieval of fear memory and contextual safety learning form potential mnemonic target mechanisms to optimize exposure-based therapy with beta-blockers. PMID:26462618
Potentiation of GluN2C/D NMDA receptor subtypes in the amygdala facilitates the retention of fear and extinction learning in mice.

PubMed

Ogden, Kevin K; Khatri, Alpa; Traynelis, Stephen F; Heldt, Scott A

2014-02-01

NMDA receptors are glutamate receptor ion channels that contribute to synaptic plasticity and are important for many forms of learning and memory. In the amygdala, NMDA receptors are critical for the acquisition, retention, and extinction of classically conditioned fear responses. Although the GluN2B subunit has been implicated in both the acquisition and extinction of conditioned fear, GluN2C-knockout mice show reduced conditioned fear responses. Moreover, D-cycloserine (DCS), which facilitates fear extinction, selectively enhances the activity of GluN2C-containing NMDA receptors. To further define the contribution of GluN2C receptors to fear learning, we infused the GluN2C/GluN2D-selective potentiator CIQ bilaterally into the basolateral amygdala (3, 10, or 30 μg/side) following either fear conditioning or fear extinction training. CIQ both increased the expression of conditioned fear 24 h later and enhanced the extinction of the previously conditioned fear response. These results support a critical role for GluN2C receptors in the amygdala in the consolidation of learned fear responses and suggest that increased activity of GluN2C receptors may underlie the therapeutic actions of DCS.
Social Fear Learning: from Animal Models to Human Function.

PubMed

Debiec, Jacek; Olsson, Andreas

2017-07-01

Learning about potential threats is critical for survival. Learned fear responses are acquired either through direct experiences or indirectly through social transmission. Social fear learning (SFL), also known as vicarious fear learning, is a paradigm successfully used for studying the transmission of threat information between individuals. Animal and human studies have begun to elucidate the behavioral, neural and molecular mechanisms of SFL. Recent research suggests that social learning mechanisms underlie a wide range of adaptive and maladaptive phenomena, from supporting flexible avoidance in dynamic environments to intergenerational transmission of trauma and anxiety disorders. This review discusses recent advances in SFL studies and their implications for basic, social and clinical sciences. Copyright © 2017 Elsevier Ltd. All rights reserved.
Generalization of Fear to Respiratory Sensations.

PubMed

Schroijen, Mathias; Pappens, Meike; Schruers, Koen; Van den Bergh, Omer; Vervliet, Bram; Van Diest, Ilse

2015-09-01

Interoceptive fear conditioning (IFC), fear generalization and a lack of safety learning have all been hypothesized to play a role in the pathogenesis of panic disorder, but have never been examined in a single paradigm. The present study aims to investigate whether healthy participants (N=43) can learn both fear and safety to an interoceptive sensation, and whether such learning generalizes to other, similar sensations. Two intensities of inspiratory breathing impairment (induced by two pressure threshold loads of 6 and 25 cm H2O) served as interoceptive conditional stimuli (CSs) in a differential conditioning paradigm. An inspiratory occlusion was used as the unconditioned stimulus (US). Generalization was tested 24h after conditioning, using four generalization stimuli with intensities in-between CS+ and CS- (GSs: 8-10.5-14-18.5 cm H2O). Measures included US-expectancy, startle blink EMG responses, electrodermal activity and respiration. Perceptual discrimination of interoceptive CSs and GSs was explored with a discrimination task prior to acquisition and after generalization. Results indicate that differential fear learning was established for US-expectancy ratings. The group with a low intensity CS+ and a high intensity CS- showed the typical pattern of differential fear responding and a similarity-based generalization gradient. In contrast, the high intensity CS+ and low intensity CS- group showed impaired differential learning and complete generalization of fear. Our findings suggest that interoceptive fear learning and generalization are modulated by stimulus intensity and that the occurrence of discriminatory learning is closely related to fear generalization. Copyright © 2015. Published by Elsevier Ltd.
Role of the amygdala GABA-A receptors in ACPA-induced deficits during conditioned fear learning.

PubMed

Nasehi, Mohammad; Roghani, Farnaz; Ebrahimi-Ghiri, Mohaddeseh; Zarrindast, Mohammad-Reza

2017-05-01

The basolateral amygdala (BLA) is a key structure for the emotional processing and storage of memories associated with emotional events, especially fear. On the other hand, endocannabinoids and CB1 receptors play a key role in learning and memory partly through long-term synaptic depression of GABAergic synapses in the BLA. The aim of this study was to explore the effects of GABA-A receptor agonist and antagonist in the fear-related memory acquisition deficits induced by ACPA (a selective CB1 cannabinoid receptor agonist). This study used context and tone fear conditioning paradigms to assess fear-related memory in male NMRI mice. Our results showed that the pre-training intraperitoneal administration of ACPA (0.5mg/kg) or (0.1 and 0.5mg/kg) decreased the percentage of freezing time in the contextual and tone fear conditioning, respectively. This indicated an impaired context- or tone-dependent fear memory acquisition. Moreover, the pre-training intra-BLA microinjection of GABA-A receptor agonist, muscimol, at 0.05 and 0.5μg/mouse impaired context-dependent fear memory, while the same doses of GABA-A antagonist, bicuculline, impaired tone-dependent fear memory. However, a subthreshold dose of muscimol or bicuculline increased the effect of ACPA at 0.1 and 0.5 or 0.05mg/kg on context- or tone-dependent fear memory, respectively. In addition, bicuculline at the lower dose increased the ACPA response on locomotor activity compared to its respective group. Such findings highlighted an interaction between BLA GABAergic and cannabinoidergic systems during the acquisition phase of conditioned fear memories. Copyright © 2017 Elsevier Inc. All rights reserved.
Fear inhibition in high trait anxiety.

PubMed

Kindt, Merel; Soeter, Marieke

2014-01-01

Trait anxiety is recognized as an individual risk factor for the development of anxiety disorders but the neurobiological mechanisms remain unknown. Here we test whether trait anxiety is associated with impaired fear inhibition utilizing the AX+/BX- conditional discrimination procedure that allows for the independent evaluation of startle fear potentiation and inhibition of fear. Sixty undergraduate students participated in the study--High Trait Anxious: n = 28 and Low Trait Anxious: n = 32. We replicated earlier findings that a transfer of conditioned inhibition for startle responses requires contingency awareness. However, contrary to the fear inhibition hypothesis, our data suggest that high trait anxious individuals show a normal fear inhibition of conditioned startle responding. Only at the cognitive level the high trait anxious individuals showed evidence for impaired inhibitory learning of the threat cue. Together with other findings where impaired fear inhibition was only observed in those PTSD patients who were either high on hyperarousal symptoms or with current anxiety symptoms, we question whether impaired fear inhibition is a biomarker for the development of anxiety disorders.
Exposure to a fearful context during periods of memory plasticity impairs extinction via hyperactivation of frontal-amygdalar circuits

PubMed Central

Stafford, James M.; Maughan, DeeAnna K.; Ilioi, Elena C.; Lattal, K. Matthew

2013-01-01

An issue of increasing theoretical and translational importance is to understand the conditions under which learned fear can be suppressed, or even eliminated. Basic research has pointed to extinction, in which an organism is exposed to a fearful stimulus (such as a context) in the absence of an expected aversive outcome (such as a shock). This extinction process results in the suppression of fear responses, but is generally thought to leave the original fearful memory intact. Here, we investigate the effects of extinction during periods of memory lability on behavioral responses and on expression of the immediate–early gene c-Fos within fear conditioning and extinction circuits. Our results show that long-term extinction is impaired when it occurs during time periods during which the memory should be most vulnerable to disruption (soon after conditioning or retrieval). These behavioral effects are correlated with hyperactivation of medial prefrontal cortex and amygdala subregions associated with fear expression rather than fear extinction. These findings demonstrate that behavioral experiences during periods of heightened fear prevent extinction and prolong the conditioned fear response. PMID:23422280
Infralimbic EphB2 Modulates Fear Extinction in Adolescent Rats.

PubMed

Cruz, Emmanuel; Soler-Cedeño, Omar; Negrón, Geovanny; Criado-Marrero, Marangelie; Chompré, Gladys; Porter, James T

2015-09-09

Adolescent rats are prone to impaired fear extinction, suggesting that mechanistic differences in extinction could exist in adolescent and adult rats. Since the infralimbic cortex (IL) is critical for fear extinction, we used PCR array technology to identify gene expression changes in IL induced by fear extinction in adolescent rats. Interestingly, the ephrin type B receptor 2 (EphB2), a tyrosine kinase receptor associated with synaptic development, was downregulated in IL after fear extinction. Consistent with the PCR array results, EphB2 levels of mRNA and protein were reduced in IL after fear extinction compared with fear conditioning, suggesting that EphB2 signaling in IL regulates fear extinction memory in adolescents. Finally, reducing EphB2 synthesis in IL with shRNA accelerated fear extinction learning in adolescent rats, but not in adult rats. These findings identify EphB2 in IL as a key regulator of fear extinction during adolescence, perhaps due to the increase in synaptic remodeling occurring during this developmental phase. Copyright © 2015 the authors 0270-6474/15/3512394-10$15.00/0.

Mapping Compulsivity in the DSM-5 Obsessive Compulsive and Related Disorders: Cognitive Domains, Neural Circuitry, and Treatment

PubMed Central

Apergis-Schoute, Annemieke M; Vaghi, Matilde M; Banca, Paula; Gillan, Claire M; Voon, Valerie; Chamberlain, Samuel R; Cinosi, Eduardo; Reid, Jemma; Shahper, Sonia; Bullmore, Edward T; Sahakian, Barbara J; Robbins, Trevor W

2018-01-01

Abstract Compulsions are repetitive, stereotyped thoughts and behaviors designed to reduce harm. Growing evidence suggests that the neurocognitive mechanisms mediating behavioral inhibition (motor inhibition, cognitive inflexibility) reversal learning and habit formation (shift from goal-directed to habitual responding) contribute toward compulsive activity in a broad range of disorders. In obsessive compulsive disorder, distributed network perturbation appears focused around the prefrontal cortex, caudate, putamen, and associated neuro-circuitry. Obsessive compulsive disorder-related attentional set-shifting deficits correlated with reduced resting state functional connectivity between the dorsal caudate and the ventrolateral prefrontal cortex on neuroimaging. In contrast, experimental provocation of obsessive compulsive disorder symptoms reduced neural activation in brain regions implicated in goal-directed behavioral control (ventromedial prefrontal cortex, caudate) with concordant increased activation in regions implicated in habit learning (presupplementary motor area, putamen). The ventromedial prefrontal cortex plays a multifaceted role, integrating affective evaluative processes, flexible behavior, and fear learning. Findings from a neuroimaging study of Pavlovian fear reversal, in which obsessive compulsive disorder patients failed to flexibly update fear responses despite normal initial fear conditioning, suggest there is an absence of ventromedial prefrontal cortex safety signaling in obsessive compulsive disorder, which potentially undermines explicit contingency knowledge and may help to explain the link between cognitive inflexibility, fear, and anxiety processing in compulsive disorders such as obsessive compulsive disorder. PMID:29036632
Sex differences in discriminating between cues predicting threat and safety.

PubMed

Day, Harriet L L; Reed, Molly M; Stevenson, Carl W

2016-09-01

Post-traumatic stress disorder (PTSD) is more prevalent in women than men. PTSD is characterized by overgeneralization of fear to innocuous stimuli and involves impaired inhibition of learned fear by cues that predict safety. While evidence indicates that learned fear inhibition through extinction differs in males and females, less is known about sex differences in fear discrimination and safety learning. Here we examined auditory fear discrimination in male and female rats. In Experiment 1A, rats underwent 1-3days of discrimination training consisting of one tone predicting threat (CS+; presented with footshock) and another tone predicting safety (CS-; presented alone). Females, but not males, discriminated between the CS+ and CS- after one day of training. After 2-3days of training, however, males discriminated whereas females generalized between the CS+ and CS-. In Experiment 1B, females showed enhanced anxiety-like behaviour and locomotor activity in the open field, although these results were unlikely to explain the sex differences in fear discrimination. In Experiment 2, we found no differences in shock sensitivity between males and females. In Experiment 3, males and females again discriminated and generalized, respectively, after three days of training. Moreover, fear generalization in females resulted from impaired safety learning, as shown by a retardation test. Whereas subsequent fear conditioning to the previous CS- retarded learning in males, females showed no such retardation. These results suggest that, while females show fear discrimination with limited training, they show fear generalization with extended training due to impaired safety learning. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.
The role of nucleus accumbens shell in learning about neutral versus excitatory stimuli during Pavlovian fear conditioning.

PubMed

Bradfield, Laura A; McNally, Gavan P

2010-07-01

We studied the role of nucleus accumbens shell (AcbSh) in Pavlovian fear conditioning. Rats were trained to fear conditioned stimulus A (CSA) in Stage I, which was then presented in compound with a neutral stimulus and paired with shock in Stage II. AcbSh lesions had no effect on fear-learning to CSA in Stage I, but selectively prevented learning about the neutral conditioned stimulus (CS) in Stage II. These results add to a growing body of evidence indicating an important role for the ventral striatum in fear-learning. They suggest that the ventral striatum and AcbSh, in particular, directs learning toward or away from a CS as a consequence of how well that CS predicts the shock unconditioned stimulus (US). AcbSh is required to reduce the processing of established predictors, thereby permitting neutral or less predictive stimuli to be learned about.
Have we met before? Neural correlates of emotional learning in women with social phobia

PubMed Central

Laeger, Inga; Keuper, Kati; Heitmann, Carina; Kugel, Harald; Dobel, Christian; Eden, Annuschka; Arolt, Volker; Zwitserlood, Pienie; Dannlowski, Udo; Zwanzger, Peter

2014-01-01

Background Altered memory processes are thought to be a key mechanism in the etiology of anxiety disorders, but little is known about the neural correlates of fear learning and memory biases in patients with social phobia. The present study therefore examined whether patients with social phobia exhibit different patterns of neural activation when confronted with recently acquired emotional stimuli. Methods Patients with social phobia and a group of healthy controls learned to associate pseudonames with pictures of persons displaying either a fearful or a neutral expression. The next day, participants read the pseudonames in the magnetic resonance imaging scanner. Afterwards, 2 memory tests were carried out. Results We enrolled 21 patients and 21 controls in our study. There were no group differences for learning performance, and results of the memory tests were mixed. On a neural level, patients showed weaker amygdala activation than controls for the contrast of names previously associated with fearful versus neutral faces. Social phobia severity was negatively related to amygdala activation. Moreover, a detailed psychophysiological interaction analysis revealed an inverse correlation between disorder severity and frontolimbic connectivity for the emotional > neutral pseudonames contrast. Limitations Our sample included only women. Conclusion Our results support the theory of a disturbed corticolimbic interplay, even for recently learned emotional stimuli. We discuss the findings with regard to the vigilance–avoidance theory and contrast them to results indicating an oversensitive limbic system in patients with social phobia. PMID:24758944
Plasticity of Fear and Safety Neurons of the Amygdala in Response to Fear Extinction

PubMed Central

Sangha, Susan

2015-01-01

Fear inhibition learning induces plasticity and remodeling of circuits within the amygdala. Most studies examine these changes in nondiscriminative fear conditioning paradigms. Using a discriminative fear, safety, and reward conditioning task, Sangha et al. (2013) have previously reported several neural microcircuits within the basal amygdala (BA) which discriminate among these cues, including a subpopulation of neurons responding selectively to a safety cue and not a fear cue. Here, the hypothesis that these “safety” neurons isolated during discriminative conditioning are biased to become fear cue responsive as a result of extinction, when fear behavior diminishes, was tested. Although 41% of “safety” neurons became fear cue responsive as a result of extinction, the data revealed that there was no bias for these neurons to become preferentially responsive during fear extinction compared to the other identified subgroups. In addition to the plasticity seen in the “safety” neurons, 44% of neurons unresponsive to either the fear cue or safety cue during discriminative conditioning became fear cue responsive during extinction. Together these emergent responses to the fear cue as a result of extinction support the hypothesis that new learning underlies extinction. In contrast, 47% of neurons responsive to the fear cue during discriminative conditioning became unresponsive to the fear cue during extinction. These findings are consistent with a suppression of neural responding mediated by inhibitory learning, or, potentially, by direct unlearning. Together, the data support extinction as an active process involving both gains and losses of responses to the fear cue and suggests the final output of the integrated BA circuit in influencing fear behavior is a balance of excitation and inhibition, and perhaps reversal of learning-induced changes. PMID:26733838
The effects of FG7142 on overexpectation of Pavlovian fear conditioning.

PubMed

Garfield, Joshua B B; McNally, Gavan P

2009-02-01

Six experiments studied the role of GABA-sub(A) receptor activation in expression of overexpectation of Pavlovian fear conditioning. After separate pairings of CSA and CSB with shock in Stage I, rats received pairings of the compound AB with shock in Stage II, producing overexpectation of fear. The expression of overexpectation was attenuated, in a dose-dependent manner, by the benzodiazepine partial inverse agonist FG7142. FG7142 had no effect on responding to a CS paired with a low magnitude US or a CS subjected to associative blocking. These results suggest that the negative prediction error generated during overexpectation training may impose a mask on fear rather than erasing the original fear learning. They support claims that overexpectation shares features with extinction. (c) 2009 APA, all rights reserved.
Human fear extinction and return of fear using reconsolidation update mechanisms: The contribution of on-line expectancy ratings

PubMed Central

Warren, Victor Taylor; Anderson, Kemp M.; Kwon, Cliffe; Bosshardt, Lauren; Jovanovic, Tanja; Bradley, Bekh; Norrholm, Seth Davin

2015-01-01

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. PMID:24183839
Opioid Receptors Mediate Direct Predictive Fear Learning: Evidence from One-Trial Blocking

ERIC Educational Resources Information Center

Cole, Sindy; McNally, Gavan P.

2007-01-01

Pavlovian fear learning depends on predictive error, so that fear learning occurs when the actual outcome of a conditioning trial exceeds the expected outcome. Previous research has shown that opioid receptors, including [mu]-opioid receptors in the ventrolateral quadrant of the midbrain periaqueductal gray (vlPAG), mediate such predictive fear…
The Influence of Personality on Neural Mechanisms of Observational Fear and Reward Learning

ERIC Educational Resources Information Center

Hooker, Christine I.; Verosky, Sara C.; Miyakawa, Asako; Knight, Robert T.; D'Esposito, Mark

2008-01-01

Fear and reward learning can occur through direct experience or observation. Both channels can enhance survival or create maladaptive behavior. We used fMRI to isolate neural mechanisms of observational fear and reward learning and investigate whether neural response varied according to individual differences in neuroticism and extraversion.…
Age-Dependent Deficits in Fear Learning in Heterozygous BDNF Knock-Out Mice

ERIC Educational Resources Information Center

Endres, Thomas; Lessmann, Volkmar

2012-01-01

Beyond its trophic function, the neurotrophin BDNF (brain-derived neurotrophic factor) is well known to crucially mediate synaptic plasticity and memory formation. Whereas recent studies suggested that acute BDNF/TrkB signaling regulates amygdala-dependent fear learning, no impairments of cued fear learning were reported in heterozygous BDNF…
Dissociable Learning Processes Underlie Human Pain Conditioning.

PubMed

Zhang, Suyi; Mano, Hiroaki; Ganesh, Gowrishankar; Robbins, Trevor; Seymour, Ben

2016-01-11

Pavlovian conditioning underlies many aspects of pain behavior, including fear and threat detection [1], escape and avoidance learning [2], and endogenous analgesia [3]. Although a central role for the amygdala is well established [4], both human and animal studies implicate other brain regions in learning, notably ventral striatum and cerebellum [5]. It remains unclear whether these regions make different contributions to a single aversive learning process or represent independent learning mechanisms that interact to generate the expression of pain-related behavior. We designed a human parallel aversive conditioning paradigm in which different Pavlovian visual cues probabilistically predicted thermal pain primarily to either the left or right arm and studied the acquisition of conditioned Pavlovian responses using combined physiological recordings and fMRI. Using computational modeling based on reinforcement learning theory, we found that conditioning involves two distinct types of learning process. First, a non-specific "preparatory" system learns aversive facial expressions and autonomic responses such as skin conductance. The associated learning signals-the learned associability and prediction error-were correlated with fMRI brain responses in amygdala-striatal regions, corresponding to the classic aversive (fear) learning circuit. Second, a specific lateralized system learns "consummatory" limb-withdrawal responses, detectable with electromyography of the arm to which pain is predicted. Its related learned associability was correlated with responses in ipsilateral cerebellar cortex, suggesting a novel computational role for the cerebellum in pain. In conclusion, our results show that the overall phenotype of conditioned pain behavior depends on two dissociable reinforcement learning circuits. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.
The Duration of Nicotine Withdrawal-Associated Deficits in Contextual Fear Conditioning Parallels Changes in Hippocampal High Affinity Nicotinic Acetylcholine Receptor Upregulation

PubMed Central

Gould, Thomas J.; Portugal, George S.; André, Jessica M.; Tadman, Matthew P.; Marks, Michael J.; Kenney, Justin W.; Yildirim, Emre; Adoff, Michael

2012-01-01

A predominant symptom of nicotine withdrawal is cognitive deficits, yet understanding of the neural basis for these deficits is limited. Withdrawal from chronic nicotine disrupts contextual learning in mice and this deficit is mediated by direct effects of nicotine in the hippocampus. Chronic nicotine treatment upregulates nicotinic acetylcholine receptors (nAChR); however, it is unknown whether upregulation is related to the observed withdawal-induced cognitive deficits. If a relationship between altered learning and nAChR levels exists, changes in nAChR levels after cessation of nicotine treatment should match the duration of learning deficits. To test this hypothesis, mice were chronically administered 6.3 mg/kg/day (freebase) nicotine for 12 days and trained in contextual fear conditioning on day 11 or between 1 to 16 days after withdrawal of treatment. Changes in [125I]-epibatidine binding at cytisine-sensitive and cytisine-resistant nAChRs and chronic nicotine-related changes in α4, α7, and β2 nAChR subunit mRNA expression were assessed. Chronic nicotine had no behavioral effect but withdrawal produced deficits in contextual fear conditioning that lasted 4 days. Nicotine withdrawal did not disrupt cued fear conditioning. Chronic nicotine upregulated hippocampal cytisine-sensitive nAChR binding; upregulation continued after cessation of nicotine administration and the duration of upregulation during withdrawal paralleled the duration of behavioral changes. Changes in binding in cortex and cerebellum did not match behavioral changes. No changes in α4, α7, and β2 subunit mRNA expression were seen with chronic nicotine. Thus, nicotine withdrawal-related deficits in contextual learning are time-limited changes that are associated with temporal changes in upregulation of high-affinity nAChR binding. PMID:22285742
Negative appraisals and fear extinction are independently related to PTSD symptoms.

PubMed

Zuj, Daniel V; Palmer, Matthew A; Gray, Kate E; Hsu, Chia-Ming K; Nicholson, Emma L; Malhi, Gin S; Bryant, Richard A; Felmingham, Kim L

2017-08-01

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. 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. 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. 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. 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. Copyright © 2017 Elsevier B.V. All rights reserved.
Erasing fear for an imagined threat event.

PubMed

Soeter, Marieke; Kindt, Merel

2012-11-01

Although memory for emotionally arousing and stressful experiences is strong and resistant to change, recent years have witnessed rapidly emerging evidence for the plasticity of fear memories. Upon retrieval a memory may be rendered labile and vulnerable to the disruptive effects of amnestic agents. This process is referred to as "disrupting reconsolidation" and may point to a novel therapeutic strategy for the permanent reduction of fear in patients suffering from anxiety disorders. However, the fear-reducing effects are thus far only demonstrated for freezing reactions in rodents and autonomic fear responding in humans. If disrupting reconsolidation will be of value for clinical practice, it should also target the subjective feelings of anxiety. Using an instructed fear-learning paradigm in humans, we here tested whether disrupting reconsolidation would diminish the subjective feelings of anxiety for a noxious event that was anticipated but never actually experienced. Beta-adrenergic receptor blockade during reconsolidation strongly diminished the behavioral expression of the instructed fear memory (i.e., startle responding) as well as the subjective feelings of anxiety 24h later, yet without affecting both the physiological and cognitive component of the anticipation of threat (i.e., skin conductance responding, expectancy ratings). Together, the present findings suggest that the various memory traces of a learned fear association do not necessarily undergo reconsolidation in harmony. Considering that patients with anxiety disorders (1) often fear objects and situations that they have never actually experienced, and (2) primarily suffer from the subjective feelings of anxiety, the present findings may have important ramifications for psychotherapy. Copyright © 2012 Elsevier Ltd. All rights reserved.
Combined effects of complex magnetic fields and agmatine for contextual fear learning deficits in rats.

PubMed

McKay, B E; Persinger, M A

2003-04-18

Acute post-training exposures to weak intensity theta-burst stimulation (TBS) patterned complex magnetic fields attenuated the magnitude of conditioned fear learning for contextual stimuli. A similar learning impairment was evoked in a linear and dose-dependent manner by pre-conditioning injections of the polyamine agmatine. The present study examined the hypothesis that whole-body applications of the TBS complex magnetic field pattern when co-administered with systemic agmatine treatment may combine to evoke impairments in contextual fear learning. Within minutes of 4 mg/kg agmatine injections, male Wistar rats were fear conditioned to contextual stimuli and immediately exposed for 30 min to the TBS patterned complex magnetic field or to sham conditions. TBS patterned complex magnetic field treatment was found to linearly summate with the contextual fear learning impairment evoked by agmatine treatment alone. Furthermore, we report for sham-treated rats, but not rats exposed to the synthetic magnetic field pattern, that the magnitude of learned fear decreased and the amount of variability in learning increased, as the K-index (a measure of change in intensity of the time-varying ambient geomagnetic field) increased during the 3-hr intervals over which conditioning and testing sessions were conducted.
Functional gene polymorphisms in the serotonin system and traumatic life events modulate the neural basis of fear acquisition and extinction.

PubMed

Hermann, Andrea; Küpper, Yvonne; Schmitz, Anja; Walter, Bertram; Vaitl, Dieter; Hennig, Jürgen; Stark, Rudolf; Tabbert, Katharina

2012-01-01

Fear acquisition and extinction are crucial mechanisms in the etiology and maintenance of anxiety disorders. Moreover, they might play a pivotal role in conveying the influence of genetic and environmental factors on the development of a (more or less) stronger proneness for, or resilience against psychopathology. There are only few insights in the neurobiology of genetically and environmentally based individual differences in fear learning and extinction. In this functional magnetic resonance imaging study, 74 healthy subjects were investigated. These were invited according to 5-HTTLPR/rs25531 (S+ vs. L(A)L(A); triallelic classification) and TPH2 (G(-703)T) (T+ vs. T-) genotype. The aim was to investigate the influence of genetic factors and traumatic life events on skin conductance responses (SCRs) and neural responses (amygdala, insula, dorsal anterior cingulate cortex (dACC) and ventromedial prefrontal cortex (vmPFC)) during acquisition and extinction learning in a differential fear conditioning paradigm. Fear acquisition was characterized by stronger late conditioned and unconditioned responses in the right insula in 5-HTTLPR S-allele carriers. During extinction traumatic life events were associated with reduced amygdala activation in S-allele carriers vs. non-carriers. Beyond that, T-allele carriers of the TPH2 (G(-703)T) polymorphism with a higher number of traumatic life events showed enhanced responsiveness in the amygdala during acquisition and in the vmPFC during extinction learning compared with non-carriers. Finally, a combined effect of the two polymorphisms with higher responses in S- and T-allele carriers was found in the dACC during extinction. The results indicate an increased expression of conditioned, but also unconditioned fear responses in the insula in 5-HTTLPR S-allele carriers. A combined effect of the two polymorphisms on dACC activation during extinction might be associated with prolonged fear expression. Gene-by-environment interactions in amygdala and vmPFC activation may reflect a neural endophenotype translating genetic and adverse environmental influences into vulnerability for or resilience against developing affective psychopathology.
Pattern Analyses Reveal Separate Experience-Based Fear Memories in the Human Right Amygdala.

PubMed

Braem, Senne; De Houwer, Jan; Demanet, Jelle; Yuen, Kenneth S L; Kalisch, Raffael; Brass, Marcel

2017-08-23

Learning fear via the experience of contingencies between a conditioned stimulus (CS) and an aversive unconditioned stimulus (US) is often assumed to be fundamentally different from learning fear via instructions. An open question is whether fear-related brain areas respond differently to experienced CS-US contingencies than to merely instructed CS-US contingencies. Here, we contrasted two experimental conditions where subjects were instructed to expect the same CS-US contingencies while only one condition was characterized by prior experience with the CS-US contingency. Using multivoxel pattern analysis of fMRI data, we found CS-related neural activation patterns in the right amygdala (but not in other fear-related regions) that dissociated between whether a CS-US contingency had been instructed and experienced versus merely instructed. A second experiment further corroborated this finding by showing a category-independent neural response to instructed and experienced, but not merely instructed, CS presentations in the human right amygdala. Together, these findings are in line with previous studies showing that verbal fear instructions have a strong impact on both brain and behavior. However, even in the face of fear instructions, the human right amygdala still shows a separable neural pattern response to experience-based fear contingencies. SIGNIFICANCE STATEMENT In our study, we addressed a fundamental problem of the science of human fear learning and memory, namely whether fear learning via experience in humans relies on a neural pathway that can be separated from fear learning via verbal information. Using two new procedures and recent advances in the analysis of brain imaging data, we localized purely experience-based fear processing and memory in the right amygdala, thereby making a direct link between human and animal research. Copyright © 2017 the authors 0270-6474/17/378116-15$15.00/0.
Prefrontal Cortical GABA Transmission Modulates Discrimination and Latent Inhibition of Conditioned Fear: Relevance for Schizophrenia

PubMed Central

Piantadosi, Patrick T; Floresco, Stan B

2014-01-01

Inhibitory gamma-aminobutyric acid (GABA) transmission within the prefrontal cortex (PFC) regulates numerous functions, and perturbations in GABAergic transmission within this region have been proposed to contribute to some of the cognitive and behavioral abnormalities associated with disorders such as schizophrenia. These abnormalities include deficits in emotional regulation and aberrant attributions of affective salience. Yet, how PFC GABA regulates these types of emotional processes are unclear. To address this issue, we investigated the contribution of PFC GABA transmission to different aspects of Pavlovian emotional learning in rats using translational discriminative fear conditioning and latent inhibition (LI) assays. Reducing prelimbic PFC GABAA transmission via infusions of the antagonist bicuculline before the acquisition or expression of fear conditioning eliminated the ability to discriminate between an aversive conditioned stimulus (CS+) paired with footshock vs a neutral CS–, resembling similar deficits observed in schizophrenic patients. In a separate experiment, blockade of PFC GABAA receptors before CS preexposure (PE) and conditioning did not affect subsequent expression of LI, but did enhance fear in rats that were not preexposed to the CS. In contrast, PFC GABA-blockade before a fear expression test disrupted the recall of learned irrelevance and abolished LI. These data suggest that normal PFC GABA transmission is critical for regulating and mitigating multiple aspects of aversive learning, including discrimination between fear vs safety signals and recall of information about the irrelevance of stimuli. Furthermore, they suggest that similar deficits in emotional regulation observed in schizophrenia may be driven in part by deficient PFC GABA activity. PMID:24784549
Prefrontal cortical GABA transmission modulates discrimination and latent inhibition of conditioned fear: relevance for schizophrenia.

PubMed

Piantadosi, Patrick T; Floresco, Stan B

2014-09-01

Inhibitory gamma-aminobutyric acid (GABA) transmission within the prefrontal cortex (PFC) regulates numerous functions, and perturbations in GABAergic transmission within this region have been proposed to contribute to some of the cognitive and behavioral abnormalities associated with disorders such as schizophrenia. These abnormalities include deficits in emotional regulation and aberrant attributions of affective salience. Yet, how PFC GABA regulates these types of emotional processes are unclear. To address this issue, we investigated the contribution of PFC GABA transmission to different aspects of Pavlovian emotional learning in rats using translational discriminative fear conditioning and latent inhibition (LI) assays. Reducing prelimbic PFC GABAA transmission via infusions of the antagonist bicuculline before the acquisition or expression of fear conditioning eliminated the ability to discriminate between an aversive conditioned stimulus (CS+) paired with footshock vs a neutral CS-, resembling similar deficits observed in schizophrenic patients. In a separate experiment, blockade of PFC GABAA receptors before CS preexposure (PE) and conditioning did not affect subsequent expression of LI, but did enhance fear in rats that were not preexposed to the CS. In contrast, PFC GABA-blockade before a fear expression test disrupted the recall of learned irrelevance and abolished LI. These data suggest that normal PFC GABA transmission is critical for regulating and mitigating multiple aspects of aversive learning, including discrimination between fear vs safety signals and recall of information about the irrelevance of stimuli. Furthermore, they suggest that similar deficits in emotional regulation observed in schizophrenia may be driven in part by deficient PFC GABA activity.
Habenula and interpeduncular nucleus differentially modulate predator odor-induced innate fear behavior in rats.

PubMed

Vincenz, Daniel; Wernecke, Kerstin E A; Fendt, Markus; Goldschmidt, Jürgen

2017-08-14

Fear is an important behavioral system helping humans and animals to survive potentially dangerous situations. Fear can be innate or learned. Whereas the neural circuits underlying learned fear are already well investigated, the knowledge about the circuits mediating innate fear is still limited. We here used a novel, unbiased approach to image in vivo the spatial patterns of neural activity in odor-induced innate fear behavior in rats. We intravenously injected awake unrestrained rats with a 99m-technetium labeled blood flow tracer (99mTc-HMPAO) during ongoing exposure to fox urine or water as control, and mapped the brain distribution of the trapped tracer using single-photon emission computed tomography (SPECT). Upon fox urine exposure blood flow increased in a number of brain regions previously associated with odor-induced innate fear such as the amygdala, ventromedial hypothalamus and dorsolateral periaqueductal grey, but, unexpectedly, decreased at higher significance levels in the interpeduncular nucleus (IPN). Significant flow changes were found in regions monosynaptically connected to the IPN. Flow decreased in the dorsal tegmentum and entorhinal cortex. Flow increased in the habenula (Hb) and correlated with odor effects on behavioral defensive strategy. Hb lesions reduced avoidance of but increased approach to the fox urine while IPN lesions only reduced avoidance behavior without approach behavior. Our study identifies a new component, the IPN, of the neural circuit mediating odor-induced innate fear behavior in mammals and suggests that the evolutionarily conserved Hb-IPN system, which has recently been implicated in cued fear, also forms an integral part of the innate fear circuitry. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Is Trypophobia a Phobia?

PubMed

Can, Wang; Zhuoran, Zhao; Zheng, Jin

2017-04-01

In the past 10 years, thousands of people have claimed to be affected by trypophobia, which is the fear of objects with small holes. Recent research suggests that people do not fear the holes; rather, images of clustered holes, which share basic visual characteristics with venomous organisms, lead to nonconscious fear. In the present study, both self-reported measures and the Preschool Single Category Implicit Association Test were adapted for use with preschoolers to investigate whether discomfort related to trypophobic stimuli was grounded in their visual features or based on a nonconsciously associated fear of venomous animals. The results indicated that trypophobic stimuli were associated with discomfort in children. This discomfort seemed to be related to the typical visual characteristics and pattern properties of trypophobic stimuli rather than to nonconscious associations with venomous animals. The association between trypophobic stimuli and venomous animals vanished when the typical visual characteristics of trypophobic features were removed from colored photos of venomous animals. Thus, the discomfort felt toward trypophobic images might be an instinctive response to their visual characteristics rather than the result of a learned but nonconscious association with venomous animals. Therefore, it is questionable whether it is justified to legitimize trypophobia.
Acute and chronic effects of selective serotonin reuptake inhibitor treatment on fear conditioning: implications for underlying fear circuits.

PubMed

Burghardt, N S; Bauer, E P

2013-09-05

Selective serotonin reuptake inhibitors (SSRIs) are widely used for the treatment of a spectrum of anxiety disorders, yet paradoxically they may increase symptoms of anxiety when treatment is first initiated. Despite extensive research over the past 30 years focused on SSRI treatment, the precise mechanisms by which SSRIs exert these opposing acute and chronic effects on anxiety remain unknown. By testing the behavioral effects of SSRI treatment on Pavlovian fear conditioning, a well characterized model of emotional learning, we have the opportunity to identify how SSRIs affect the functioning of specific brain regions, including the amygdala, bed nucleus of the stria terminalis (BNST) and hippocampus. In this review, we first define different stages of learning involved in cued and context fear conditioning and describe the neural circuits underlying these processes. We examine the results of numerous rodent studies investigating how acute SSRI treatment modulates fear learning and relate these effects to the known functions of serotonin in specific brain regions. With these findings, we propose a model by which acute SSRI administration, by altering neural activity in the extended amygdala and hippocampus, enhances both acquisition and expression of cued fear conditioning, but impairs the expression of contextual fear conditioning. Finally, we review the literature examining the effects of chronic SSRI treatment on fear conditioning in rodents and describe how downregulation of N-methyl-d-aspartate (NMDA) receptors in the amygdala and hippocampus may mediate the impairments in fear learning and memory that are reported. While long-term SSRI treatment effectively reduces symptoms of anxiety, their disruptive effects on fear learning should be kept in mind when combining chronic SSRI treatment and learning-based therapies, such as cognitive behavioral therapy. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.
The Influence of State Anxiety on Fear Discrimination and Extinction in Females

PubMed Central

Dibbets, Pauline; Evers, Elisabeth A. T.

2017-01-01

Formal theories have linked pathological anxiety to a failure in fear response inhibition. Previously, we showed that aberrant response inhibition is not restricted to anxiety patients, but can also be observed in anxiety-prone adults. However, less is known about the influence of currently experienced levels of anxiety on inhibitory learning. The topic is highly important as state anxiety has a debilitating effect on cognition, emotion, and physiology and is linked to several anxiety disorders. In the present study, healthy female volunteers performed a fear conditioning task, after being informed that they will have to perform the Trier Social Stress Test task (n = 25; experimental group) or a control task (n = 25; control group) upon completion of the conditioning task. The results showed that higher levels of state anxiety corresponded with a reduced discrimination between a stimulus (CS+) typically followed by an aversive event and a stimulus (CS-) that is never followed by an aversive event both during the acquisition and the extinction phase. No effect of state anxiety on the skin conductance response associated with CS+ and CS- was found. Additionally, higher levels of state anxiety coincided with more negative valence ratings of the CSs. The results suggest that increased stress-induced state anxiety might lead to stimulus generalization during fear acquisition, thereby impairing associative learning. PMID:28360869
Chronic stress enhanced fear memories are associated with increased amygdala zif268 mRNA expression and are resistant to reconsolidation

PubMed Central

Hoffman, Ann N.; Parga, Alejandro; Paode, Pooja; Watterson, Lucas R.; Nikulina, Ella M.; Hammer, Ronald P.; Conrad, Cheryl D.

2015-01-01

The chronically stressed brain may present a vulnerability to develop maladaptive fear-related behaviors in response to a traumatic event. In rodents, chronic stress leads to amygdala hyperresponsivity and dendritic hypertrophy and produces a post traumatic stress disorder (PTSD)-like phenotype that includes exaggerated fear learning following Pavlovian fear conditioning and resistance to extinction. It is unknown whether chronic stress-induced enhanced fear memories are vulnerable to disruption via reconsolidation blockade, as a novel therapeutic approach for attenuating exaggerated fear memories. We used a chronic stress procedure in a rat model (wire mesh restraint for 6h/d/21d) to create a vulnerable brain that leads to a PTSD-like phenotype. We then examined freezing behavior during acquisition, reactivation and after post-reactivation rapamycin administration (i.p., 40 mg/kg) in a Pavlovian fear conditioning paradigm to determine its effects on reconsolidation as well as the subsequent functional activation of limbic structures using zif268 mRNA. Chronic stress increased amygdala zif268 mRNA during fear memory retrieval at reactivation. Moreover, these enhanced fear memories were unaffected by post reactivation rapamycin to disrupt long-term fear memory. Also, post-reactivation long term memory processing was also associated with increased amygdala (LA and BA), and decreased hippocampal CA1 zif268 mRNA expression. These results suggest potential challenges for reconsolidation blockade as an effective approach in treating exaggerated fear memories, as in PTSD. Our findings also support chronic stress manipulations combined with fear conditioning as a useful preclinical approach to study a PTSD-like phenotype. PMID:25732249
Developmental emergence of fear/threat learning: neurobiology, associations and timing.

PubMed

Tallot, L; Doyère, V; Sullivan, R M

2016-01-01

Pavlovian fear or threat conditioning, where a neutral stimulus takes on aversive properties through pairing with an aversive stimulus, has been an important tool for exploring the neurobiology of learning. In the past decades, this neurobehavioral approach has been expanded to include the developing infant. Indeed, protracted postnatal brain development permits the exploration of how incorporating the amygdala, prefrontal cortex and hippocampus into this learning system impacts the acquisition and expression of aversive conditioning. Here, we review the developmental trajectory of these key brain areas involved in aversive conditioning and relate it to pups' transition to independence through weaning. Overall, the data suggests that adult-like features of threat learning emerge as the relevant brain areas become incorporated into this learning. Specifically, the developmental emergence of the amygdala permits cue learning and the emergence of the hippocampus permits context learning. We also describe unique features of learning in early life that block threat learning and enhance interaction with the mother or exploration of the environment. Finally, we describe the development of a sense of time within this learning and its involvement in creating associations. Together these data suggest that the development of threat learning is a useful tool for dissecting adult-like functioning of brain circuits, as well as providing unique insights into ecologically relevant developmental changes. © 2015 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.
Postnatal TLR2 activation impairs learning and memory in adulthood.

PubMed

Madar, Ravit; Rotter, Aviva; Waldman Ben-Asher, Hiba; Mughal, Mohamed R; Arumugam, Thiruma V; Wood, W H; Becker, K G; Mattson, Mark P; Okun, Eitan

2015-08-01

Neuroinflammation in the central nervous system is detrimental for learning and memory, as evident form epidemiological studies linking developmental defects and maternal exposure to harmful pathogens. Postnatal infections can also induce neuroinflammatory responses with long-term consequences. These inflammatory responses can lead to motor deficits and/or behavioral disabilities. Toll like receptors (TLRs) are a family of innate immune receptors best known as sensors of microbial-associated molecular patterns, and are the first responders to infection. TLR2 forms heterodimers with either TLR1 or TLR6, is activated in response to gram-positive bacterial infections, and is expressed in the brain during embryonic development. We hypothesized that early postnatal TLR2-mediated neuroinflammation would adversely affect cognitive behavior in the adult. Our data indicate that postnatal TLR2 activation affects learning and memory in adult mice in a heterodimer-dependent manner. TLR2/6 activation improved motor function and fear learning, while TLR2/1 activation impaired spatial learning and enhanced fear learning. Moreover, developmental TLR2 deficiency significantly impairs spatial learning and enhances fear learning, stressing the involvement of the TLR2 pathway in learning and memory. Analysis of the transcriptional effects of TLR2 activation reveals both common and unique transcriptional programs following heterodimer-specific TLR2 activation. These results imply that adult cognitive behavior could be influenced in part, by activation or alterations in the TLR2 pathway at birth. Copyright © 2015 Elsevier Inc. All rights reserved.
Fear in the Classroom: An Examination of Teachers' Use of Fear Appeals and Students' Learning Outcomes

ERIC Educational Resources Information Center

Sprinkle, Rose; Hunt, Stephen; Simonds, Cheri; Comadena, Mark

2006-01-01

This study examined the impact of teachers' use of fear appeals and efficacy statements on student affective learning, motivation, likelihood of taking a course with the instructor, and likelihood of visiting with the instructor for help. The results suggest that fear and efficacy interact to more positively influence students' perceptions of…
Effects of chronic stress in adolescence on learned fear, anxiety, and synaptic transmission in the rat prelimbic cortex.

PubMed

Negrón-Oyarzo, Ignacio; Pérez, Miguel Ángel; Terreros, Gonzalo; Muñoz, Pablo; Dagnino-Subiabre, Alexies

2014-02-01

The prelimbic cortex and amygdala regulate the extinction of conditioned fear and anxiety, respectively. In adult rats, chronic stress affects the dendritic morphology of these brain areas, slowing extinction of learned fear and enhancing anxiety. The aim of this study was to determine whether rats subjected to chronic stress in adolescence show changes in learned fear, anxiety, and synaptic transmission in the prelimbic cortex during adulthood. Male Sprague Dawley rats were subjected to seven days of restraint stress on postnatal day forty-two (PND 42, adolescence). Afterward, the fear-conditioning paradigm was used to study conditioned fear extinction. Anxiety-like behavior was measured one day (PND 50) and twenty-one days (PND 70, adulthood) after stress using the elevated-plus maze and dark-light box tests, respectively. With another set of rats, excitatory synaptic transmission was analyzed with slices of the prelimbic cortex. Rats that had been stressed during adolescence and adulthood had higher anxiety-like behavior levels than did controls, while stress-induced slowing of learned fear extinction in adolescence was reversed during adulthood. As well, the field excitatory postsynaptic potentials of stressed adolescent rats had significantly lower amplitudes than those of controls, although the amplitudes were higher in adulthood. Our results demonstrate that short-term stress in adolescence induces strong effects on excitatory synaptic transmission in the prelimbic cortex and extinction of learned fear, where the effect of stress on anxiety is more persistent than on the extinction of learned fear. These data contribute to the understanding of stress neurobiology. Copyright © 2013 Elsevier B.V. All rights reserved.
Enhanced discrimination between threatening and safe contexts in high-anxious individuals

PubMed Central

Glotzbach-Schoon, Evelyn; Tadda, Regina; Andreatta, Marta; Tröger, Christian; Ewald, Heike; Grillon, Christian; Pauli, Paul; Mühlberger, Andreas

2014-01-01

Trait anxiety, a stable personality trait associated with increased fear responses to threat, is regarded as a risk factor for the development and maintenance of anxiety disorders. Although the effect of trait anxiety has been examined with regard to explicit threat cues, little is known about the effect of trait anxiety on contextual threat learning. To assess this issue, extreme groups of low and high trait anxiety underwent a contextual fear conditioning protocol using virtual reality. Two virtual office rooms served as the conditioned contexts. One virtual office room (CXT+) was paired with unpredictable electrical stimuli. In the other virtual office room, no electrical stimuli were delivered (CXT−). High-anxious participants tended to show faster acquisition of startle potentiation in the CXT+ versus the CXT− than low-anxious participants. This enhanced contextual fear learning might function as a risk factor for anxiety disorders that are characterized by sustained anxiety. PMID:23384512
Genetic disruptions of Drosophila Pavlovian learning leave extinction learning intact.

PubMed

Qin, H; Dubnau, J

2010-03-01

Individuals who experience traumatic events may develop persistent posttraumatic stress disorder. Patients with this disorder are commonly treated with exposure therapy, which has had limited long-term success. In experimental neurobiology, fear extinction is a model for exposure therapy. In this behavioral paradigm, animals are repeatedly exposed in a safe environment to the fearful stimulus, which leads to greatly reduced fear. Studying animal models of extinction already has lead to better therapeutic strategies and development of new candidate drugs. Lack of a powerful genetic model of extinction, however, has limited progress in identifying underlying molecular and genetic factors. In this study, we established a robust behavioral paradigm to study the short-term effect (acquisition) of extinction in Drosophila melanogaster. We focused on the extinction of olfactory aversive 1-day memory with a task that has been the main workhorse for genetics of memory in flies. Using this paradigm, we show that extinction can inhibit each of two genetically distinct forms of consolidated memory. We then used a series of single-gene mutants with known impact on associative learning to examine the effects on extinction. We find that extinction is intact in each of these mutants, suggesting that extinction learning relies on different molecular mechanisms than does Pavlovian learning.
D-cycloserine enhances generalization of fear extinction in children.

PubMed

Byrne, Simon P; Rapee, Ronald M; Richardson, Rick; Malhi, Gin S; Jones, Michael; Hudson, Jennifer L

2015-06-01

For exposure therapy to be successful, it is essential that fear extinction learning extends beyond the treatment setting. D-cycloserine (DCS) may facilitate treatment gains by increasing generalization of extinction learning, however, its effects have not been tested in children. We examined whether DCS enhanced generalization of fear extinction learning across different stimuli and contexts among children with specific phobias. The study was a double-blind placebo-controlled randomized controlled trial among dog or spider phobic children aged 6-14. Participants ingested either 50 mg of DCS (n = 18) or placebo (n = 17) before receiving a single prolonged exposure session to their feared stimulus. Return of fear was examined 1 week later to a different stimulus (a different dog or spider), presented in both the original treatment context and an alternate context. Avoidance and fear were measured with Behavior Approach Tests (BATs), where the child was asked to increase proximity to the stimulus while reporting their fear level. There were no differences in BAT performance between groups during the exposure session or when a new stimulus was later presented in the treatment context. However, when the new stimulus was presented in a different context, relative to placebo, the DCS group showed less avoidance (P = .03) and less increase in fear (P = .04) with moderate effect sizes. DCS enabled children to better retain their fear extinction learning. This new learning generalized to different stimuli and contexts. © 2015 Wiley Periodicals, Inc.
Disrupting reconsolidation of fear memory in humans by a noradrenergic β-blocker.

PubMed

Kindt, Merel; Soeter, Marieke; Sevenster, Dieuwke

2014-12-18

The basic design used in our human fear-conditioning studies on disrupting reconsolidation includes testing over different phases across three consecutive days. On day 1 - the fear acquisition phase, healthy participants are exposed to a series of picture presentations. One picture stimulus (CS1+) is repeatedly paired with an aversive electric stimulus (US), resulting in the acquisition of a fear association, whereas another picture stimulus (CS2-) is never followed by an US. On day 2 - the memory reactivation phase, the participants are re-exposed to the conditioned stimulus without the US (CS1-), which typically triggers a conditioned fear response. After the memory reactivation we administer an oral dose of 40 mg of propranolol HCl, a β-adrenergic receptor antagonist that indirectly targets the protein synthesis required for reconsolidation by inhibiting the noradrenaline-stimulated CREB phosphorylation. On day 3 - the test phase, the participants are again exposed to the unreinforced conditioned stimuli (CS1- and CS2-) in order to measure the fear-reducing effect of the manipulation. This retention test is followed by an extinction procedure and the presentation of situational triggers to test for the return of fear. Potentiation of the eye blink startle reflex is measured as an index for conditioned fear responding. Declarative knowledge of the fear association is measured through online US expectancy ratings during each CS presentation. In contrast to extinction learning, disrupting reconsolidation targets the original fear memory thereby preventing the return of fear. Although the clinical applications are still in their infancy, disrupting reconsolidation of fear memory seems to be a promising new technique with the prospect to persistently dampen the expression of fear memory in patients suffering from anxiety disorders and other psychiatric disorders.
Dissociation of the Role of Infralimbic Cortex in Learning and Consolidation of Extinction of Recent and Remote Aversion Memory

PubMed Central

Awad, Walaa; Ferreira, Guillaume; Maroun, Mouna

2015-01-01

Medial prefrontal circuits have been reported to undergo a major reorganization over time and gradually take a more important role for remote emotional memories such as contextual fear memory or food aversion memory. The medial prefrontal cortex, and specifically its ventral subregion, the infralimbic cortex (IL), was also reported to be critical for recent memory extinction of contextual fear conditioning and conditioned odor aversion. However, its exact role in the extinction of remotely acquired information is still not clear. Using postretrieval blockade of protein synthesis or inactivation of the IL, we showed that the IL is similarly required for extinction consolidation of recent and remote fear memory. However, in odor aversion memory, the IL was only involved in extinction consolidation of recent, but not remote, memory. In contrast, only remote retrieval of aversion memory induced c-Fos activation in the IL and preretrieval inactivation of the IL with lidocaine impaired subsequent extinction of remote but not recent memory, indicating IL is necessary for extinction learning of remote aversion memory. In contrast to the effects in odor aversion, our data show that the involvement of the IL in the consolidation of fear extinction does not depend on the memory age. More importantly, our data indicate that the IL is implicated in the extinction of fear and nonfear-based associations and suggest dissociation in the engagement of the IL in the learning and consolidation of food aversion extinction over time. PMID:25872918
Learned Together, Extinguished Apart: Reducing Fear to Complex Stimuli

ERIC Educational Resources Information Center

Jones, Carolyn E.; Ringuet, Stephanie; Monfils, Marie-H.

2013-01-01

Pairing a previously neutral conditioned stimulus (CS; e.g., a tone) to an aversive unconditioned stimulus (US; e.g., a footshock) leads to associative learning such that the tone alone comes to elicit a conditioned response (e.g., freezing). We have previously shown that an extinction session that occurs within the reconsolidation window…
Stress-enhanced fear learning in rats is resistant to the effects of immediate massed extinction

PubMed Central

Long, Virginia A.; Fanselow, Michael S.

2014-01-01

Enhanced fear learning occurs subsequent to traumatic or stressful events and is a persistent challenge to the treatment of post-traumatic stress disorder (PTSD). Facilitation of learning produced by prior stress can elicit an exaggerated fear response to a minimally aversive event or stimulus. Stress-enhanced fear learning (SEFL) is a rat model of PTSD; rats previously exposed to the SEFL 15 electrical shocks procedure exhibit several behavioral responses similar to those seen in patients with PTSD. However, past reports found that SEFL is not mitigated by extinction (a model of exposure therapy) when the spaced extinction began 24 h after stress. Recent studies found that extinction from 10 min to 1 h subsequent to fear conditioning “erased” learning, whereas later extinction, occurring from 24 to 72 h after conditioning did not. Other studies indicate that massed extinction is more effective than spaced procedures. Therefore, we examined the time-dependent nature of extinction on the stress-induced enhancement of fear learning using a massed trial’s procedure. Experimental rats received 15 foot shocks and were given either no extinction or massed extinction 10 min or 72 h later. Our present data indicate that SEFL, following traumatic stress, is resistant to immediate massed extinction. Experimental rats showed exaggerated new fear learning regardless of when extinction training occurred. Thus, post-traumatic reactivity such as SEFL does not seem responsive to extinction treatments. PMID:22176467
Inhibition of the amygdala central nucleus by stimulation of cerebellar output in rats: a putative mechanism for extinction of the conditioned fear response.

PubMed

Magal, Ari; Mintz, Matti

2014-11-01

The amygdala and the cerebellum serve two distinctively different functions. The amygdala plays a role in the expression of emotional information, whereas the cerebellum is involved in the timing of discrete motor responses. Interaction between these two systems is the basis of the two-stage theory of learning, according to which an encounter with a challenging event triggers fast classical conditioning of fear-conditioned responses in the amygdala and slow conditioning of motor-conditioned responses in the cerebellum. A third stage was hypothesised when an apparent interaction between amygdala and cerebellar associative plasticity was observed: an adaptive rate of cerebellum-dependent motor-conditioned responses was associated with a decrease in amygdala-dependent fear-conditioned responses, and was interpreted as extinction of amygdala-related fear-conditioned responses by the cerebellar output. To explore this hypothesis, we mimicked some components of classical eyeblink conditioning in anesthetised rats by applying an aversive periorbital pulse as an unconditioned stimulus and a train of pulses to the cerebellar output nuclei as a cerebellar neuronal-conditioned response. The central amygdala multiple unit response to the periorbital pulse was measured with or without a preceding train to the cerebellar output nuclei. The results showed that activation of the cerebellar output nuclei prior to periorbital stimulation produced diverse patterns of inhibition of the amygdala response to the periorbital aversive stimulus, depending upon the nucleus stimulated, the laterality of the nucleus stimulated, and the stimulus interval used. These results provide a putative extinction mechanism of learned fear behavior, and could have implications for the treatment of pathologies involving abnormal fear responses by using motor training as therapy. © 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.
Can Transcranial Direct Current Stimulation Augment Extinction of Conditioned Fear?

PubMed Central

van ’t Wout, Mascha; Mariano, Timothy Y.; Garnaat, Sarah L.; Reddy, Madhavi K.; Rasmussen, Steven A.; Greenberg, Benjamin D.

2016-01-01

Background Exposure-based therapy parallels extinction learning of conditioned fear. Prior research points to the ventromedial prefrontal cortex as a potential site for the consolidation of extinction learning and subsequent retention of extinction memory. Objective/hypothesis The present study aimed to evaluate whether the application of non-invasive transcranial direct current stimulation (tDCS) during extinction learning enhances late extinction and early recall in human participants. Methods Forty-four healthy volunteers completed a 2-day Pavlovian fear conditioning, extinction, and recall paradigm while skin conductance activity was continuously measured. Twenty-six participants received 2 mA anodal tDCS over EEG coordinate AF3 during extinction of a first conditioned stimulus. The remaining 18 participants received similar tDCS during extinction of a second conditioned stimulus. Sham stimulation was applied for the balance of extinction trials in both groups. Normalized skin conductance changes were analyzed using linear mixed models to evaluate effects of tDCS over late extinction and early recall trials. Results We observed a significant interaction between timing of tDCS during extinction blocks and changes in skin conductance reactivity over late extinction trials. These data indicate that tDCS was associated with accelerated late extinction learning of a second conditioned stimulus after tDCS was combined with extinction learning of a previous conditioned stimulus. No significant effects of tDCS timing were observed on early extinction recall. Conclusions Results could be explained by an anxiolytic aftereffect of tDCS and extend previous studies on tDCS-induced modulation of fear and threat related learning processes. These findings support further exploration of the clinical use of tDCS. PMID:27037186
Inhibiting corticosterone synthesis during fear memory formation exacerbates cued fear extinction memory deficits within the single prolonged stress model.

PubMed

Keller, Samantha M; Schreiber, William B; Stanfield, Briana R; Knox, Dayan

2015-01-01

Using the single prolonged stress (SPS) animal model of post-traumatic stress disorder (PTSD), previous studies suggest that enhanced glucocorticoid receptor (GR) expression leads to cued fear extinction retention deficits. However, it is unknown how the endogenous ligand of GRs, corticosterone (CORT), may contribute to extinction retention deficits in the SPS model. Given that CORT synthesis during fear learning is critical for fear memory consolidation and SPS enhances GR expression, CORT synthesis during fear memory formation could strengthen fear memory in SPS rats by enhancing GR activation during fear learning. In turn, this could lead to cued fear extinction retention deficits. We tested the hypothesis that CORT synthesis during fear learning leads to cued fear extinction retention deficits in SPS rats by administering the CORT synthesis inhibitor metyrapone to SPS and control rats prior to fear conditioning, and observed the effect this had on extinction memory. Inhibiting CORT synthesis during fear memory formation in control rats tended to decrease cued freezing, though this effect never reached statistical significance. Contrary to our hypothesis, inhibiting CORT synthesis during fear memory formation disrupted extinction retention in SPS rats. This finding suggests that even though SPS exposure leads to cued fear extinction memory deficits, CORT synthesis during fear memory formation enhances extinction retention in SPS rats. This suggests that stress-induced CORT synthesis in previously stressed rats can be beneficial. Copyright © 2015 Elsevier B.V. All rights reserved.
Development of fear acquisition and extinction in children: effects of age and anxiety.

PubMed

Jovanovic, Tanja; Nylocks, Karin Maria; Gamwell, Kaitlyn L; Smith, Ami; Davis, Telsie A; Norrholm, Seth Davin; Bradley, Bekh

2014-09-01

Development of anxiety disorders is associated with neurobiological changes in areas that are a critical part of the fear neurocircuitry. Fear conditioning paradigms can offer insight into the mechanisms underlying the neurobiological ontogeny of anxiety. A small number of studies have focused on the effects of age and anxiety separately in school age children. The present study aimed to investigate these effects in 8-13 year old children with higher and lower trait anxiety. We examined differential fear conditioning and extinction using skin conductance responses and fear-potentiated startle in 60 children recruited from a low-income urban population. The results indicated that children under 10 years of age show poor discrimination of conditioned stimuli, and that anxiety increases fear responses during fear acquisition. After controlling for age and trauma exposure, fear-potentiated startle to the safety cue predicted child anxiety levels suggesting that impaired safety signal learning may be a risk factor for anxiety disorders in adulthood. Identifying risk phenotypes in children may provide opportunities for early intervention and prevention of illness. Copyright © 2013 Elsevier Inc. All rights reserved.
Development of Fear Acquisition and Extinction in Children: Effects of Age and Anxiety

PubMed Central

Jovanovic, Tanja; Nylocks, Karin Maria; Gamwell, Kaitlyn L.; Smith, Ami; Davis, Telsie A.; Norrholm, Seth Davin; Bradley, Bekh

2013-01-01

Development of anxiety disorders is associated with neurobiological changes in areas that are a critical part of the fear neurocircuitry. Fear conditioning paradigms can offer insight into the mechanisms underlying the neurobiological ontogeny of anxiety. A small number of studies have focused on the effects of age and anxiety separately in school age children. The present study aimed to investigate these effects in 8-13 year old children with higher and lower trait anxiety. We examined differential fear conditioning and extinction using skin conductance responses and fear-potentiated startle in 60 children recruited from a low-income urban population. The results indicated that children under 10 years of age show poor discrimination of conditioned stimuli, and that anxiety increases fear responses during fear acquisition. After controlling for age and trauma exposure, fear-potentiated startle to the safety cue predicted child anxiety levels suggesting that impaired safety signal learning may be a risk factor for anxiety disorders in adulthood. Identifying risk phenotypes in children may provide opportunities for early intervention and prevention of illness. PMID:24183838

Trace Fear Conditioning Differentially Modulates Intrinsic Excitability of Medial Prefrontal Cortex-Basolateral Complex of Amygdala Projection Neurons in Infralimbic and Prelimbic Cortices.

PubMed

Song, Chenghui; Ehlers, Vanessa L; Moyer, James R

2015-09-30

Neuronal activity in medial prefrontal cortex (mPFC) is critical for the formation of trace fear memory, yet the cellular mechanisms underlying these memories remain unclear. One possibility involves the modulation of intrinsic excitability within mPFC neurons that project to the basolateral complex of amygdala (BLA). The current study used a combination of retrograde labeling and in vitro whole-cell patch-clamp recordings to examine the effect of trace fear conditioning on the intrinsic excitability of layer 5 mPFC-BLA projection neurons in adult rats. Trace fear conditioning significantly enhanced the intrinsic excitability of regular spiking infralimbic (IL) projection neurons, as evidenced by an increase in the number of action potentials after current injection. These changes were also associated with a reduction in spike threshold and an increase in h current. In contrast, trace fear conditioning reduced the excitability of regular spiking prelimbic (PL) projection neurons, through a learning-related decrease of input resistance. Interestingly, the amount of conditioned freezing was (1) positively correlated with excitability of IL-BLA projection neurons after conditioning and (2) negatively correlated with excitability of PL-BLA projection neurons after extinction. Trace fear conditioning also significantly enhanced the excitability of burst spiking PL-BLA projection neurons. In both regions, conditioning-induced plasticity was learning specific (observed in conditioned but not in pseudoconditioned rats), flexible (reversed by extinction), and transient (lasted <10 d). Together, these data suggest that intrinsic plasticity within mPFC-BLA projection neurons occurs in a subregion- and cell-type-specific manner during acquisition, consolidation, and extinction of trace fear conditioning. Significance statement: Frontal lobe-related function is vital for a variety of important behaviors, some of which decline during aging. This study involves a novel combination of electrophysiological recordings from fluorescently labeled mPFC-to-amygdala projection neurons in rats with acquisition and extinction of trace fear conditioning to determine how specific neurons change during behavior. This is the first study to demonstrate that trace fear conditioning significantly alters the intrinsic excitability of mPFC-to-amygdala projection neurons in a subregion- and cell-type-specific manner, which is also transient and reversed by extinction. These data are of broad interest to the neuroscientific community, and the results will inspire additional studies investigating the cellular mechanisms underlying circuit-specific changes within the brain as a result of associative learning and memory. Copyright © 2015 the authors 0270-6474/15/3513511-14$15.00/0.
Extinguishing trace fear engages the retrosplenial cortex rather than the amygdala

PubMed Central

Kwapis, Janine L.; Jarome, Timothy J.; Lee, Jonathan L.; Gilmartin, Marieke R.; Helmstetter, Fred J.

2013-01-01

Extinction learning underlies the treatment for a variety of anxiety disorders. Most of what is known about the neurobiology of extinction is based on standard “delay” fear conditioning, in which awareness is not required for learning. Little is known about how complex, explicit associations extinguish, however. “Trace” conditioning is considered to be a rodent model of explicit fear because it relies on both the cortex and hippocampus and requires explicit contingency awareness in humans. Here, we explore the neural circuit supporting trace fear extinction in order to better understand how complex memories extinguish. We first show that the amygdala is selectively involved in delay fear extinction; blocking intra-amygdala glutamate receptors disrupted delay, but not trace extinction. Further, ERK phosphorylation was increased in the amygdala after delay, but not trace extinction. We then identify the retrosplenial cortex (RSC) as a key structure supporting trace extinction. ERK phosphorylation was selectively increased in the RSC following trace extinction and blocking intra-RSC NMDA receptors impaired trace, but not delay extinction. These findings indicate that delay and trace extinction require different neural circuits; delay extinction requires plasticity in the amygdala whereas trace extinction requires the RSC. Anxiety disorders linked to explicit memory may therefore depend on cortical processes that have not been traditionally targeted by extinction studies based on delay fear. PMID:24055593
Potentiating mGluR5 function with a positive allosteric modulator enhances adaptive learning.

PubMed

Xu, Jian; Zhu, Yongling; Kraniotis, Stephen; He, Qionger; Marshall, John J; Nomura, Toshihiro; Stauffer, Shaun R; Lindsley, Craig W; Conn, P Jeffrey; Contractor, Anis

2013-07-18

Metabotropic glutamate receptor 5 (mGluR5) plays important roles in modulating neural activity and plasticity and has been associated with several neuropathological disorders. Previous work has shown that genetic ablation or pharmacological inhibition of mGluR5 disrupts fear extinction and spatial reversal learning, suggesting that mGluR5 signaling is required for different forms of adaptive learning. Here, we tested whether ADX47273, a selective positive allosteric modulator (PAM) of mGluR5, can enhance adaptive learning in mice. We found that systemic administration of the ADX47273 enhanced reversal learning in the Morris Water Maze, an adaptive task. In addition, we found that ADX47273 had no effect on single-session and multi-session extinction, but administration of ADX47273 after a single retrieval trial enhanced subsequent fear extinction learning. Together these results demonstrate a role for mGluR5 signaling in adaptive learning, and suggest that mGluR5 PAMs represent a viable strategy for treatment of maladaptive learning and for improving behavioral flexibility.
Potentiating mGluR5 function with a positive allosteric modulator enhances adaptive learning

PubMed Central

Xu, Jian; Zhu, Yongling; Kraniotis, Stephen; He, Qionger; Marshall, John J.; Nomura, Toshihiro; Stauffer, Shaun R.; Lindsley, Craig W.; Conn, P. Jeffrey; Contractor, Anis

2013-01-01

Metabotropic glutamate receptor 5 (mGluR5) plays important roles in modulating neural activity and plasticity and has been associated with several neuropathological disorders. Previous work has shown that genetic ablation or pharmacological inhibition of mGluR5 disrupts fear extinction and spatial reversal learning, suggesting that mGluR5 signaling is required for different forms of adaptive learning. Here, we tested whether ADX47273, a selective positive allosteric modulator (PAM) of mGluR5, can enhance adaptive learning in mice. We found that systemic administration of the ADX47273 enhanced reversal learning in the Morris Water Maze, an adaptive task. In addition, we found that ADX47273 had no effect on single-session and multi-session extinction, but administration of ADX47273 after a single retrieval trial enhanced subsequent fear extinction learning. Together these results demonstrate a role for mGluR5 signaling in adaptive learning, and suggest that mGluR5 PAMs represent a viable strategy for treatment of maladaptive learning and for improving behavioral flexibility. PMID:23869026
Sex differences in stress effects on emotional learning.

PubMed

Merz, Christian J; Wolf, Oliver T

2017-01-02

Stress influences emotional learning and memory processes. These effects are thought to underlie stress-associated mental disorders. Sex differences in stress reactivity and in central nervous system stress sensitivity illustrate the important modulatory role of sex hormones. This Review outlines how stress hormones influence different stages of the fear conditioning process, such as fear acquisition, extinction, and retrieval. Results will be compared with findings on the impact of stress on episodic memory. The focus is on the available human data on sex differences and the impact sex hormones have on the stress effects on emotional learning and memory. It will become apparent that the menstrual cycle but also the intake of hormonal contraceptives modulates the impact of stress on brain and behavior. Additional basic research is needed for a deeper insight regarding the interplay between stress and sex hormones in emotion and cognition. In addition, new treatment options might be derived to optimize existing strategies such as exposure therapy, which relies on the principles of fear conditioning. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.
Adolescent transitions in reflexive and non-reflexive behavior: Review of fear conditioning and impulse control in rodent models.

PubMed

Hunt, Pamela S; Burk, Joshua A; Barnet, Robert C

2016-11-01

Adolescence is a time of critical brain changes that pave the way for adult learning processes. However, the extent to which learning in adolescence is best characterized as a transitional linear progression from childhood to adulthood, or represents a period that differs from earlier and later developmental stages, remains unclear. Here we examine behavioral literature on associative fear conditioning and complex choice behavior with rodent models. Many aspects of fear conditioning are intact by adolescence and do not differ from adult patterns. Sufficient evidence, however, suggests that adolescent learning cannot be characterized simply as an immature precursor to adulthood. Across different paradigms assessing choice behavior, literature suggests that adolescent animals typically display more impulsive patterns of responding compared to adults. The extent to which the development of basic conditioning processes serves as a scaffold for later adult decision making is an additional research area that is important for theory, but also has widespread applications for numerous psychological conditions. Copyright © 2016 Elsevier Ltd. All rights reserved.
Differential splicing and glycosylation of Apoer2 alters synaptic plasticity and fear learning.

PubMed

Wasser, Catherine R; Masiulis, Irene; Durakoglugil, Murat S; Lane-Donovan, Courtney; Xian, Xunde; Beffert, Uwe; Agarwala, Anandita; Hammer, Robert E; Herz, Joachim

2014-11-25

Apoer2 is an essential receptor in the central nervous system that binds to the apolipoprotein ApoE. Various splice variants of Apoer2 are produced. We showed that Apoer2 lacking exon 16, which encodes the O-linked sugar (OLS) domain, altered the proteolytic processing and abundance of Apoer2 in cells and synapse number and function in mice. In cultured cells expressing this splice variant, extracellular cleavage of OLS-deficient Apoer2 was reduced, consequently preventing γ-secretase-dependent release of the intracellular domain of Apoer2. Mice expressing Apoer2 lacking the OLS domain had increased Apoer2 abundance in the brain, hippocampal spine density, and glutamate receptor abundance, but decreased synaptic efficacy. Mice expressing a form of Apoer2 lacking the OLS domain and containing an alternatively spliced cytoplasmic tail region that promotes glutamate receptor signaling showed enhanced hippocampal long-term potentiation (LTP), a phenomenon associated with learning and memory. However, these mice did not display enhanced spatial learning in the Morris water maze, and cued fear conditioning was reduced. Reducing the expression of the mutant Apoer2 allele so that the abundance of the protein was similar to that of Apoer2 in wild-type mice normalized spine density, hippocampal LTP, and cued fear learning. These findings demonstrated a role for ApoE receptors as regulators of synaptic glutamate receptor activity and established differential receptor glycosylation as a potential regulator of synaptic function and memory. Copyright © 2014, American Association for the Advancement of Science.
Inactivation of the Infralimbic but Not the Prelimbic Cortex Impairs Consolidation and Retrieval of Fear Extinction

ERIC Educational Resources Information Center

Laurent, Vincent; Westbrook, R. Frederick

2009-01-01

Rats were subjected to one or two cycles of context fear conditioning and extinction to study the roles of the prelimbic cortex (PL) and infralimbic cortex (IL) in learning and relearning to inhibit fear responses. Inactivation of the PL depressed fear responses across the first or second extinction but did not impair learning or relearning fear…
Zinc Transporter 3 Is Involved in Learned Fear and Extinction, but Not in Innate Fear

ERIC Educational Resources Information Center

Martel, Guillaume; Hevi, Charles; Friebely, Olivia; Baybutt, Trevor; Shumyatsky, Gleb P.

2010-01-01

Synaptically released Zn[superscript 2+] is a potential modulator of neurotransmission and synaptic plasticity in fear-conditioning pathways. Zinc transporter 3 (ZnT3) knock-out (KO) mice are well suited to test the role of zinc in learned fear, because ZnT3 is colocalized with synaptic zinc, responsible for its transport to synaptic vesicles,…
A "Fear" Studies Perspective and Critique: Analyzing English and Stengel's Progressive Study of Fear and Learning in "Education Theory." Technical Paper No. 37

ERIC Educational Resources Information Center

Fisher, R. Michael

2011-01-01

The author critiques the progressive approach of two contemporary educational philosophers (English and Stengel) on the topic of fear and learning. Using a postmodern integral approach, this article examines the tendency of reductionism, individualism, and psychologism as part of a hegemonic liberalism and modernism in discourses on fear and…
NMDA receptor antagonism disrupts the acquisition and retention of the Context Preexposure Facilitation Effect in adolescent rats

PubMed Central

Heroux, Nicholas A.; Robinson-Drummer, Patrese A.; Rosen, Jeffrey B.; Stanton, Mark E.

2016-01-01

The context preexposure facilitation effect (CPFE) is a contextual fear conditioning paradigm in which learning about the context, acquiring the context-shock association, and retrieving/expressing contextual fear are temporally dissociated. The current study investigated the involvement of NMDA receptors in contextual fear acquisition, retention, and expression across all phases of the CPFE in adolescent rats. In Experiment 1 systemic injections of 0.1 mg/kg MK-801, a non-competitive NMDA receptor antagonist, given before multiple context preexposure disrupted the acquisition of a context representation. In Experiment 2, pre-training MK-801 disrupted both immediate acquisition of contextual fear measured by postshock freezing, as well as retention test freezing 24 hours later. Experiment 3 showed that expression of contextual fear via a 24hr retention freezing test does not depend on NMDA receptors, indicating that MK-801 disrupts learning rather than performance of freezing behavior. In Experiment 4, consolidation of contextual information was partially disrupted by post-preexposure MK-801 whereas consolidation of contextual fear was not disrupted by post-training MK-801. Finally, Experiment 5 employed a dose-response design and found that a pre-training dose of 0.1 mg/kg MK-801 disrupted both postshock and retention test freezing while lower pre-training doses of MK-801 (0.025 or 0.05 mg/kg) only disrupted retention freezing. This is the first study to distinguish the role of NMDA receptors in acquisition (post-shock freezing), retention, expression, and consolidation of context vs. context-shock learning using the CPFE paradigm in adolescent rats. The findings provide a foundation for similar developmental studies examining these effects from early ontogeny through adulthood. PMID:26711910
Galectin-3 Negatively Regulates Hippocampus-Dependent Memory Formation through Inhibition of Integrin Signaling and Galectin-3 Phosphorylation

PubMed Central

Chen, Yan-Chu; Ma, Yun-Li; Lin, Cheng-Hsiung; Cheng, Sin-Jhong; Hsu, Wei-Lun; Lee, Eminy H.-Y.

2017-01-01

Galectin-3, a member of the galectin protein family, has been found to regulate cell proliferation, inhibit apoptosis and promote inflammatory responses. Galectin-3 is also expressed in the adult rat hippocampus, but its role in learning and memory function is not known. Here, we found that contextual fear-conditioning training, spatial training or injection of NMDA into the rat CA1 area each dramatically decreased the level of endogenous galectin-3 expression. Overexpression of galectin-3 impaired fear memory, whereas galectin-3 knockout (KO) enhanced fear retention, spatial memory and hippocampal long-term potentiation. Galectin-3 was further found to associate with integrin α3, an association that was decreased after fear-conditioning training. Transfection of the rat CA1 area with small interfering RNA against galectin-3 facilitated fear memory and increased phosphorylated focal adhesion kinase (FAK) levels, effects that were blocked by co-transfection of the FAK phosphorylation-defective mutant Flag-FAKY397F. Notably, levels of serine-phosphorylated galectin-3 were decreased by fear conditioning training. In addition, blockade of galectin-3 phosphorylation at Ser-6 facilitated fear memory, whereas constitutive activation of galectin-3 at Ser-6 impaired fear memory. Interestingly galectin-1 plays a role in fear-memory formation similar to that of galectin-3. Collectively, our data provide the first demonstration that galectin-3 is a novel negative regulator of memory formation that exerts its effects through both extracellular and intracellular mechanisms. PMID:28744198
Aversive olfactory associative memory loses odor specificity over time

PubMed Central

König, Christian; Antwi-Adjei, Emmanuel; Ganesan, Mathangi; Kilonzo, Kasyoka; Viswanathan, Vignesh; Durairaja, Archana; Voigt, Anne

2017-01-01

ABSTRACT Avoiding associatively learned predictors of danger is crucial for survival. Aversive memories can, however, become counter-adaptive when they are overly generalized to harmless cues and contexts. In a fruit fly odor–electric shock associative memory paradigm, we found that learned avoidance lost its specificity for the trained odor and became general to novel odors within a day of training. We discuss the possible neural circuit mechanisms of this effect and highlight the parallelism to over-generalization of learned fear behavior after an incubation period in rodents and humans, with due relevance for post-traumatic stress disorder. PMID:28468811
Positive affect protects against deficient safety learning during extinction of fear of movement-related pain in healthy individuals scoring relatively high on trait anxiety.

PubMed

Meulders, Ann; Meulders, Michel; Vlaeyen, Johan W S

2014-06-01

From a treatment perspective, it is highly relevant to pinpoint individual vulnerability factors for resistance to exposure treatment in highly fearful chronic pain patients. Previous fear conditioning research showed that healthy individuals scoring relatively high on trait anxiety display sustained fear to safety cues during extinction. In the context of fear of movement-related pain, this intriguing question has been largely neglected so far. Even more importantly, positive psychological traits such as trait positive affect may function as protective factors against the spreading of fear to safe movements and improve exposure treatment outcomes. In this study, healthy participants completed a trait anxiety and trait positive affect questionnaire and underwent acquisition and extinction of fear of movement-related pain using an experimental voluntary movement paradigm. During acquisition, one movement (CS+) was paired with a painful stimulus and another movement was not (CS-). During extinction, the CS+ was no longer reinforced. Results show failure of fear inhibition to the CS- during extinction in healthy individuals scoring relatively high on trait anxiety or relatively low on positive affect. These findings seem to suggest that safety learning is more vulnerable in healthy people with a high anxious disposition and/or relatively lower levels of positive affect. In addition, this is the first study to show that the negative impact of high trait anxiety on fear inhibition to safety cues during extinction can be countered by high levels of positive affect. These findings may have important clinical implications. Both low positive affect and high trait anxiety are associated with impaired fear inhibition to nonpainful movements during fear extinction. Interestingly, high levels of positive affect buffer against the negative impact of trait anxiety. Increasing positive affect during exposure may counter the effects of trait vulnerabilities and improve treatment outcomes. Copyright © 2014 American Pain Society. Published by Elsevier Inc. All rights reserved.
Extended fear conditioning reveals a role for both N-methyl-D-aspartic acid and non-N-methyl-D-aspartic acid receptors in the amygdala in the acquisition of conditioned fear.

PubMed

Pistell, P J; Falls, W A

2008-09-09

Pavlovian conditioning is a useful tool for elucidating the neural mechanisms involved with learning and memory, especially in regard to the stimuli associated with aversive events. The amygdala has been repeatedly implicated as playing a significant role in the acquisition and expression of fear. If the amygdala is critical for the acquisition of fear, then it should contribute to this processes regardless of the parameters used to induce or evaluate conditioned fear. A series of experiments using reversible inactivation techniques evaluated the role of the amygdala in the acquisition of conditioned fear when training was conducted over several days in rats. Fear-potentiated startle was used to evaluate the acquisition of conditioned fear. Pretraining infusions of N-methyl-d-aspartic acid (NMDA) or non-NMDA receptor antagonists alone into the amygdala interfered with the acquisition of fear early in training, but not later. Pretraining infusions of a cocktail consisting of both an NMDA and non-NMDA antagonist interfered with the acquisition of conditioned fear across all days of training. Taken together these results suggest the amygdala may potentially be critical for the acquisition of conditioned fear regardless of the parameters utilized.
Fears and Phobias

MedlinePlus

... a strong swimmer might have a fear of deep water. In this case, the fear is helpful because it cautions the person to stay safe. Someone could overcome this fear by learning how to swim safely. A fear can be ...
Contextual Change After Fear Acquisition Affects Conditioned Responding and the Time Course of Extinction Learning-Implications for Renewal Research.

PubMed

Sjouwerman, Rachel; Niehaus, Johanna; Lonsdorf, Tina B

2015-01-01

Context plays a central role in retrieving (fear) memories. Accordingly, context manipulations are inherent to most return of fear (ROF) paradigms (in particular renewal), involving contextual changes after fear extinction. Context changes are, however, also often embedded during earlier stages of ROF experiments such as context changes between fear acquisition and extinction (e.g., in ABC and ABA renewal). Previous studies using these paradigms have however focused exclusively on the context switch after extinction (i.e., renewal). Thus, the possibility of a general effect of context switch on conditioned responding that may not be conditional to preceding extinction learning remains unstudied. Hence, the current study investigated the impact of a context switch between fear acquisition and extinction on immediate conditioned responding and on the time-course of extinction learning by using a multimodal approach. A group that underwent contextual change after fear conditioning (AB; n = 36) was compared with a group without a contextual change from acquisition to extinction (AA; n = 149), while measuring physiological (skin conductance and fear potentiated startle) measures and subjective fear ratings. Contextual change between fear acquisition and extinction had a pronounced effect on both immediate conditioned responding and on the time course of extinction learning in skin conductance responses and subjective fear ratings. This may have important implications for the mechanisms underlying and the interpretation of the renewal effect (i.e., contextual switch after extinction). Consequently, future studies should incorporate designs and statistical tests that disentangle general effects of contextual change from genuine ROF effects.
Nicotine Modulation of Fear Memories and Anxiety: Implications for Learning and Anxiety Disorders

PubMed Central

Kutlu, Munir Gunes; Gould, Thomas J.

2015-01-01

Anxiety disorders are a group of crippling mental diseases affecting millions of Americans with a 30% lifetime prevalence and costs associated with healthcare of $42.3 billion. While anxiety disorders show high levels of co-morbidity with smoking (45.3% vs. 22.5% in healthy individuals), anxiety disorders are also more common among the smoking population (22% vs. 11.1% in the non-smoking population). Moreover, there is clear evidence that smoking modulates symptom severity in patients with anxiety disorders. In order to better understand this relationship, several animal paradigms are used to model several key symptoms of anxiety disorders; these include fear conditioning and measures of anxiety. Studies clearly demonstrate that nicotine mediates acquisition and extinction of fear as well as anxiety through the modulation of specific subtypes of nicotinic acetylcholine receptors (nAChRs) in brain regions involved in emotion processing such as the hippocampus. However, the direction of nicotine’s effects on these behaviors is determined by several factors that include the length of administration, hippocampus-dependency of the fear learning task, and source of anxiety (novelty-driven vs. social anxiety). Overall, the studies reviewed here suggest that nicotine alters behaviors related to fear and anxiety and that nicotine contributes to the development, maintenance, and reoccurrence of anxiety disorders. PMID:26231942
Fear conditioning and extinction in anxiety- and depression-prone persons.

PubMed

Dibbets, Pauline; van den Broek, Anne; Evers, Elisabeth A T

2015-01-01

Anxiety and depression frequently co-occur and may share similar deficits in the processing of emotional stimuli. High anxiety is associated with a failure in the acquisition and extinction of fear conditioning. Despite the supposed common deficits, no research has been conducted on fear acquisition and extinction in depression. The main aim of the present study was to investigate and compare fear acquisition and extinction in anxiety- and depression-prone participants. Non-clinical anxious, depressive, anxious-depressive and control participants performed a fear discrimination task. During acquisition, the CS+ predicted an aversive event (unconditioned stimulus, US) and the CS- safety (no US). During extinction, the CS+ was no longer followed by the US, rendering it (temporarily) into a safety signal. On each CS participants rated their US expectancy; skin conductance responses (SCRs) were measured throughout. The expectancy scores indicated that high anxiety resulted in less safety learning during acquisition and extinction; no effect of depression was observed. SCRs showed that high-anxiety persons displayed less discrimination learning (CS+ minus CS-) during acquisition than low-anxiety persons. During extinction, high-depression persons demonstrated more discriminative SCR than low-depression persons. The observed discrepancies in response patterns of high-anxiety and -depression persons seem to indicate distinctive information processing of emotional stimuli.
Collective interaction effects associated with mammalian behavioral traits reveal genetic factors connecting fear and hemostasis.

PubMed

Woo, Hyung Jun; Reifman, Jaques

2018-06-05

Investigation of the genetic architectures that influence the behavioral traits of animals can provide important insights into human neuropsychiatric phenotypes. These traits, however, are often highly polygenic, with individual loci contributing only small effects to the overall association. The polygenicity makes it challenging to explain, for example, the widely observed comorbidity between stress and cardiac disease. We present an algorithm for inferring the collective association of a large number of interacting gene variants with a quantitative trait. Using simulated data, we demonstrate that by taking into account the non-uniform distribution of genotypes within a cohort, we can achieve greater power than regression-based methods for high-dimensional inference. We analyzed genome-wide data sets of outbred mice and pet dogs, and found neurobiological pathways whose associations with behavioral traits arose primarily from interaction effects: γ-carboxylated coagulation factors and downstream neuronal signaling were highly associated with conditioned fear, consistent with our previous finding in human post-traumatic stress disorder (PTSD) data. Prepulse inhibition in mice was associated with serotonin transporter and platelet homeostasis, and noise-induced fear in dogs with hemostasis. Our findings suggest a novel explanation for the observed comorbidity between PTSD/anxiety and cardiovascular diseases: key coagulation factors modulating hemostasis also regulate synaptic plasticity affecting the learning and extinction of fear.

The Role of Nucleus Accumbens Shell in Learning about Neutral versus Excitatory Stimuli during Pavlovian Fear Conditioning

ERIC Educational Resources Information Center

Bradfield, Laura A.; McNally, Gavan P.

2010-01-01

We studied the role of nucleus accumbens shell (AcbSh) in Pavlovian fear conditioning. Rats were trained to fear conditioned stimulus A (CSA) in Stage I, which was then presented in compound with a neutral stimulus and paired with shock in Stage II. AcbSh lesions had no effect on fear-learning to CSA in Stage I, but selectively prevented learning…
Increasing the GluN2A/GluN2B Ratio in Neurons of the Mouse Basal and Lateral Amygdala Inhibits the Modification of an Existing Fear Memory Trace.

PubMed

Holehonnur, Roopashri; Phensy, Aarron J; Kim, Lily J; Milivojevic, Milica; Vuong, Dat; Daison, Delvin K; Alex, Saira; Tiner, Michael; Jones, Lauren E; Kroener, Sven; Ploski, Jonathan E

2016-09-07

Reconsolidation updating is a form of memory modification in which an existing memory can become destabilized upon retrieval and subsequently be modified via protein-synthesis-dependent reconsolidation. However, not all memories appear to destabilize upon retrieval and thus are not modifiable via reconsolidation updating approaches and the neurobiological basis for this remains poorly understood. Here, we report that auditory fear memories created with 10 tone-shock pairings are resistant to retrieval-dependent memory destabilization and are associated with an increase in the synaptic GluN2A/GluN2B ratio in neurons of the basal and lateral amygdala (BLA) compared with weaker fear memories created via one or three tone-shock pairings. To increase the GluN2A/GluN2B ratio after learning, we generated a line of mice that expresses an inducible and doxycycline-dependent GFP-GluN2A transgene specifically in α-CaMKII-positive neurons. Our findings indicate that increasing the GluN2A/GluN2B ratio in BLA α-CaMKII-positive neurons after a weak fear memory has consolidated inhibits retrieval-dependent memory destabilization and modification of the fear memory trace. This was associated with a reduction in retrieval-dependent AMPA receptor trafficking, as evidenced by a reduction in retrieval-dependent phosphorylation of GluR1 at serine-845. In addition, we determined that increasing the GluN2A/GluN2B ratio before fear learning significantly impaired long term memory consolidation, whereas short-term memory remained unaltered. An increase in the GluN2A/GluN2B ratio after fear learning had no influence on fear extinction or expression. Our results underscore the importance of NMDAR subunit composition for memory destabilization and suggest a mechanism for why some memories are resistant to modification. Memory modification using reconsolidation updating is being examined as one of the potential treatment approaches for attenuating maladaptive memories associated with emotional disorders. However, studies have shown that, whereas weak memories can be modified using reconsolidation updating, strong memories can be resistant to this approach. Therefore, treatments targeting the reconsolidation process are unlikely to be clinically effective unless methods are devised to enhance retrieval-dependent memory destabilization. Currently, little is known about the cellular and molecular events that influence the induction of reconsolidation updating. Here, we determined that an increase in the GluN2A/GluN2B ratio interferes with retrieval-dependent memory destabilization and inhibits the initiation of reconsolidation updating. Copyright © 2016 the authors 0270-6474/16/369490-15$15.00/0.
Evolutionary perspectives on learning: conceptual and methodological issues in the study of adaptive specializations.

PubMed

Krause, Mark A

2015-07-01

Inquiry into evolutionary adaptations has flourished since the modern synthesis of evolutionary biology. Comparative methods, genetic techniques, and various experimental and modeling approaches are used to test adaptive hypotheses. In psychology, the concept of adaptation is broadly applied and is central to comparative psychology and cognition. The concept of an adaptive specialization of learning is a proposed account for exceptions to general learning processes, as seen in studies of Pavlovian conditioning of taste aversions, sexual responses, and fear. The evidence generally consists of selective associations forming between biologically relevant conditioned and unconditioned stimuli, with conditioned responses differing in magnitude, persistence, or other measures relative to non-biologically relevant stimuli. Selective associations for biologically relevant stimuli may suggest adaptive specializations of learning, but do not necessarily confirm adaptive hypotheses as conceived of in evolutionary biology. Exceptions to general learning processes do not necessarily default to an adaptive specialization explanation, even if experimental results "make biological sense". This paper examines the degree to which hypotheses of adaptive specializations of learning in sexual and fear response systems have been tested using methodologies developed in evolutionary biology (e.g., comparative methods, quantitative and molecular genetics, survival experiments). A broader aim is to offer perspectives from evolutionary biology for testing adaptive hypotheses in psychological science.
Learning enhances intrinsic excitability in a subset of lateral amygdala neurons

PubMed Central

Sehgal, Megha; Ehlers, Vanessa L.; Moyer, James R.

2014-01-01

Learning-induced modulation of neuronal intrinsic excitability is a metaplasticity mechanism that can impact the acquisition of new memories. Although the amygdala is important for emotional learning and other behaviors, including fear and anxiety, whether learning alters intrinsic excitability within the amygdala has received very little attention. Fear conditioning was combined with intracellular recordings to investigate the effects of learning on the intrinsic excitability of lateral amygdala (LA) neurons. To assess time-dependent changes, brain slices were prepared either immediately or 24-h post-conditioning. Fear conditioning significantly enhanced excitability of LA neurons, as evidenced by both decreased afterhyperpolarization (AHP) and increased neuronal firing. These changes were time-dependent such that reduced AHPs were evident at both time points whereas increased neuronal firing was only observed at the later (24-h) time point. Moreover, these changes occurred within a subset (32%) of LA neurons. Previous work also demonstrated that learning-related changes in synaptic plasticity are also evident in less than one-third of amygdala neurons, suggesting that the neurons undergoing intrinsic plasticity may be critical for fear memory. These data may be clinically relevant as enhanced LA excitability following fear learning could influence future amygdala-dependent behaviors. PMID:24554670
Memory Deficits Are Associated with Impaired Ability to Modulate Neuronal Excitability in Middle-Aged Mice

ERIC Educational Resources Information Center

Kaczorowski, Catherine C.; Disterhoft, John F.

2009-01-01

Normal aging disrupts hippocampal neuroplasticity and learning and memory. Aging deficits were exposed in a subset (30%) of middle-aged mice that performed below criterion on a hippocampal-dependent contextual fear conditioning task. Basal neuronal excitability was comparable in middle-aged and young mice, but learning-related modulation of the…
The Unconscious Allocation of Cognitive Resources to Task-Relevant and Task-Irrelevant Thoughts

ERIC Educational Resources Information Center

Kuldas, Seffetullah; Hashim, Shahabuddin; Ismail, Hairul Nizam; Samsudin, Mohd Ali; Bakar, Zainudin Abu

2014-01-01

Conscious allocation of cognitive resources to task-relevant thoughts is necessary for learning. However, task-irrelevant thoughts often associated with fear of failure can enter the mind and interfere with learning. Effects like this prompt the question of whether or not learners consciously shift their cognitive resources from task-relevant to…
Persistence of Amygdala-Hippocampal Connectivity and Multi-Voxel Correlation Structures During Awake Rest After Fear Learning Predicts Long-Term Expression of Fear.

PubMed

Hermans, Erno J; Kanen, Jonathan W; Tambini, Arielle; Fernández, Guillén; Davachi, Lila; Phelps, Elizabeth A

2017-05-01

After encoding, memories undergo a process of consolidation that determines long-term retention. For conditioned fear, animal models postulate that consolidation involves reactivations of neuronal assemblies supporting fear learning during postlearning "offline" periods. However, no human studies to date have investigated such processes, particularly in relation to long-term expression of fear. We tested 24 participants using functional MRI on 2 consecutive days in a fear conditioning paradigm involving 1 habituation block, 2 acquisition blocks, and 2 extinction blocks on day 1, and 2 re-extinction blocks on day 2. Conditioning blocks were preceded and followed by 4.5-min rest blocks. Strength of spontaneous recovery of fear on day 2 served as a measure of long-term expression of fear. Amygdala connectivity primarily with hippocampus increased progressively during postacquisition and postextinction rest on day 1. Intraregional multi-voxel correlation structures within amygdala and hippocampus sampled during a block of differential fear conditioning furthermore persisted after fear learning. Critically, both these main findings were stronger in participants who exhibited spontaneous recovery 24 h later. Our findings indicate that neural circuits activated during fear conditioning exhibit persistent postlearning activity that may be functionally relevant in promoting consolidation of the fear memory. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
Intra-amygdala microinfusion of IL-6 impairs the auditory fear conditioning of rats via JAK/STAT activation.

PubMed

Hao, Yongxin; Jing, He; Bi, Qiang; Zhang, Jiaozhen; Qin, Ling; Yang, Pingting

2014-12-15

Though accumulating literature implicates that cytokines are involved in the pathophysiology of mental disorders, the role of interleukin-6 (IL-6) in learning and memory functions remains unresolved. The present study was undertaken to investigate the effect of IL-6 on amygdala-dependent fear learning. Adult Wistar rats were used along with the auditory fear conditioning test and pharmacological techniques. The data showed that infusions of IL-6, aimed at the amygdala, dose-dependently impaired the acquisition and extinction of conditioned fear. In addition, the results in the Western blot analysis confirmed that JAK/STAT was temporally activated-phosphorylated by the IL-6 treatment. Moreover, the rats were treated with JSI-124, a JAK/STAT3 inhibitor, prior to the IL-6 treatment showed a significant decrease in the IL-6 induced impairments of fear conditioning. Taken together, our results demonstrate that the learning behavior of rats in the auditory fear conditioning could be modulated by IL-6 via the amygdala. Furthermore, the JAK/STAT3 activation in the amygdala seemed to play a role in the IL-6 mediated behavioral alterations of rats in auditory fear learning. Copyright © 2014 Elsevier B.V. All rights reserved.
Social inference and social anxiety: evidence of a fear-congruent self-referential learning bias.

PubMed

Button, Katherine S; Browning, Michael; Munafò, Marcus R; Lewis, Glyn

2012-12-01

Fears of negative evaluation characterise social anxiety, and preferential processing of fear-relevant information is implicated in maintaining symptoms. Little is known, however, about the relationship between social anxiety and the process of inferring negative evaluation. The ability to use social information to learn what others think about one, referred to here as self-referential learning, is fundamental for effective social interaction. The aim of this research was to examine whether social anxiety is associated with self-referential learning. 102 Females with either high (n = 52) or low (n = 50) self-reported social anxiety completed a novel probabilistic social learning task. Using trial and error, the task required participants to learn two self-referential rules, 'I am liked' and 'I am disliked'. Participants across the sample were better at learning the positive rule 'I am liked' than the negative rule 'I am disliked', β = -6.4, 95% CI [-8.0, -4.7], p < 0.001. This preference for learning positive self-referential information was strongest in the lowest socially anxious and was abolished in the most symptomatic participants. Relative to the low group, the high anxiety group were better at learning they were disliked and worse at learning they were liked, social anxiety by rule interaction β = 3.6; 95% CI [+0.3, +7.0], p = 0.03. The specificity of the results to self-referential processing requires further research. Healthy individuals show a robust preference for learning that they are liked relative to disliked. This positive self-referential bias is reduced in social anxiety in a way that would be expected to exacerbate anxiety symptoms. Copyright © 2012 Elsevier Ltd. All rights reserved.
BAF53b, a Neuron-Specific Nucleosome Remodeling Factor, Is Induced after Learning and Facilitates Long-Term Memory Consolidation.

PubMed

Yoo, Miran; Choi, Kwang-Yeon; Kim, Jieun; Kim, Mujun; Shim, Jaehoon; Choi, Jun-Hyeok; Cho, Hye-Yeon; Oh, Jung-Pyo; Kim, Hyung-Su; Kaang, Bong-Kiun; Han, Jin-Hee

2017-03-29

Although epigenetic mechanisms of gene expression regulation have recently been implicated in memory consolidation and persistence, the role of nucleosome-remodeling is largely unexplored. Recent studies show that the functional loss of BAF53b, a postmitotic neuron-specific subunit of the BAF nucleosome-remodeling complex, results in the deficit of consolidation of hippocampus-dependent memory and cocaine-associated memory in the rodent brain. However, it is unclear whether BAF53b expression is regulated during memory formation and how BAF53b regulates fear memory in the amygdala, a key brain site for fear memory encoding and storage. To address these questions, we used viral vector approaches to either decrease or increase BAF53b function specifically in the lateral amygdala of adult mice in auditory fear conditioning paradigm. Knockdown of Baf53b before training disrupted long-term memory formation with no effect on short-term memory, basal synaptic transmission, and spine structures. We observed in our qPCR analysis that BAF53b was induced in the lateral amygdala neurons at the late consolidation phase after fear conditioning. Moreover, transient BAF53b overexpression led to persistently enhanced memory formation, which was accompanied by increase in thin-type spine density. Together, our results provide the evidence that BAF53b is induced after learning, and show that such increase of BAF53b level facilitates memory consolidation likely by regulating learning-related spine structural plasticity. SIGNIFICANCE STATEMENT Recent works in the rodent brain begin to link nucleosome remodeling-dependent epigenetic mechanism to memory consolidation. Here we show that BAF53b, an epigenetic factor involved in nucleosome remodeling, is induced in the lateral amygdala neurons at the late phase of consolidation after fear conditioning. Using specific gene knockdown or overexpression approaches, we identify the critical role of BAF53b in the lateral amygdala neurons for memory consolidation during long-term memory formation. Our results thus provide an idea about how nucleosome remodeling can be regulated during long-term memory formation and contributes to the permanent storage of associative fear memory in the lateral amygdala, which is relevant to fear and anxiety-related mental disorders. Copyright © 2017 the authors 0270-6474/17/373686-12$15.00/0.
Exposure to an obesogenic diet during adolescence leads to abnormal maturation of neural and behavioral substrates underpinning fear and anxiety.

PubMed

Vega-Torres, Julio David; Haddad, Elizabeth; Lee, Jeong Bin; Kalyan-Masih, Priya; Maldonado George, Wanda I; López Pérez, Leonardo; Piñero Vázquez, Darla M; Arroyo Torres, Yaría; Santiago Santana, José M; Obenaus, Andre; Figueroa, Johnny D

2018-05-01

Post-traumatic stress disorder (PTSD) and obesity are highly prevalent in adolescents. Emerging findings from our laboratory and others are consistent with the novel hypothesis that obese individuals may be predisposed to developing PTSD. Given that aberrant fear responses are pivotal in the pathogenesis of PTSD, the objective of this study was to determine the impact of an obesogenic Western-like high-fat diet (WD) on neural substrates associated with fear. Adolescent Lewis rats (n = 72) were fed with either the experimental WD (41.4% kcal from fat) or the control diet. The fear-potentiated startle paradigm was used to determine sustained and phasic fear responses. Diffusion tensor imaging metrics and T2 relaxation times were used to determine the structural integrity of the fear circuitry including the medial prefrontal cortex (mPFC) and the basolateral complex of the amygdala (BLA). The rats that consumed the WD exhibited attenuated fear learning and fear extinction. These behavioral impairments were associated with oversaturation of the fear circuitry and astrogliosis. The BLA T2 relaxation times were significantly decreased in the WD rats relative to the controls. We found elevated fractional anisotropy in the mPFC of the rats that consumed the WD. We show that consumption of a WD may lead to long-lasting damage to components of the fear circuitry. Our findings demonstrate that consumption of an obesogenic diet during adolescence has a profound impact in the maturation of the fear neurocircuitry. The implications of this research are significant as they identify potential biomarkers of risk for psychopathology in the growing obese population. Copyright © 2018 Elsevier Inc. All rights reserved.
Preventing the return of fear using reconsolidation updating and methylene blue is differentially dependent on extinction learning

PubMed Central

Auchter, Allison M.; Shumake, Jason; Gonzalez-Lima, Francisco; Monfils, Marie H.

2017-01-01

Many factors account for how well individuals extinguish conditioned fears, such as genetic variability, learning capacity and conditions under which extinction training is administered. We predicted that memory-based interventions would be more effective to reduce the reinstatement of fear in subjects genetically predisposed to display more extinction learning. We tested this hypothesis in rats genetically selected for differences in fear extinction using two strategies: (1) attenuation of fear memory using post-retrieval extinction training, and (2) pharmacological enhancement of the extinction memory after extinction training by low-dose USP methylene blue (MB). Subjects selectively bred for divergent extinction phenotypes were fear conditioned to a tone stimulus and administered either standard extinction training or retrieval + extinction. Following extinction, subjects received injections of saline or MB. Both reconsolidation updating and MB administration showed beneficial effects in preventing fear reinstatement, but differed in the groups they targeted. Reconsolidation updating showed an overall effect in reducing fear reinstatement, whereas pharmacological memory enhancement using MB was an effective strategy, but only for individuals who were responsive to extinction. PMID:28397861
New technologies for examining the role of neuronal ensembles in drug addiction and fear.

PubMed

Cruz, Fabio C; Koya, Eisuke; Guez-Barber, Danielle H; Bossert, Jennifer M; Lupica, Carl R; Shaham, Yavin; Hope, Bruce T

2013-11-01

Correlational data suggest that learned associations are encoded within neuronal ensembles. However, it has been difficult to prove that neuronal ensembles mediate learned behaviours because traditional pharmacological and lesion methods, and even newer cell type-specific methods, affect both activated and non-activated neurons. In addition, previous studies on synaptic and molecular alterations induced by learning did not distinguish between behaviourally activated and non-activated neurons. Here, we describe three new approaches--Daun02 inactivation, FACS sorting of activated neurons and Fos-GFP transgenic rats--that have been used to selectively target and study activated neuronal ensembles in models of conditioned drug effects and relapse. We also describe two new tools--Fos-tTA transgenic mice and inactivation of CREB-overexpressing neurons--that have been used to study the role of neuronal ensembles in conditioned fear.
Bridging the Gap: Towards a Cell-Type Specific Understanding of Neural Circuits Underlying Fear Behaviors

PubMed Central

McCullough, KM; Morrison, FG; Ressler, KJ

2016-01-01

Fear and anxiety-related disorders are remarkably common and debilitating, and are often characterized by dysregulated fear responses. Rodent models of fear learning and memory have taken great strides towards elucidating the specific neuronal circuitries underlying the learning of fear responses. The present review addresses recent research utilizing optogenetic approaches to parse circuitries underlying fear behaviors. It also highlights the powerful advances made when optogenetic techniques are utilized in a genetically defined, cell-type specific, manner. The application of next-generation genetic and sequencing approaches in a cell-type specific context will be essential for a mechanistic understanding of the neural circuitry underlying fear behavior and for the rational design of targeted, circuit specific, pharmacologic interventions for the treatment and prevention of fear-related disorders. PMID:27470092
PI3-kinase cascade has a differential role in acquisition and extinction of conditioned fear memory in juvenile and adult rats.

PubMed

Slouzkey, Ilana; Maroun, Mouna

2016-12-01

The basolateral amygdala (BLA), medial prefrontal cortex (mPFC) circuit, plays a crucial role in acquisition and extinction of fear memory. Extinction of aversive memories is mediated, at least in part, by the phosphoinositide-3 kinase (PI3K)/Akt pathway in adult rats. There is recent interest in the neural mechanisms that mediate fear and extinction in juvenile animals and whether these mechanisms are distinctive from those in adult animals. In the present study, we examined (1) changes in phosphorylation of Akt in the BLA and mPFC after fear conditioning and extinction in juvenile and adult rats and (2) the effect of BLA and mPFC localized inhibition of the PI3K following acquisition and extinction of contextual fear memory. Our results show that Akt phosphorylation is increased following acquisition of contextual fear learning in the BLA but not in the mPFC in adult and juvenile rats. Extinction learning was not associated with changes in Akt phosphorylation. Although there were no differences in the pattern of phosphorylation of Akt either in adult or juvenile rats, microinjection of the PI3K inhibitor, LY294002, into the BLA or mPFC elicited differential effects on fear memory acquisition and extinction, depending on the site and timing of the microinjection, as well as on the age of the animal. These results suggest that PI3K/Akt has a differential role in formation, retrieval, and extinction of contextual fear memory in juvenile and adult animals, and point to developmental differences between adult and juvenile rats in mechanisms of extinction. © 2016 Slouzkey and Maroun; Published by Cold Spring Harbor Laboratory Press.
Using c-Jun to identify fear extinction learning-specific patterns of neural activity that are affected by single prolonged stress.

PubMed

Knox, Dayan; Stanfield, Briana R; Staib, Jennifer M; David, Nina P; DePietro, Thomas; Chamness, Marisa; Schneider, Elizabeth K; Keller, Samantha M; Lawless, Caroline

2018-04-02

Neural circuits via which stress leads to disruptions in fear extinction is often explored in animal stress models. Using the single prolonged stress (SPS) model of post traumatic stress disorder and the immediate early gene (IEG) c-Fos as a measure of neural activity, we previously identified patterns of neural activity through which SPS disrupts extinction retention. However, none of these stress effects were specific to fear or extinction learning and memory. C-Jun is another IEG that is sometimes regulated in a different manner to c-Fos and could be used to identify emotional learning/memory specific patterns of neural activity that are sensitive to SPS. Animals were either fear conditioned (CS-fear) or presented with CSs only (CS-only) then subjected to extinction training and testing. C-Jun was then assayed within neural substrates critical for extinction memory. Inhibited c-Jun levels in the hippocampus (Hipp) and enhanced functional connectivity between the ventromedial prefrontal cortex (vmPFC) and basolateral amygdala (BLA) during extinction training was disrupted by SPS in the CS-fear group only. As a result, these effects were specific to emotional learning/memory. SPS also disrupted inhibited Hipp c-Jun levels, enhanced BLA c-Jun levels, and altered functional connectivity among the vmPFC, BLA, and Hipp during extinction testing in SPS rats in the CS-fear and CS-only groups. As a result, these effects were not specific to emotional learning/memory. Our findings suggest that SPS disrupts neural activity specific to extinction memory, but may also disrupt the retention of fear extinction by mechanisms that do not involve emotional learning/memory. Copyright © 2017 Elsevier B.V. All rights reserved.
In Search for Boundary Conditions of Reconsolidation: A Failure of Fear Memory Interference

PubMed Central

Schroyens, Natalie; Beckers, Tom; Kindt, Merel

2017-01-01

The presentation of a fear memory cue can result in mere memory retrieval, destabilization of the reactivated memory trace, or the formation of an extinction memory. The interaction between the degree of novelty during reactivation and previous learning conditions is thought to determine the outcome of a reactivation session. This study aimed to evaluate whether contextual novelty can prevent cue-induced destabilization and disruption of a fear memory acquired by non-asymptotic learning. To this end, fear memory was reactivated in a novel context or in the original context of learning, and fear memory reactivation was followed by the administration of propranolol, an amnestic drug. Remarkably, fear memory was not impaired by post-reactivation propranolol administration or extinction training under the usual conditions used in our lab, irrespective of the reactivation context. These unexpected findings are discussed in the light of our current experimental parameters and alleged boundary conditions on memory destabilization. PMID:28469565
Early life programming of fear conditioning and extinction in adult male rats.

PubMed

Stevenson, Carl W; Spicer, Clare H; Mason, Rob; Marsden, Charles A

2009-12-28

The early rearing environment programs corticolimbic function and neuroendocrine stress reactivity in adulthood. Although early environmental programming of innate fear has been previously examined, its impact on fear learning and memory later in life remains poorly understood. Here we examined the role of the early rearing environment in programming fear conditioning and extinction in adult male rats. Pups were subjected to maternal separation (MS; 360 min), brief handling (H; 15 min), or animal facility rearing (AFR) on post-natal days 2-14. As adults, animals were tested in a 3-day fear learning and memory paradigm which assessed the acquisition, expression and extinction of fear conditioning to an auditory cue; the recall of extinction was also assessed. In addition, contextual fear was assessed prior to cued extinction and its recall. We found that the acquisition of fear conditioning to the cue was modestly impaired by MS. However, no early rearing group differences were observed in cue-induced fear expression. In contrast, both the rate of extinction and extinction recall were attenuated by H. Finally, although contextual fear was reduced after extinction to the cue, no differences in context-induced fear were observed between the early rearing groups. These results add to a growing body of evidence supporting an important role for early environmental programming of fear conditioning and extinction. They also indicate that different early rearing conditions can program varying effects on distinct fear learning and memory processes in adulthood.
Inhibition of Fear by Learned Safety Signals: minisymposium review

PubMed Central

Fernando, Anushka B. P.; Kazama, Andy M.; Jovanovic, Tanja; Ostroff, Linnaea E.; Sangha, Susan

2012-01-01

Safety signals are learned cues that predict the non-occurrence of an aversive event. As such, safety signals are potent inhibitors of fear and stress responses. Investigations of safety signal learning have increased over the last few years due in part to the finding that traumatized persons are unable to utilize safety cues to inhibit fear, making it a clinically relevant phenotype. The goal of this review is to present recent advances relating to the neural and behavioral mechanisms of safety learning and expression in rodents, non-human primates and humans. PMID:23055481
Orexin A Differentially Influences the Extinction Retention of Recent and Remote Fear Memory.

PubMed

Shi, Le; Chen, Wenhao; Deng, Jiahui; Chen, Sijing; Han, Ying; Khan, Muhammad Z; Liu, Jiajia; Que, Jianyu; Bao, Yanping; Lu, Lin; Shi, Jie

2018-01-01

Recently the role of the orexin system in the learning and memory, especially orexin A, which could enhance fear memory through regulating the activity of amygdala, has drawn considerable attention. However, the relationship between orexin A and extinction memory remains unclear. To investigate the effect of orexin A on extinction memory in humans, we recruited 43 male subjects and divided them into a recent group and remote group. After acquiring Pavlovian fear conditioning, individuals in recent group experienced fear extinction 24 h after acquisition, and remote group underwent extinction 2 weeks later. Meanwhile, plasma orexin A levels before extinction were measured by enzyme-linked immunosorbent assay. Both groups received memory test 24 h after fear extinction. The results showed that both recent and remote groups successfully acquired fear conditioning and had spontaneous recovery at test. In particular, the correlational analysis indicated that orexin A levels before extinction were negatively associated with fear responses during test only in recent group, but not in remote group. Moreover, individuals with high orexin A levels still kept low fear responses after extinction in recent group by subgroup analyses. The results suggest that orexin A could influence the retention of recent fear memory extinction, without affecting remote fear extinction. These findings remind us the orexin system can be a potential treatment target for fear-related disorders, and the mechanisms of recent and remote fear extinction may be different.

Effect of Vicarious Fear Learning on Children’s Heart Rate Responses and Attentional Bias for Novel Animals

PubMed Central

2014-01-01

Research with children has shown that vicarious learning can result in changes to 2 of Lang’s (1968) 3 anxiety response systems: subjective report and behavioral avoidance. The current study extended this research by exploring the effect of vicarious learning on physiological responses (Lang’s final response system) and attentional bias. The study used Askew and Field’s (2007) vicarious learning procedure and demonstrated fear-related increases in children’s cognitive, behavioral, and physiological responses. Cognitive and behavioral changes were retested 1 week and 1 month later, and remained elevated. In addition, a visual search task demonstrated that fear-related vicarious learning creates an attentional bias for novel animals, which is moderated by increases in fear beliefs during learning. The findings demonstrate that vicarious learning leads to lasting changes in all 3 of Lang’s anxiety response systems and is sufficient to create attentional bias to threat in children. PMID:25151521
G protein-gated K+ channel ablation in forebrain pyramidal neurons selectively impairs fear learning

PubMed Central

Victoria, Nicole C.; de Velasco, Ezequiel Marron Fernandez; Ostrovskaya, Olga; Metzger, Stefania; Xia, Zhilian; Kotecki, Lydia; Benneyworth, Michael A.; Zink, Anastasia N.; Martemyanov, Kirill A.; Wickman, Kevin

2015-01-01

Background Cognitive dysfunction occurs in many debilitating conditions including Alzheimer’s disease, Down syndrome, schizophrenia, and mood disorders. The dorsal hippocampus is a critical locus of cognitive processes linked to spatial and contextual learning. G protein-gated inwardly rectifying K+ (GIRK/Kir3) channels, which mediate the postsynaptic inhibitory effect of many neurotransmitters, have been implicated in hippocampal-dependent cognition. Available evidence, however, derives primarily from constitutive gain-of-function models that lack cellular specificity. Methods We used constitutive and neuron-specific gene ablation models targeting an integral subunit of neuronal GIRK channels (GIRK2) to probe the impact of GIRK channels on associative learning and memory. Results Constitutive Girk2−/− mice exhibited a striking deficit in hippocampal-dependent (contextual) and hippocampal-independent (cue) fear conditioning. Mice lacking GIRK2 in GABA neurons (GAD-Cre:Girk2flox/flox mice) exhibited a clear deficit in GIRK-dependent signaling in dorsal hippocampal GABA neurons, but no evident behavioral phenotype. Mice lacking GIRK2 in forebrain pyramidal neurons (CaMKII-Cre(+):Girk2flox/flox mice) exhibited diminished GIRK-dependent signaling in dorsal, but not ventral, hippocampal pyramidal neurons. CaMKII-Cre(+):Girk2flox/flox mice also displayed a selective impairment in contextual fear conditioning, as both cue-fear and spatial learning were intact in these mice. Finally, loss of GIRK2 in forebrain pyramidal neurons correlated with enhanced long-term depression and blunted depotentiation of long-term potentiation at the Schaffer collateral/CA1 synapse in the dorsal hippocampus. Conclusions Our data suggest that GIRK channels in dorsal hippocampal pyramidal neurons are necessary for normal learning involving aversive stimuli, and support the contention that dysregulation of GIRK-dependent signaling may underlie cognitive dysfunction in some disorders. PMID:26612516
Plastic Synaptic Networks of the Amygdala for the Acquisition, Expression, and Extinction of Conditioned Fear

PubMed Central

Pape, Hans-Christian; Pare, Denis

2009-01-01

The last ten years have witnessed a surge of interest for the mechanisms underlying the acquisition and extinction of classically conditioned fear responses. In part, this results from the realization that abnormalities in fear learning mechanisms likely participate to the development and/or maintenance of human anxiety disorders. The simplicity and robustness of this learning paradigm, coupled to the fact that the underlying circuitry is evolutionarily well conserved makes it an ideal model to study the basic biology of memory and identify genetic factors and neuronal systems that regulate the normal and pathological expressions of learned fear. Critical advances have been made in determining how modified neuronal functions upon fear acquisition become stabilized during fear memory consolidation and how these processes are controlled in the course of fear memory extinction. With these advances, came the realization that activity in remote neuronal networks must be coordinated for these events to take place. In this paper, we review these mechanisms of coordinated network activity and the molecular cascades leading to enduring fear memory, and allowing for their extinction. We will focus on Pavlovian fear conditioning as a model and the amygdala as a key component for the acquisition and extinction of fear responses. PMID:20393190
Evidence for recovery of fear following immediate extinction in rats and humans

PubMed Central

Schiller, Daniela; Cain, Christopher K.; Curley, Nina G.; Schwartz, Jennifer S.; Stern, Sarah A.; LeDoux, Joseph E.; Phelps, Elizabeth A.

2008-01-01

Fear responses can be eliminated through extinction, a procedure involving the presentation of fear-eliciting stimuli without aversive outcomes. Extinction is believed to be mediated by new inhibitory learning that acts to suppress fear expression without erasing the original memory trace. This hypothesis is supported mainly by behavioral data demonstrating that fear can recover following extinction. However, a recent report by Myers and coworkers suggests that extinction conducted immediately after fear learning may erase or prevent the consolidation of the fear memory trace. Since extinction is a major component of nearly all behavioral therapies for human fear disorders, this finding supports the notion that therapeutic intervention beginning very soon after a traumatic event will be more efficacious. Given the importance of this issue, and the controversy regarding immediate versus delayed therapeutic interventions, we examined two fear recovery phenomena in both rats and humans: spontaneous recovery (SR) and reinstatement. We found evidence for SR and reinstatement in both rats and humans even when extinction was conducted immediately after fear learning. Thus, our data do not support the hypothesis that immediate extinction erases the original memory trace, nor do they suggest that a close temporal proximity of therapeutic intervention to the traumatic event might be advantageous. PMID:18509113
The role of GluN2B-containing NMDA receptors in short- and long-term fear recall.

PubMed

Mikics, Eva; Toth, Mate; Biro, Laszlo; Bruzsik, Biborka; Nagy, Boglarka; Haller, Jozsef

2017-08-01

N-methyl-d-aspartate (NMDA) receptors are crucial synaptic elements in long-term memory formation, including the associative learning of fearful events. Although NMDA blockers were consistently shown to inhibit fear memory acquisition and recall, the clinical use of general NMDA blockers is hampered by their side effects. Recent studies revealed significant heterogeneity in the distribution and neurophysiological characteristics of NMDA receptors with different GluN2 (NR2) subunit composition, which may have differential role in fear learning and recall. To investigate the specific role of NMDA receptor subpopulations with different GluN2 subunit compositions in the formation of lasting traumatic memories, we contrasted the effects of general NMDA receptor blockade with GluN2A-, GluN2B-, and GluN2C/D subunit selective antagonists (MK-801, PEAQX, Ro25-6981, PPDA, respectively). To investigate acute and lasting consequences, behavioral responses were investigated 1 and 28days after fear conditioning. We found that MK-801 (0.05 and 0.1mg/kg) decreased fear recall at both time points. GluN2B receptor subunit blockade produced highly similar effects, albeit efficacy was somewhat smaller 28days after fear conditioning. Unlike MK-801, Ro25-6981 (3 and 10mg/kg) did not affect locomotor activity in the open-field. In contrast, GluN2A and GluN2C/D blockers (6 and 20mg/kg PEAQX; 3 and 10mg/kg PPDA, respectively) had no effect on conditioned fear recall at any time point and dose. This sharp contrast between GluN2B- and other subunit-containing NMDA receptor function indicates that GluN2B receptor subunits are intimately involved in fear memory formation, and may provide a novel pharmacological target in post-traumatic stress disorder or other fear-related disorders. Copyright © 2017 Elsevier Inc. All rights reserved.
Cholinergic Modulation during Acquisition of Olfactory Fear Conditioning Alters Learning and Stimulus Generalization in Mice

ERIC Educational Resources Information Center

Pavesi, Eloisa; Gooch, Allison; Lee, Elizabeth; Fletcher, Max L.

2013-01-01

We investigated the role of cholinergic neurotransmission in olfactory fear learning. Mice receiving pairings of odor and foot shock displayed fear to the trained odor the following day. Pretraining injections of the nicotinic antagonist mecamylamine had no effect on subsequent freezing, while the muscarinic antagonist scopolamine significantly…
Brain structural connectivity and context-dependent extinction memory.

PubMed

Hermann, Andrea; Stark, Rudolf; Blecker, Carlo R; Milad, Mohammed R; Merz, Christian J

2017-08-01

Extinction of conditioned fear represents an important mechanism in the treatment of anxiety disorders. Return of fear after successful extinction or exposure therapy in patients with anxiety disorders might be linked to poor temporal or contextual generalization of extinction due to individual differences in brain structural connectivity. The goal of this magnetic resonance imaging study was therefore to investigate the association of context-dependent extinction recall with brain structural connectivity. Diffusion-tensor imaging was used to determine the fractional anisotropy as a measure of white matter structural integrity of fiber tracts connecting central brain regions of the fear and extinction circuit (uncinate fasciculus, cingulum). Forty-five healthy men participated in a two-day fear conditioning experiment with fear acquisition in context A and extinction learning in context B on the first day. Extinction recall in the extinction context as well as renewal in the acquisition context and a novel context C took place one day later. Renewal of conditioned fear (skin conductance responses) in the acquisition context was associated with higher structural integrity of the hippocampal part of the cingulum. Enhanced structural integrity of the cingulum might be related to stronger hippocampal modulation of the dorsal anterior cingulate cortex, a region important for modulating conditioned fear output by excitatory projections to the amygdala. This finding underpins the crucial role of individual differences in the structural integrity of relevant fiber tracts for context-dependent extinction recall and return of fear after exposure therapy in anxiety disorders. © 2017 Wiley Periodicals, Inc.
Experience-dependent modification of a central amygdala fear circuit

PubMed Central

Li, Haohong; Penzo, Mario A.; Taniguchi, Hiroki; Kopec, Charles D.; Huang, Z. Josh; Li, Bo

2013-01-01

The amygdala is essential for fear learning and expression. The central amygdala (CeA), once viewed as a passive relay between the amygdala complex and downstream fear effectors, has emerged as an active participant in fear conditioning. However, how CeA contributes to the learning and expression of fear is unclear. Here we show in mice that fear conditioning induces robust plasticity of excitatory synapses onto inhibitory neurons in the lateral subdivision of CeA (CeL). This experience-dependent plasticity is cell-specific, bidirectional, and expressed presynaptically by inputs from the lateral amygdala. In particular, preventing synaptic potentiation onto somatostatin-positive neurons impairs fear memory formation. Furthermore, activation of these neurons is necessary for fear memory recall and sufficient to drive fear responses. Our findings support a model in which the fear conditioning-induced synaptic modifications in CeL favor the activation of somatostatin-positive neurons, which inhibit CeL output thereby disinhibiting the medial subdivision of CeA and releasing fear expression. PMID:23354330
Epigenetic regulation of BDNF gene transcription in the consolidation of fear memory.

PubMed

Lubin, Farah D; Roth, Tania L; Sweatt, J David

2008-10-15

Long-term memory formation requires selective changes in gene expression. Here, we determined the contribution of chromatin remodeling to learning-induced changes in brain-derived neurotrophic factor (bdnf) gene expression in the adult hippocampus. Contextual fear learning induced differential regulation of exon-specific bdnf mRNAs (I, IV, VI, IX) that was associated with changes in bdnf DNA methylation and altered local chromatin structure. Infusions of zebularine (a DNA methyltransferase inhibitor) significantly altered bdnf DNA methylation and triggered changes in exon-specific bdnf mRNA levels, indicating that altered DNA methylation is sufficient to drive differential bdnf transcript regulation in the hippocampus. In addition, NMDA receptor blockade prevented memory-associated alterations in bdnf DNA methylation, resulting in a block of altered bdnf gene expression in hippocampus and a deficit in memory formation. These results suggest epigenetic modification of the bdnf gene as a mechanism for isoform-specific gene readout during memory consolidation.
Impaired contextual fear-conditioning in MAM rodent model of schizophrenia.

PubMed

Gill, Kathryn M; Miller, Sarah A; Grace, Anthony A

2018-05-01

The methylazoxymethanol acetate (MAM) rodent neurodevelopmental model of schizophrenia exhibits aberrant dopamine system activation attributed to hippocampal dysfunction. Context discrimination is a component of numerous behavioral and cognitive functions and relies on intact hippocampal processing. The present study explored context processing behaviors, along with dopamine system activation, during fear learning in the MAM model. Male offspring of dams treated with MAM (20mg/kg, i.p.) or saline on gestational day 17 were used for electrophysiological and behavioral experiments. Animals were tested on the immediate shock fear conditioning paradigm, with either different pre-conditioning contexts or varying amounts of context pre-exposure (0-10 sessions). Amphetamine-induced locomotor activity and dopamine neural activity was measured 1-week after fear conditioning. Saline, but not MAM animals, demonstrated enhanced fear responses following a single context pre-exposure in the conditioning context. One week following fear learning, saline rats with 2 or 7min of context pre-exposure prior to fear conditioning also demonstrated enhanced amphetamine-induced locomotor response relative to MAM animals. Dopamine neuron recordings showed fear learning-induced reductions in spontaneous dopamine neural activity in MAM rats that was further reduced by amphetamine. Apomorphine administration confirmed that reductions in dopamine neuron activity in MAM animals resulted from over excitation, or depolarization block. These data show a behavioral insensitivity to contextual stimuli in MAM rats that coincide with a less dynamic dopamine response after fear learning. Copyright © 2017 Elsevier B.V. All rights reserved.
Pharmacogenetic reactivation of the original engram evokes an extinguished fear memory.

PubMed

Yoshii, Takahiro; Hosokawa, Hiroshi; Matsuo, Naoki

2017-02-01

Fear memory extinction has several characteristic behavioral features, such as spontaneous recovery, renewal, and reinstatement, suggesting that extinction training does not erase the original association between the conditioned stimulus (CS) and the unconditioned stimulus (US). However, it is unclear whether reactivation of the original physical record of memory (i.e., memory trace) is sufficient to produce conditioned fear response after extinction. Here, we performed pharmacogenetic neuronal activation using transgenic mice expressing hM3Dq DREADD (designer receptor exclusively activated by designer drug) under the control of the activity-dependent c-fos gene promoter. Neuronal ensembles activated during fear-conditioned learning were tagged with hM3Dq and subsequently reactivated after extinction training. The mice exhibited significant freezing, even when the fear memory was no longer triggered by external CS, indicating that the artificial reactivation of a specific neuronal ensemble was sufficient to evoke the extinguished fear response. This freezing was not observed in non-fear-conditioned mice expressing hM3dq in the same brain areas. These results directly demonstrated that at least part of the original fear memory trace remains after extinction, and such residual plasticity might reflect the persistent memory. Copyright Â© 2016 Elsevier Ltd. All rights reserved.
Recognizing Student Fear: The Elephant in the Classroom

ERIC Educational Resources Information Center

Bledsoe, T. Scott; Baskin, Janice J.

2014-01-01

Understanding fear, its causes, and its impact on students can be important for educators who seek ways to help students manage their fears. This paper explores common types of student fears such as performance-based anxiety, fear of failure, fear of being laughed at, and cultural components of fear that impact learning. The cognitive, emotional,…
The central amygdala controls learning in the lateral amygdala

PubMed Central

Yu, Kai; Ahrens, Sandra; Zhang, Xian; Schiff, Hillary; Ramakrishnan, Charu; Fenno, Lief; Deisseroth, Karl; Zhao, Fei; Luo, Min-Hua; Gong, Ling; He, Miao; Zhou, Pengcheng; Paninski, Liam; Li, Bo

2018-01-01

Experience-driven synaptic plasticity in the lateral amygdala (LA) is thought to underlie the formation of associations between sensory stimuli and an ensuing threat. However, how the central amygdala (CeA) participates in such learning process remains unclear. Here we show that PKC-δ-expressing CeA neurons are essential for the synaptic plasticity underlying learning in the LA, as they convey information about unconditioned stimulus to LA neurons during fear conditioning. PMID:29184202
Feedback from the heart: Emotional learning and memory is controlled by cardiac cycle, interoceptive accuracy and personality.

PubMed

Pfeifer, Gaby; Garfinkel, Sarah N; Gould van Praag, Cassandra D; Sahota, Kuljit; Betka, Sophie; Critchley, Hugo D

2017-05-01

Feedback processing is critical to trial-and-error learning. Here, we examined whether interoceptive signals concerning the state of cardiovascular arousal influence the processing of reinforcing feedback during the learning of 'emotional' face-name pairs, with subsequent effects on retrieval. Participants (N=29) engaged in a learning task of face-name pairs (fearful, neutral, happy faces). Correct and incorrect learning decisions were reinforced by auditory feedback, which was delivered either at cardiac systole (on the heartbeat, when baroreceptors signal the contraction of the heart to the brain), or at diastole (between heartbeats during baroreceptor quiescence). We discovered a cardiac influence on feedback processing that enhanced the learning of fearful faces in people with heightened interoceptive ability. Individuals with enhanced accuracy on a heartbeat counting task learned fearful face-name pairs better when feedback was given at systole than at diastole. This effect was not present for neutral and happy faces. At retrieval, we also observed related effects of personality: First, individuals scoring higher for extraversion showed poorer retrieval accuracy. These individuals additionally manifested lower resting heart rate and lower state anxiety, suggesting that attenuated levels of cardiovascular arousal in extraverts underlies poorer performance. Second, higher extraversion scores predicted higher emotional intensity ratings of fearful faces reinforced at systole. Third, individuals scoring higher for neuroticism showed higher retrieval confidence for fearful faces reinforced at diastole. Our results show that cardiac signals shape feedback processing to influence learning of fearful faces, an effect underpinned by personality differences linked to psychophysiological arousal. Copyright © 2017 Elsevier B.V. All rights reserved.
Nicotinic Receptors in the Dorsal and Ventral Hippocampus Differentially Modulate Contextual Fear Conditioning

PubMed Central

Kenney, Justin W.; Raybuck, Jonathan D.; Gould, Thomas J.

2012-01-01

Nicotine administration alters various forms of hippocampus-dependent learning and memory. Increasing work has found that the dorsal and ventral hippocampus differentially contribute to multiple behaviors. Thus, the present study examined whether the effects of nicotine in the dorsal and ventral hippocampus have distinct influences on contextual fear learning in male C57BL/6J mice. Direct infusion of nicotine into the dorsal hippocampus resulted in an enhancement of contextual fear learning, whereas nicotine infused into the ventral hippocampus resulted in deficits. Nicotine infusions into the ventral hippocampus did not alter hippocampus-independent cued fear conditioning or time spent in the open arm of the elevated plus maze, a measure of anxiety, suggesting the effects are due to alterations in contextual learning and not other general processes. Finally, results from using direct infusions of MLA, a low-affinity α7 nicotinic acetylcholine receptor (nAChR) antagonist, in conjunction with systemic nicotine, provide evidence that α7-nAChRs in the ventral hippocampus mediate the detrimental effect of ventral hippocampal nicotine on contextual fear learning. These results suggest that with systemic nicotine administration, competition exists between the dorsal and ventral hippocampus for behavioral control over contextual learning. PMID:22271264
A preliminary study of the effects of individual response to challenge tests and stress induced by humans on learning performance of weaned piglets (Sus scrofa).

PubMed

Brajon, Sophie; Laforest, Jean-Paul; Schmitt, Océane; Devillers, Nicolas

2016-08-01

This study investigated whether individual behavioural characteristics of piglets and stress induced by experience with humans can influence learning performance. After weaning, piglets received a chronic experience with humans to modulate their emotional state: rough (ROU), gentle (GEN), or minimal (MIN) experience. Simultaneously, they were trained on a discrimination task. Afterward, their behaviour during challenge tests was assessed. The first learning step of the task involved associating a positive sound cue with a response (approach a trough) and success of piglets depended mostly on motivation to seek for reward. Although the experience with humans did not have direct effect, the degree of fear of handler, measured based on their reactivity to a human approach test, was related to motivation to seek rewards and learning speed of this first step in stressed ROU piglets, but not in MIN and GEN piglets. In contrast, the second learning step was more cognitively challenging, since it involved discrimination learning, including negative cues during which piglets had to learn to avoid the trough. Locomotion activity, measured during an open-field test, was associated with performance of the discrimination learning. To conclude, fearfulness towards humans and locomotion activity are linked with learning performance in relation to task complexity, highlighting the necessity to take into account these factors in animal research and management. Crown Copyright © 2016. Published by Elsevier B.V. All rights reserved.
A role for the anteromedial thalamic nucleus in the acquisition of contextual fear memory to predatory threats.

PubMed

de Lima, Miguel Antonio Xavier; Baldo, Marcus Vinicius C; Canteras, Newton Sabino

2017-01-01

Previous studies from our group have shown that cytotoxic lesions in the ventral portion of the anteromedial thalamic nucleus (AMv), one of the main targets of the hypothalamic predator-responsive circuit, strongly impairs contextual fear responses to an environment previously associated with a predator. The AMv is in a position to convey information to cortico-hippocampal-amygdalar circuits involved in the processing of fear memory. However, it remains to be determined whether the nucleus is involved in the acquisition or subsequent expression of contextual fear. In the present investigation, we addressed this question by inactivating the rat AMv with muscimol either prior to cat exposure or prior to exposure to the cat-related context. Accordingly, AMv pharmacological inactivation prior to cat exposure did not interfere with innate fear responses, but it drastically reduced contextual conditioning to the predator-associated environment. On the other hand, AMv inactivation prior to exposure to the environment associated with the predator threat did not affect contextual fear responses. The behavioral results were further supported by the demonstration that AMv inactivation prior to cat exposure also blocked the activation of sites critically involved in the expression of anti-predatory contextual defensive responses (i.e., the dorsal premammillary nucleus and the dorsolateral periaqueductal gray) in animals exposed to the predator-associated context. The AMv projections were also examined, and the results of this investigation outline important paths that can influence hippocampal circuitry and raise new ideas for anterior thalamic-hippocampal paths involved in emotional learning.
The central amygdala circuits in fear regulation

NASA Astrophysics Data System (ADS)

Li, Bo

The amygdala is essential for fear learning and expression. The central amygdala (CeA), once viewed as a passive relay between the amygdala complex and downstream fear effectors, has emerged as an active participant in fear conditioning. However, how the CeA contributes to the learning and expression of fear remains unclear. Our recent studies in mice indicate that fear conditioning induces robust plasticity of excitatory synapses onto inhibitory neurons in the lateral subdivision of CeA (CeL). In particular, this plasticity is cell-type specific and is required for the formation of fear memory. In addition, sensory cues that predict threat can cause activation of the somatostatin-positive CeL neurons, which is sufficient to drive freezing behavior. Here I will report our recent findings regarding the circuit and cellular mechanisms underlying CeL function in fear processing.
Molecular mechanisms of D-cycloserine in facilitating fear extinction: insights from RNAseq.

PubMed

Malan-Müller, Stefanie; Fairbairn, Lorren; Daniels, Willie M U; Dashti, Mahjoubeh Jalali Sefid; Oakeley, Edward J; Altorfer, Marc; Kidd, Martin; Seedat, Soraya; Gamieldien, Junaid; Hemmings, Sîan Megan Joanna

2016-02-01

D-cycloserine (DCS) has been shown to be effective in facilitating fear extinction in animal and human studies, however the precise mechanisms whereby the co-administration of DCS and behavioural fear extinction reduce fear are still unclear. This study investigated the molecular mechanisms of intrahippocampally administered D-cycloserine in facilitating fear extinction in a contextual fear conditioning animal model. Male Sprague Dawley rats (n = 120) were grouped into four experimental groups (n = 30) based on fear conditioning and intrahippocampal administration of either DCS or saline. The light/dark avoidance test was used to differentiate maladapted (MA) (anxious) from well-adapted (WA) (not anxious) subgroups. RNA extracted from the left dorsal hippocampus was used for RNA sequencing and gene expression data was compared between six fear-conditioned + saline MA (FEAR + SALINE MA) and six fear-conditioned + DCS WA (FEAR + DCS WA) animals. Of the 424 significantly downregulated and 25 significantly upregulated genes identified in the FEAR + DCS WA group compared to the FEAR + SALINE MA group, 121 downregulated and nine upregulated genes were predicted to be relevant to fear conditioning and anxiety and stress-related disorders. The majority of downregulated genes transcribed immune, proinflammatory and oxidative stress systems molecules. These molecules mediate neuroinflammation and cause neuronal damage. DCS also regulated genes involved in learning and memory processes, and genes associated with anxiety, stress-related disorders and co-occurring diseases (e.g., cardiovascular diseases, digestive system diseases and nervous system diseases). Identifying the molecular underpinnings of DCS-mediated fear extinction brings us closer to understanding the process of fear extinction.
Differential Regulation of Glutamic Acid Decarboxylase Gene Expression after Extinction of a Recent Memory vs. Intermediate Memory

ERIC Educational Resources Information Center

Sangha, Susan; Ilenseer, Jasmin; Sosulina, Ludmila; Lesting, Jorg; Pape, Hans-Christian

2012-01-01

Extinction reduces fear to stimuli that were once associated with an aversive event by no longer coupling the stimulus with the aversive event. Extinction learning is supported by a network comprising the amygdala, hippocampus, and prefrontal cortex. Previous studies implicate a critical role of GABA in extinction learning, specifically the GAD65…

Potentiating mGluR5 Function with a Positive Allosteric Modulator Enhances Adaptive Learning

ERIC Educational Resources Information Center

Xu, Jian; Zhu, Yongling; Kraniotis, Stephen; He, Qionger; Marshall, John J.; Nomura, Toshihiro; Stauffer, Shaun R.; Lindsley, Craig W.; Conn, P. Jeffrey; Contractor, Anis

2013-01-01

Metabotropic glutamate receptor 5 (mGluR5) plays important roles in modulating neural activity and plasticity and has been associated with several neuropathological disorders. Previous work has shown that genetic ablation or pharmacological inhibition of mGluR5 disrupts fear extinction and spatial reversal learning, suggesting that mGluR5…
Racial stereotypes impair flexibility of emotional learning

PubMed Central

Kubota, Jennifer T.; Li, Jian; Coelho, Cesar A.O.; Phelps, Elizabeth A.

2016-01-01

Flexibility of associative learning can be revealed by establishing and then reversing cue-outcome discriminations. Here, we used functional MRI to examine whether neurobehavioral correlates of reversal-learning are impaired in White and Asian volunteers when initial learning involves fear-conditioning to a racial out-group. For one group, the picture of a Black male was initially paired with shock (threat) and a White male was unpaired (safe). For another group, the White male was a threat and the Black male was safe. These associations reversed midway through the task. Both groups initially discriminated threat from safety, as expressed through skin conductance responses (SCR) and activity in the insula, thalamus, midbrain and striatum. After reversal, the group initially conditioned to a Black male exhibited impaired reversal of SCRs to the new threat stimulus (White male), and impaired reversals in the striatum, anterior cingulate cortex, midbrain and thalamus. In contrast, the group initially conditioned to a White male showed successful reversal of SCRs and successful reversal in these brain regions toward the new threat. These findings provide new evidence that an aversive experience with a racial out-group member impairs the ability to flexibly and appropriately adjust fear expression towards a new threat in the environment. PMID:27107298
Inhibition of spontaneous recovery of fear by mGluR5 after prolonged extinction training.

PubMed

Mao, Sheng-Chun; Chang, Chih-Hua; Wu, Chia-Chen; Orejarena, M Juliana; Orejanera, Maria Juliana; Manzoni, Olivier J; Gean, Po-Wu

2013-01-01

Fear behavior is vital for survival and involves learning contingent associations of non-threatening cues with aversive stimuli. In contrast, excessive levels of fear can be maladaptive and lead to anxiety disorders. Generally, extensive sessions of extinction training correlates with reduced spontaneous recovery. The molecular mechanisms underlying the long-term inhibition of fear recovery following repeated extinction training are not fully understood. Here we show that in rats, prolonged extinction training causes greater reduction in both fear-potentiated startle and spontaneous recovery. This effect was specifically blocked by metabotropic glutamate receptor 5 (mGluR5), but not by mGluR1 antagonists and by a protein synthesis inhibitor. Similar inhibition of memory recovery following prolonged extinction training was also observed in mice. In agreement with the instrumental role of mGluR5 in the prolonged inhibition of fear recovery, we found that FMR1-/- mice which exhibit enhanced mGluR5-mediated signaling exhibit lower spontaneous recovery of fear after extinction training than wild-type littermates. At the molecular level, we discovered that prolonged extinction training reversed the fear conditioning-induced increase in surface expression of GluR1, AMPA/NMDA ratio, postsynaptic density-95 (PSD-95) and synapse-associated protein-97 (SAP97). Accordingly, delivery of Tat-GluR2(3Y), a synthetic peptide that blocks AMPA receptor endocytosis, inhibited prolonged extinction training-induced inhibition of fear recovery. Together, our results demonstrate that prolonged extinction training results in the mGluR5-dependent long-term inhibition of fear recovery. This effect may involve the degradation of original memory and may explain the beneficial effects of prolonged exposure therapy for the treatment of phobias.
Learning about associations: evidence for a hierarchical account of occasion setting.

PubMed

Bonardi, Charlotte; Jennings, Dómhnall

2009-07-01

In 2 experiments rats were trained on a switching discrimination, with 4 occasion setters, A, B, C, and D and 2 target stimuli, x and y. When signaled either by A or by B, x was reinforced with food and y was not, whereas when signaled either by C or by D these reinforcement relations were reversed (i.e., A: --> x+, A: y --> -, B: x --> +, B: y --> -, C: x --> -, C: y --> +, D: x --> -, D: y --> +). In a subsequent Stage A was paired with shock, and then the degree to which food-reinforced (Experiment 1a) and nonreinforced (Experiment 1b) presentations of x and y were capable of eliciting fear was assessed. Those conditioned stimulus (CS)/unconditioned stimulus (US) relations that had been operative in the presence of the fear-eliciting occasion setter A (i.e., x --> +, y --> -) elicited more fear than the alternative CS/US combinations (i.e., x --> -, y --> +). The implications of these findings are discussed with reference to theories of occasion setting and of configural learning.
Prediction errors to emotional expressions: the roles of the amygdala in social referencing.

PubMed

Meffert, Harma; Brislin, Sarah J; White, Stuart F; Blair, James R

2015-04-01

Social referencing paradigms in humans and observational learning paradigms in animals suggest that emotional expressions are important for communicating valence. It has been proposed that these expressions initiate stimulus-reinforcement learning. Relatively little is known about the role of emotional expressions in reinforcement learning, particularly in the context of social referencing. In this study, we examined object valence learning in the context of a social referencing paradigm. Participants viewed objects and faces that turned toward the objects and displayed a fearful, happy or neutral reaction to them, while judging the gender of these faces. Notably, amygdala activation was larger when the expressions following an object were less expected. Moreover, when asked, participants were both more likely to want to approach, and showed stronger amygdala responses to, objects associated with happy relative to objects associated with fearful expressions. This suggests that the amygdala plays two roles in social referencing: (i) initiating learning regarding the valence of an object as a function of prediction errors to expressions displayed toward this object and (ii) orchestrating an emotional response to the object when value judgments are being made regarding this object. Published by Oxford University Press 2014. This work is written by US Government employees and is in the public domain in the US.
Anxiety and Decision-Making

PubMed Central

Hartley, Catherine A.; Phelps, Elizabeth A.

2013-01-01

While the everyday decision-making of clinically anxious individuals is clearly influenced by their excessive fear and worry, the relationship between anxiety and decision-making remains relatively unexplored in neuroeconomic studies. In this review, we attempt to explore the role of anxiety in decision-making using a neuroeconomic approach. We first review the neural systems mediating fear and anxiety, which overlap with a network of brain regions implicated in studies of economic decision-making. We then discuss the potential influence of cognitive biases associated with anxiety upon economic choice, focusing on a set of decision-making biases involving choice in the face of potential aversive outcomes. We propose that the neural circuitry supporting fear learning and regulation may mediate the influence of anxiety upon choice, and suggest that techniques for altering fear and anxiety may also change decisions. PMID:22325982
Bupropion Dose-Dependently Reverses Nicotine Withdrawal Deficits in Contextual Fear Conditioning

PubMed Central

Portugal, George S.; Gould, Thomas J.

2007-01-01

Bupropion, a norepinephrine and dopamine reuptake inhibitor and nicotinic acetylcholine receptor antagonist, facilitates smoking cessation and reduces some symptoms of nicotine withdrawal. However, the effects of bupropion on nicotine withdrawal-associated deficits in learning remain unclear. The present study investigated whether bupropion has effects on contextual and cued fear conditioning following withdrawal from chronic nicotine or when administered alone. Bupropion was administered alone for a range of doses (2.5, 5, 10, 20 or 40 mg/kg), and dose-dependent impairments in contextual and cued fear conditioning were observed (20 or 40 mg/kg). Follow-up studies investigated if bupropion disrupted acquisition or expression of fear conditioning. Bupropion (40 mg/kg) administration on training day only produced deficits in contextual fear conditioning. Alternatively, bupropion (20 or 40 mg/kg) administration during testing dose-dependently produced deficits in contextual and cued fear conditioning. To test the effect of bupropion on nicotine withdrawal, mice were withdrawn from 12 days of chronic nicotine (6.3 mg/kg/day) or saline treatment. Withdrawal from chronic nicotine disrupted contextual fear conditioning; however, 5 mg/kg bupropion reversed this deficit. Overall, these results indicate that a low dose of bupropion can reverse nicotine withdrawal deficits in contextual fear conditioning, but that high doses of bupropion produce deficits in fear conditioning. PMID:17868796
Blockade of estrogen by hormonal contraceptives impairs fear extinction in female rats and women.

PubMed

Graham, Bronwyn M; Milad, Mohammed R

2013-02-15

Fear extinction is a laboratory model of fear inhibition and is the basis of exposure therapy for anxiety disorders. Emerging evidence from naturally cycling female rodents and women indicates that estrogens are necessary to the consolidation of fear extinction. Hormonal contraceptives (HCs) inhibit estrogen production; yet, their effects on fear extinction are unknown. We used a cross-species translational approach to investigate the impact of HCs and estradiol supplementation on fear extinction in healthy women (n=76) and female rats (n = 140). Women using HCs exhibited significantly poorer extinction recall compared with naturally cycling women. The extinction impairment was also apparent in HC-treated female rats and was associated with reduced serum estradiol levels. The impairment could be rescued in HC-treated rats either by terminating HC treatment after fear learning or by systemic injection of estrogen-receptor agonists before fear extinction, all of which restored serum estradiol levels. Finally, a single administration of estradiol to naturally cycling women significantly enhanced their ability to recall extinction memories. Together, these findings suggest that HCs may impact women's ability to inhibit fear but that this impairment is not permanent and could potentially be alleviated with estrogen treatment. Copyright © 2013 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
Cortisol modifies extinction learning of recently acquired fear in men

PubMed Central

Hermann, Andrea; Stark, Rudolf; Wolf, Oliver Tobias

2014-01-01

Exposure therapy builds on the mechanism of fear extinction leading to decreased fear responses. How the stress hormone cortisol affects brain regions involved in fear extinction in humans is unknown. For this reason, we tested 32 men randomly assigned to receive either 30 mg hydrocortisone or placebo 45 min before fear extinction. In fear acquisition, a picture of a geometrical figure was either partially paired (conditioned stimulus; CS+) or not paired (CS−) with an electrical stimulation (unconditioned stimulus; UCS). In fear extinction, each CS was presented again, but no UCS occurred. Cortisol increased conditioned skin conductance responses in early and late extinction. In early extinction, higher activation towards the CS− than to the CS+ was found in the amygdala, hippocampus and posterior parahippocampal gyrus. This pattern might be associated with the establishment of a new memory trace. In late extinction, the placebo compared with the cortisol group displayed enhanced CS+/CS− differentiation in the amygdala, medial frontal cortex and nucleus accumbens. A change from early deactivation to late activation of the extinction circuit as seen in the placebo group seems to be needed to enhance extinction and to reduce fear. Cortisol appears to interfere with this process thereby impairing extinction of recently acquired conditioned fear. PMID:23945999
Learned Helplessness and "Fear of Success" in College Women.

ERIC Educational Resources Information Center

Ris, Martin D.; Woods, Donald J.

1983-01-01

Examines anagram performance of 90 high, medium, and low fear-of-success (FOS) women, after the subjects had experienced conditions within the traditional triadic learned helplessness design. Concluded that increased attention should be given to personality variables within the learned helplessness paradigm. (CMG)
New technologies for examining neuronal ensembles in drug addiction and fear

PubMed Central

Cruz, Fabio C.; Koya, Eisuke; Guez-Barber, Danielle H.; Bossert, Jennifer M.; Lupica, Carl R.; Shaham, Yavin; Hope, Bruce T.

2015-01-01

Correlational data suggest that learned associations are encoded within neuronal ensembles. However, it has been difficult to prove that neuronal ensembles mediate learned behaviours because traditional pharmacological and lesion methods, and even newer cell type-specific methods, affect both activated and non-activated neurons. Additionally, previous studies on synaptic and molecular alterations induced by learning did not distinguish between behaviourally activated and non-activated neurons. Here, we describe three new approaches—Daun02 inactivation, FACS sorting of activated neurons and c-fos-GFP transgenic rats — that have been used to selectively target and study activated neuronal ensembles in models of conditioned drug effects and relapse. We also describe two new tools — c-fos-tTA mice and inactivation of CREB-overexpressing neurons — that have been used to study the role of neuronal ensembles in conditioned fear. PMID:24088811
Arc expression identifies the lateral amygdala fear memory trace

PubMed Central

Gouty-Colomer, L A; Hosseini, B; Marcelo, I M; Schreiber, J; Slump, D E; Yamaguchi, S; Houweling, A R; Jaarsma, D; Elgersma, Y; Kushner, S A

2016-01-01

Memories are encoded within sparsely distributed neuronal ensembles. However, the defining cellular properties of neurons within a memory trace remain incompletely understood. Using a fluorescence-based Arc reporter, we were able to visually identify the distinct subset of lateral amygdala (LA) neurons activated during auditory fear conditioning. We found that Arc-expressing neurons have enhanced intrinsic excitability and are preferentially recruited into newly encoded memory traces. Furthermore, synaptic potentiation of thalamic inputs to the LA during fear conditioning is learning-specific, postsynaptically mediated and highly localized to Arc-expressing neurons. Taken together, our findings validate the immediate-early gene Arc as a molecular marker for the LA neuronal ensemble recruited during fear learning. Moreover, these results establish a model of fear memory formation in which intrinsic excitability determines neuronal selection, whereas learning-related encoding is governed by synaptic plasticity. PMID:25802982
Increased perceived self-efficacy facilitates the extinction of fear in healthy participants

PubMed Central

Zlomuzica, Armin; Preusser, Friederike; Schneider, Silvia; Margraf, Jürgen

2015-01-01

Self-efficacy has been proposed as an important element of a successful cognitive behavioral treatment (CBT). Positive changes in perceived self-efficacy have been linked to an improved adaptive emotional and behavioral responding in the context of anxiety-provoking situations. Furthermore, a positive influence of increased self-efficacy on cognitive functions has been confirmed. The present study examined the effect of verbal persuasion on perceived self-efficacy and fear extinction. Healthy participants were subjected to a standardized differential fear conditioning paradigm. After fear acquisition, half of the participants received a verbal persuasion aimed at increasing perceived self-efficacy. The extinction of fear was assessed immediately thereafter on both the implicit and explicit level. Our results suggest that an increased perceived self-efficacy was associated with enhanced extinction, evidenced on the psychophysiological level and accompanied by more pronounced decrements in conditioned negative valence. Changes in extinction were not due to a decrease in overall emotional reactivity to conditioned stimuli (CS). In addition, debriefing participants about the false positive feedback did not affect the processing of already extinguished conditioned responses during a subsequent continued extinction phase. Our results suggest that positive changes in perceived self-efficacy can be beneficial for emotional learning. Findings are discussed with respect to strategies aimed at increasing extinction learning in the course of exposure-based treatments. PMID:26528152
Cholinergic signaling controls conditioned-fear behaviors and enhances plasticity of cortical-amygdala circuits

PubMed Central

Jiang, Li; Kundu, Srikanya; Lederman, James D.; López-Hernández, Gretchen Y.; Ballinger, Elizabeth C.; Wang, Shaohua; Talmage, David A.; Role, Lorna W.

2016-01-01

Summary We examined the contribution of endogenous cholinergic signaling to the acquisition and extinction of fear- related memory by optogenetic regulation of cholinergic input to the basal lateral amygdala (BLA). Stimulation of cholinergic terminal fields within the BLA in awake-behaving mice during training in a cued fear-conditioning paradigm slowed the extinction of learned fear as assayed by multi-day retention of extinction learning. Inhibition of cholinergic activity during training reduced the acquisition of learned fear behaviors. Circuit mechanisms underlying the behavioral effects of cholinergic signaling in the BLA were assessed by in vivo and ex vivo electrophysiological recording. Photo-stimulation of endogenous cholinergic input: (1) enhances firing of putative BLA principal neurons through activation of acetylcholine receptors (AChRs); (2) enhances glutamatergic synaptic transmission in the BLA and (3) induces LTP of cortical-amygdala circuits. These studies support an essential role of cholinergic modulation of BLA circuits in the inscription and retention of fear memories. PMID:27161525
Learning to avoid spiders: fear predicts performance, not competence.

PubMed

Luo, Xijia; Becker, Eni S; Rinck, Mike

2018-01-05

We used an immersive virtual environment to examine avoidance learning in spider-fearful participants. In 3 experiments, participants were asked to repeatedly lift one of 3 virtual boxes, under which either a toy car or a spider appeared and then approached the participant. Participants were not told that the probability of encountering a spider differed across boxes. When the difference was large (Exps. 1 and 2), spider-fearfuls learned to avoid spiders by lifting the few-spiders-box more often and the many-spiders-box less often than non-fearful controls did. However, they hardly managed to do so when the probability differences were small (Exp. 3), and they did not escape from threat more quickly (Exp. 2). In contrast to the observed performance differences, spider-fearfuls and non-fearfuls showed equal competence, that is comparable post-experimental knowledge about the probability to encounter spiders under the 3 boxes. The limitations and implications of the present study are discussed.
Orexin A Differentially Influences the Extinction Retention of Recent and Remote Fear Memory

PubMed Central

Shi, Le; Chen, Wenhao; Deng, Jiahui; Chen, Sijing; Han, Ying; Khan, Muhammad Z.; Liu, Jiajia; Que, Jianyu; Bao, Yanping; Lu, Lin; Shi, Jie

2018-01-01

Recently the role of the orexin system in the learning and memory, especially orexin A, which could enhance fear memory through regulating the activity of amygdala, has drawn considerable attention. However, the relationship between orexin A and extinction memory remains unclear. To investigate the effect of orexin A on extinction memory in humans, we recruited 43 male subjects and divided them into a recent group and remote group. After acquiring Pavlovian fear conditioning, individuals in recent group experienced fear extinction 24 h after acquisition, and remote group underwent extinction 2 weeks later. Meanwhile, plasma orexin A levels before extinction were measured by enzyme-linked immunosorbent assay. Both groups received memory test 24 h after fear extinction. The results showed that both recent and remote groups successfully acquired fear conditioning and had spontaneous recovery at test. In particular, the correlational analysis indicated that orexin A levels before extinction were negatively associated with fear responses during test only in recent group, but not in remote group. Moreover, individuals with high orexin A levels still kept low fear responses after extinction in recent group by subgroup analyses. The results suggest that orexin A could influence the retention of recent fear memory extinction, without affecting remote fear extinction. These findings remind us the orexin system can be a potential treatment target for fear-related disorders, and the mechanisms of recent and remote fear extinction may be different. PMID:29773974
Extinction training during the reconsolidation window prevents recovery of fear.

PubMed

Schiller, Daniela; Raio, Candace M; Phelps, Elizabeth A

2012-08-24

Fear is maladaptive when it persists long after circumstances have become safe. It is therefore crucial to develop an approach that persistently prevents the return of fear. Pavlovian fear-conditioning paradigms are commonly employed to create a controlled, novel fear association in the laboratory. After pairing an innocuous stimulus (conditioned stimulus, CS) with an aversive outcome (unconditioned stimulus, US) we can elicit a fear response (conditioned response, or CR) by presenting just the stimulus alone. Once fear is acquired, it can be diminished using extinction training, whereby the conditioned stimulus is repeatedly presented without the aversive outcome until fear is no longer expressed. This inhibitory learning creates a new, safe representation for the CS, which competes for expression with the original fear memory. Although extinction is effective at inhibiting fear, it is not permanent. Fear can spontaneously recover with the passage of time. Exposure to stress or returning to the context of initial learning can also cause fear to resurface. Our protocol addresses the transient nature of extinction by targeting the reconsolidation window to modify emotional memory in a more permanent manner. Ample evidence suggests that reactivating a consolidated memory returns it to a labile state, during which the memory is again susceptible to interference. This window of opportunity appears to open shortly after reactivation and close approximately 6 hrs later, although this may vary depending on the strength and age of the memory. By allowing new information to incorporate into the original memory trace, this memory may be updated as it reconsolidates. Studies involving non-human animals have successfully blocked the expression of fear memory by introducing pharmacological manipulations within the reconsolidation window, however, most agents used are either toxic to humans or show equivocal effects when used in human studies. Our protocol addresses these challenges by offering an effective, yet non-invasive, behavioral manipulation that is safe for humans. By prompting fear memory retrieval prior to extinction, we essentially trigger the reconsolidation process, allowing new safety information (i.e., extinction) to be incorporated while the fear memory is still susceptible to interference. A recent study employing this behavioral manipulation in rats has successfully blocked fear memory using these temporal parameters. Additional studies in humans have demonstrated that introducing new information after the retrieval of previously consolidated motor, episodic, or declarative memories leads to interference with the original memory trace. We outline below a novel protocol used to block fear recovery in humans.
Fear Conditioning Increases NREM Sleep

PubMed Central

Hellman, Kevin; Abel, Ted

2010-01-01

To understand the role that sleep may play in memory storage, the authors investigated how fear conditioning affects sleep–wake states by performing electroencephalographic (EEG) and electromyographic recordings of C57BL/6J mice receiving fear conditioning, exposure to conditioning stimuli, or immediate shock treatment. This experimental design allowed us to examine the effects of associative learning, presentation of the conditioning stimuli, and presentation of the unconditioned stimuli on sleep–wake states. During the 24 hr after training, fear-conditioned mice had approximately 1 hr more of nonrapid-eye-movement (NREM) sleep and less wakefulness than mice receiving exposure to conditioning stimuli or immediate shock treatment. Mice receiving conditioning stimuli had more delta power during NREM sleep, whereas mice receiving fear conditioning had less theta power during rapid-eye-movement sleep. These results demonstrate that a single trial of fear conditioning alters sleep–wake states and EEG oscillations over a 24-hr period, supporting the idea that sleep is modified by experience and that such changes in sleep–wake states and EEG oscillations may play a role in memory consolidation. PMID:17469920
Specific phobias.

PubMed

Hamm, Alfons O

2009-09-01

Exposure based treatments in which patients are systematically confronted with their feared objects of situations are highly effective in the treatment of specific phobias and produce stable improvement both in reported fear and behavioral avoidance. Exposure in reality is more effective in most cases than exposure in sensu. For situations that are difficult to realize, exposure in virtual environments has become increasingly valuable. Exposure in vivo is clearly superior to pharmacotherapy, although cognitive enhancers have been successfully used recently to increase the effect of exposure therapy. The induction of relaxation is not a necessary precondition for exposure therapy. Rather the current mechanisms of change focus on extinction learning as being the central mechanism both on a cognitive level namely that the feared object is no longer associated with severely threatening consequence but also on an affective level, meaning that feared cue is no longer capable to activate the fear circuit in the brain. Accordingly future diagnostic categorizations of phobic disorders in the DSM-V should rather focus on the pattern of the fear response that needs to be changed than on the eliciting cues or situations that are avoided.
Neurobiological Basis of Failure to Recall Extinction Memory in Posttraumatic Stress Disorder

PubMed Central

Milad, Mohammed R.; Pitman, Roger K.; Ellis, Cameron B.; Gold, Andrea L.; Shin, Lisa M; Lasko, Natasha B.; Zeidan, Mohamed A.; Handwerger, Kathryn; Orr, Scott P.; Rauch, Scott L.

2009-01-01

Background: A clinical characteristic of posttraumatic stress disorder (PTSD) is persistently elevated fear responses to stimuli associated with the traumatic event. The objective herein is to determine whether extinction of fear responses is impaired in PTSD and whether such impairment is related to dysfunctional activation of brain regions known to be involved in fear extinction, viz., amygdala, hippocampus, ventromedial prefrontal cortex (vmPFC), and dorsal anterior cingulate cortex (dACC). Methods: Sixteen individuals diagnosed with PTSD and 15 trauma-exposed non-PTSD controls (TENCs) underwent a two-day fear conditioning and extinction protocol in a 3T fMRI scanner. Conditioning and extinction training were conducted on day 1. Extinction recall (or extinction memory) test was conducted on day 2 (extinguished conditioned stimuli presented in the absence of shock). Skin conductance response (SCR) was scored throughout the experiment as an index of the conditioned response. Results: SCR data revealed no significant differences between groups during acquisition and extinction of conditioned fear on day 1. On day 2, however, PTSD subjects showed impaired recall of extinction memory. Analysis of fMRI data showed greater amygdala activation in the PTSD group during day 1 extinction learning. During extinction recall, lesser activation in hippocampus and vmPFC, and greater activation in dACC, was observed in the PTSD group. The magnitude of extinction memory across all subjects was correlated with activation of hippocampus and vmPFC during extinction recall testing. Conclusions: These findings support the hypothesis that fear extinction is impaired in PTSD. They further suggest that dysfunctional activation in brain structures that mediate fear extinction learning, and especially its recall, underlie this impairment. PMID:19748076

The role of safety signals in fear extinction: An analogue study.

PubMed

Restrepo-Castro, Juan C; Castro-Camacho, Leonidas; Javier Labrador, Francisco

2017-12-01

Safety signals are conditioned inhibitory stimuli that indicate the absence of unconditioned stimuli. It is not clear whether the presence of safety signals is detrimental or beneficial in extinction-based interventions. The purpose of this study was to evaluate the effect of safety signals on autonomic and expectancy fear-related responses. Following the conditional discrimination paradigm (AX +, BX-), undergraduate students (N = 48) underwent an aversive conditioning procedure, while safety signals were experimentally created. Participants were randomly assigned to one of two conditions during extinction: presence or absence of safety signals. Significant reductions of fear-related responses were found in both groups. Expectancy measures showed that the presence of safety signals did not interfere with reduction of fear related responses at follow-up. The analogue nature of the study affects its ecological validity. There are some methodological issues. Safety signals did not interfere with extinction learning. Attention may be a mechanism associated with the maintenance of fear responses. Copyright © 2017 Elsevier Ltd. All rights reserved.
Developmental aspects of fear: Comparing the acquisition and generalization of conditioned fear in children and adults.

PubMed

Schiele, Miriam A; Reinhard, Julia; Reif, Andreas; Domschke, Katharina; Romanos, Marcel; Deckert, Jürgen; Pauli, Paul

2016-05-01

Most research on human fear conditioning and its generalization has focused on adults whereas only little is known about these processes in children. Direct comparisons between child and adult populations are needed to determine developmental risk markers of fear and anxiety. We compared 267 children and 285 adults in a differential fear conditioning paradigm and generalization test. Skin conductance responses (SCR) and ratings of valence and arousal were obtained to indicate fear learning. Both groups displayed robust and similar differential conditioning on subjective and physiological levels. However, children showed heightened fear generalization compared to adults as indexed by higher arousal ratings and SCR to the generalization stimuli. Results indicate overgeneralization of conditioned fear as a developmental correlate of fear learning. The developmental change from a shallow to a steeper generalization gradient is likely related to the maturation of brain structures that modulate efficient discrimination between danger and (ambiguous) safety cues. © 2016 The Authors. Developmental Psychobiology Published by Wiley Periodicals, Inc.
Intolerance of uncertainty and startle potentiation in relation to different threat reinforcement rates.

PubMed

Chin, Brian; Nelson, Brady D; Jackson, Felicia; Hajcak, Greg

2016-01-01

Fear conditioning research on threat predictability has primarily examined the impact of temporal (i.e., timing) predictability on the startle reflex. However, there are other key features of threat that can vary in predictability. For example, the reinforcement rate (i.e., frequency) of threat is a crucial factor underlying fear learning. The present study examined the impact of threat reinforcement rate on the startle reflex and self-reported anxiety during a fear conditioning paradigm. Forty-five participants completed a fear learning task in which the conditioned stimulus was reinforced with an electric shock to the forearm on 50% of trials in one block and 75% of trials in a second block, in counter-balanced order. The present study also examined whether intolerance of uncertainty (IU), the tendency to perceive or experience uncertainty as stressful or unpleasant, was associated with the startle reflex during conditions of low (50%) vs. high (75%) reinforcement. Results indicated that, across all participants, startle was greater during the 75% relative to the 50% reinforcement condition. IU was positively correlated with startle potentiation (i.e., increased startle response to the CS+ relative to the CS-) during the 50%, but not the 75%, reinforcement condition. Thus, despite receiving fewer electric shocks during the 50% reinforcement condition, individuals with high IU uniquely demonstrated greater defense system activation when impending threat was more uncertain. The association between IU and startle was independent of state anxiety. The present study adds to a growing literature on threat predictability and aversive responding, and suggests IU is associated with abnormal responding in the context of uncertain threat. Copyright © 2015 Elsevier B.V. All rights reserved.
Sensitive periods in fear learning and memory.

PubMed

King, Elizabeth C; Pattwell, Siobhan S; Glatt, Charles E; Lee, Francis S

2014-01-01

Adolescence represents a uniquely sensitive developmental stage in the transition from childhood to adulthood. During this transition, neuronal circuits are particularly susceptible to modification by experience. In addition, adolescence is a stage in which the incidence of anxiety disorders peaks in humans and over 75% of adults with fear-related disorders met diagnostic criteria as children and adolescents. While postnatal critical periods of plasticity for primary sensory processes, such as in the visual system are well established, less is known about potential critical or sensitive periods for fear learning and memory. Here, we review the non-linear developmental aspects of fear learning and memory during a transition period into and out of adolescence. We also review the literature on the non-linear development of GABAergic neurotransmission, a key regulator of critical period plasticity. We provide a model that may inform improved treatment strategies for children and adolescents with fear-related disorders.
Sensitive periods in fear learning and memory

PubMed Central

King, Elizabeth C.; Pattwell, Siobhan S.; Glatt, Charles E.; Lee, Francis S.

2015-01-01

Adolescence represents a uniquely sensitive developmental stage in the transition from childhood to adulthood. During this transition, neuronal circuits are particularly susceptible to modification by experience. In addition, adolescence is a stage in which the incidence of anxiety disorders peaks in humans and over 75% of adults with fear-related disorders met diagnostic criteria as children and adolescents. While postnatal critical periods of plasticity for primary sensory processes, such as in the visual system are well established, less is known about potential critical or sensitive periods for fear learning and memory. Here, we review the nonlinear developmental aspects of fear learning and memory during a transition period into and out of adolescence. We also review the literature on the non-linear development of GABAergic neurotransmission, a key regulator of critical period plasticity. We provide a model that may inform improved treatment strategies for children and adolescents with fear-related disorders. PMID:23611461
Gut vagal afferents differentially modulate innate anxiety and learned fear.

PubMed

Klarer, Melanie; Arnold, Myrtha; Günther, Lydia; Winter, Christine; Langhans, Wolfgang; Meyer, Urs

2014-05-21

Vagal afferents are an important neuronal component of the gut-brain axis allowing bottom-up information flow from the viscera to the CNS. In addition to its role in ingestive behavior, vagal afferent signaling has been implicated modulating mood and affect, including distinct forms of anxiety and fear. Here, we used a rat model of subdiaphragmatic vagal deafferentation (SDA), the most complete and selective vagal deafferentation method existing to date, to study the consequences of complete disconnection of abdominal vagal afferents on innate anxiety, conditioned fear, and neurochemical parameters in the limbic system. We found that compared with Sham controls, SDA rats consistently displayed reduced innate anxiety-like behavior in three procedures commonly used in preclinical rodent models of anxiety, namely the elevated plus maze test, open field test, and food neophobia test. On the other hand, SDA rats exhibited increased expression of auditory-cued fear conditioning, which specifically emerged as attenuated extinction of conditioned fear during the tone re-exposure test. The behavioral manifestations in SDA rats were associated with region-dependent changes in noradrenaline and GABA levels in key areas of the limbic system, but not with functional alterations in the hypothalamus-pituitary-adrenal grand stress. Our study demonstrates that innate anxiety and learned fear are both subjected to visceral modulation through abdominal vagal afferents, possibly via changing limbic neurotransmitter systems. These data add further weight to theories emphasizing an important role of afferent visceral signals in the regulation of emotional behavior. Copyright © 2014 the authors 0270-6474/14/347067-10$15.00/0.
Mapping and Deciphering Neural Codes of NMDA Receptor-Dependent Fear Memory Engrams in the Hippocampus

PubMed Central

Tsien, Joe Z.

2013-01-01

Mapping and decoding brain activity patterns underlying learning and memory represents both great interest and immense challenge. At present, very little is known regarding many of the very basic questions regarding the neural codes of memory: are fear memories retrieved during the freezing state or non-freezing state of the animals? How do individual memory traces give arise to a holistic, real-time associative memory engram? How are memory codes regulated by synaptic plasticity? Here, by applying high-density electrode arrays and dimensionality-reduction decoding algorithms, we investigate hippocampal CA1 activity patterns of trace fear conditioning memory code in inducible NMDA receptor knockout mice and their control littermates. Our analyses showed that the conditioned tone (CS) and unconditioned foot-shock (US) can evoke hippocampal ensemble responses in control and mutant mice. Yet, temporal formats and contents of CA1 fear memory engrams differ significantly between the genotypes. The mutant mice with disabled NMDA receptor plasticity failed to generate CS-to-US or US-to-CS associative memory traces. Moreover, the mutant CA1 region lacked memory traces for “what at when” information that predicts the timing relationship between the conditioned tone and the foot shock. The degraded associative fear memory engram is further manifested in its lack of intertwined and alternating temporal association between CS and US memory traces that are characteristic to the holistic memory recall in the wild-type animals. Therefore, our study has decoded real-time memory contents, timing relationship between CS and US, and temporal organizing patterns of fear memory engrams and demonstrated how hippocampal memory codes are regulated by NMDA receptor synaptic plasticity. PMID:24302990
Sleep Deprivation Disrupts Recall of Conditioned Fear Extinction.

PubMed

Straus, Laura D; Acheson, Dean T; Risbrough, Victoria B; Drummond, Sean P A

2017-03-01

Learned fear is crucial in the development and maintenance of posttraumatic stress disorder (PTSD) and other anxiety disorders, and extinction of learned fear is necessary for response to exposure-based treatments. In humans, research suggests disrupted sleep impairs consolidation of extinction, though no studies have examined this experimentally using total sleep deprivation. Seventy-one healthy controls underwent a paradigm to acquire conditioned fear to a visual cue. Twenty-four hours after fear conditioning, participants underwent extinction learning. Twenty-four hours after extinction learning, participants underwent extinction recall. Participants were randomized to three groups: 1) well-rested throughout testing ("normal sleep"; n = 21); 2) 36 hours total sleep deprivation before extinction learning ("pre-extinction deprivation"; n = 25); or 3) 36 hours total sleep deprivation after extinction learning and before extinction recall ("post-extinction deprivation"; n = 25). The groups were compared on blink EMG reactivity to the condition stimulus during extinction learning and recall. There were no differences among the three groups during extinction learning. During extinction recall, the pre-extinction deprivation group demonstrated significantly less extinction recall than the normal sleep group. There was no significant difference between the normal sleep and post-extinction deprivation group during extinction recall. Results indicated sleep deprivation prior to extinction training significantly disrupts extinction recall. These findings suggest that (1) sleep deprivation in the immediate aftermath of trauma could be a potential contributor to PTSD development and maintenance via interference with natural extinction processes and (2) management of sleep symptoms should be considered during extinction-based therapy.
A role for the interoceptive insular cortex in the consolidation of learned fear.

PubMed

Casanova, José Patricio; Madrid, Carlos; Contreras, Marco; Rodríguez, María; Vasquez, Mónica; Torrealba, Fernando

2016-01-01

A growing body of evidence suggests that learned fear may be related to the function of the interoceptive insular cortex. Using an auditory fear conditioning paradigm in rats, we show that the inactivation of the posterior insular cortex (pIC), the target of the interoceptive thalamus, prior to training produced a marked reduction in fear expression tested 24h later. Accordingly, post-training anisomycin infused immediately, but not 6h after, also reduced fear expression tested the following day, supporting a role for the pIC in consolidation of fear memory. The long-term (ca. a week) and reversible inactivation of the pIC with the sodium channel blocker neosaxitoxin, immediately after fear memory reactivation induced a progressive decrease in the behavioral expression of conditioned fear. In turn, we observed that fear memory reactivation is accompanied by an enhanced expression of Fos and Zif268, early genes involved in neural activity and plasticity. Taken together these data indicate that the pIC is involved in the regulation of fear memories. Copyright © 2015 Elsevier B.V. All rights reserved.
Histone acetylation rescues contextual fear conditioning in nNOS KO mice and accelerates extinction of cued fear conditioning in wild type mice.

PubMed

Itzhak, Yossef; Anderson, Karen L; Kelley, Jonathan B; Petkov, Martin

2012-05-01

Epigenetic regulation of chromatin structure is an essential molecular mechanism that contributes to the formation of synaptic plasticity and long-term memory (LTM). An important regulatory process of chromatin structure is acetylation and deacetylation of histone proteins. Inhibition of histone deacetylase (HDAC) increases acetylation of histone proteins and facilitate learning and memory. Nitric oxide (NO) signaling pathway has a role in synaptic plasticity, LTM and regulation of histone acetylation. We have previously shown that NO signaling pathway is required for contextual fear conditioning. The present study investigated the effects of systemic administration of the HDAC inhibitor sodium butyrate (NaB) on fear conditioning in neuronal nitric oxide synthase (nNOS) knockout (KO) and wild type (WT) mice. The effect of single administration of NaB on total H3 and H4 histone acetylation in hippocampus and amygdala was also investigated. A single administration of NaB prior to fear conditioning (a) rescued contextual fear conditioning of nNOS KO mice and (b) had long-term (weeks) facilitatory effect on the extinction of cued fear memory of WT mice. The facilitatory effect of NaB on extinction of cued fear memory of WT mice was confirmed in a study whereupon NaB was administered during extinction. Results suggest that (a) the rescue of contextual fear conditioning in nNOS KO mice is associated with NaB-induced increase in H3 histone acetylation and (b) the accelerated extinction of cued fear memory in WT mice is associated with NaB-induced increase in H4 histone acetylation. Hence, a single administration of HDAC inhibitor may rescue NO-dependent cognitive deficits and afford a long-term accelerating effect on extinction of fear memory of WT mice. Copyright © 2012 Elsevier Inc. All rights reserved.
Nicotine increases fear responses and brain acetylcholinesterase activity in a context-dependent manner in zebrafish.

PubMed

Ziani, Paola R; Müller, Talise E; Stefanello, Flavia V; Fontana, Barbara D; Duarte, Tâmie; Canzian, Julia; Rosemberg, Denis B

2018-07-01

Nicotine is an alkaloid with positive effects on learning and memory processes. Exposure to conspecific alarm substance (CAS) elicits fear responses in zebrafish, but the effects of nicotine on aversive behaviors and associative learning in this species remain unclear. Here, we evaluated whether nicotine enhances contextual fear responses in zebrafish and investigated a putative involvement of brain acetylcholinesterase (AChE) in associative learning. Fish were exposed to 1 mg/L nicotine for 3 min and then kept in non-chlorinated water for 20 min. Later, animals were transferred to experimental tanks in the absence or presence of 3.5 mL/L CAS for 5 min (training session). After 24 h, fish were tested in tanks with similar or altered context in the absence of CAS (post-training session) and brain AChE activity was further assessed. At training, CAS increased freezing, erratic movements, and decreased the time spent in top area, while nicotine abolished the effects of CAS on erratic movements. Nicotine/CAS group tested in a similar context showed exacerbated freezing and reduced transitions to top area. Moreover, a decrease in distance traveled was observed in control, nicotine, and nicotine/CAS groups at post-training. Nicotine also stimulated brain AChE activity in CAS-exposed animals reintroduced in tanks with similar context. Although freezing bouts and time spent in top could serve as behavioral endpoints that reflect CAS-induced sensitization, the effects of nicotine occurred in a context-dependent manner. Collectively, our data suggest an involvement of cholinergic signaling in aversive learning, reinforcing the growing utility of zebrafish models to explore the neurobehavioral effects of nicotine in vertebrates. Copyright © 2018 Elsevier Inc. All rights reserved.
The Fear Factor: How It Affects Students Learning to Program in a Tertiary Environment

ERIC Educational Resources Information Center

Rogerson, Christine; Scott, Elsje

2010-01-01

This paper examines how students' experiences of learning to program are affected by feelings of fear, using a phenomenological approach to elicit rich descriptions of personal experiences from the narratives of final year undergraduate students. In the course of reviewing current work concerning learning or teaching programming, certain focal…
Activation of orexin/hypocretin neurons is associated with individual differences in cued fear extinction.

PubMed

Sharko, Amanda C; Fadel, Jim R; Kaigler, Kris F; Wilson, Marlene A

2017-09-01

Identifying the neurobiological mechanisms that underlie differential sensitivity to stress is critical for understanding the development and expression of stress-induced disorders, such as post-traumatic stress disorder (PTSD). Preclinical studies have suggested that rodents display different phenotypes associated with extinction of Pavlovian conditioned fear responses, with some rodent populations being resistant to extinction. An emerging literature also suggests a role for orexins in the consolidation processes associated with fear learning and extinction. To examine the possibility that the orexin system might be involved in individual differences in fear extinction, we used a Pavlovian conditioning paradigm in outbred Long-Evans rats. Rats showed significant variability in the extinction of cue-conditioned freezing and extinction recall, and animals were divided into groups based on their extinction profiles based on a median split of percent freezing behavior during repeated exposure to the conditioned cue. Animals resistant to extinction (high freezers) showed more freezing during repeated cue presentations during the within trial and between trial extinction sessions compared with the group showing significant extinction (low freezers), although there were no differences between these groups in freezing upon return to the conditioned context or during the conditioning session. Following the extinction recall session, activation of orexin neurons was determined using dual label immunohistochemistry for cFos in orexin positive neurons in the hypothalamus. Individual differences in the extinction of cue conditioned fear were associated with differential activation of hypothalamic orexin neurons. Animals showing poor extinction of cue-induced freezing (high freezers) had significantly greater percentage of orexin neurons with Fos in the medial hypothalamus than animals displaying significant extinction and good extinction recall (low freezers). Further, the freezing during extinction learning was positively correlated with the percentage of activated orexin neurons in both the lateral and medial hypothalamic regions. No differences in the overall density of orexin neurons or Fos activation were seen between extinction phenotypes. Although correlative, our results support other studies implicating a role of the orexinergic system in regulating extinction of conditioned responses to threat. Copyright © 2016 Elsevier Inc. All rights reserved.
The paraventricular thalamus controls a central amygdala fear circuit.

PubMed

Penzo, Mario A; Robert, Vincent; Tucciarone, Jason; De Bundel, Dimitri; Wang, Minghui; Van Aelst, Linda; Darvas, Martin; Parada, Luis F; Palmiter, Richard D; He, Miao; Huang, Z Josh; Li, Bo

2015-03-26

Appropriate responses to an imminent threat brace us for adversities. The ability to sense and predict threatening or stressful events is essential for such adaptive behaviour. In the mammalian brain, one putative stress sensor is the paraventricular nucleus of the thalamus (PVT), an area that is readily activated by both physical and psychological stressors. However, the role of the PVT in the establishment of adaptive behavioural responses remains unclear. Here we show in mice that the PVT regulates fear processing in the lateral division of the central amygdala (CeL), a structure that orchestrates fear learning and expression. Selective inactivation of CeL-projecting PVT neurons prevented fear conditioning, an effect that can be accounted for by an impairment in fear-conditioning-induced synaptic potentiation onto somatostatin-expressing (SOM(+)) CeL neurons, which has previously been shown to store fear memory. Consistently, we found that PVT neurons preferentially innervate SOM(+) neurons in the CeL, and stimulation of PVT afferents facilitated SOM(+) neuron activity and promoted intra-CeL inhibition, two processes that are critical for fear learning and expression. Notably, PVT modulation of SOM(+) CeL neurons was mediated by activation of the brain-derived neurotrophic factor (BDNF) receptor tropomysin-related kinase B (TrkB). As a result, selective deletion of either Bdnf in the PVT or Trkb in SOM(+) CeL neurons impaired fear conditioning, while infusion of BDNF into the CeL enhanced fear learning and elicited unconditioned fear responses. Our results demonstrate that the PVT-CeL pathway constitutes a novel circuit essential for both the establishment of fear memory and the expression of fear responses, and uncover mechanisms linking stress detection in PVT with the emergence of adaptive behaviour.
Systemic or Intra-Amygdala Infusion of the Benzodiazepine, Midazolam, Impairs Learning, but Facilitates Re-Learning to Inhibit Fear Responses in Extinction

ERIC Educational Resources Information Center

Hart, Genevra; Harris, Justin A.; Westbrook, R. Frederick

2010-01-01

A series of experiments used rats to study the effect of a systemic or intra-amygdala infusion of the benzodiazepine, midazolam, on learning and re-learning to inhibit context conditioned fear (freezing) responses. Rats were subjected to two context-conditioning episodes followed by extinction under drug or vehicle, or to two cycles of context…
Acute Ethanol Withdrawal Impairs Contextual Learning and Enhances Cued Learning

PubMed Central

Tipps, Megan E.; Raybuck, Jonathan D.; Buck, Kari J.; Lattal, K. Matthew

2014-01-01

Background Alcohol affects many of the brain regions and neural processes that support learning and memory, and these effects are thought to underlie, at least in part, the development of addiction. Although much work has been done regarding the effects of alcohol intoxication on learning and memory, little is known about the effects of acute withdrawal from a single alcohol exposure. Methods We assess the effects of acute ethanol withdrawal (6 h post-injection with 4 g/kg ethanol) on two forms of fear conditioning (delay and trace fear conditioning) in C57BL/6J and DBA/2J mice. The influence of a number of experimental parameters (pre- and post-training withdrawal exposure; foreground/background processing; training strength; non-associative effects) is also investigated. Results Acute ethanol withdrawal during training had a bidirectional effect on fear conditioned responses, decreasing contextual responses and increasing cued responses. These effects were apparent for both trace and delay conditioning in DBA/2J mice and for trace conditioning in C57BL/6J mice; however, C57BL/6J mice were selectively resistant to the effects of acute withdrawal on delay cued responses. Conclusions Our results show that acute withdrawal from a single, initial ethanol exposure is sufficient to alter long-term learning in mice. In addition, the differences between the strains and conditioning paradigms used suggest that specific learning processes can be differentially affected by acute withdrawal in a manner that is distinct from the reported effects of both alcohol intoxication and withdrawal following chronic alcohol exposure. Thus, our results suggest a unique effect of acute alcohol withdrawal on learning and memory processes. PMID:25684050
AMYGDALA MICROCIRCUITS CONTROLLING LEARNED FEAR

PubMed Central

Duvarci, Sevil; Pare, Denis

2014-01-01

We review recent work on the role of intrinsic amygdala networks in the regulation of classically conditioned defensive behaviors, commonly known as conditioned fear. These new developments highlight how conditioned fear depends on far more complex networks than initially envisioned. Indeed, multiple parallel inhibitory and excitatory circuits are differentially recruited during the expression versus extinction of conditioned fear. Moreover, shifts between expression and extinction circuits involve coordinated interactions with different regions of the medial prefrontal cortex. However, key areas of uncertainty remain, particularly with respect to the connectivity of the different cell types. Filling these gaps in our knowledge is important because much evidence indicates that human anxiety disorders results from an abnormal regulation of the networks supporting fear learning. PMID:24908482
Sleep supports cued fear extinction memory consolidation independent of circadian phase.

PubMed

Melo, Irene; Ehrlich, Ingrid

2016-07-01

Sleep promotes memory, particularly for declarative learning. However, its role in non-declarative, emotional memories is less well understood. Some studies suggest that sleep may influence fear-related memories, and thus may be an important factor determining the outcome of treatments for emotional disorders such as post-traumatic stress disorder. Here, we investigated the effect of sleep deprivation and time of day on fear extinction memory consolidation. Mice were subjected to a cued Pavlovian fear and extinction paradigm at the beginning of their resting or active phase. Immediate post-extinction learning sleep deprivation for 5h compromised extinction memory when tested 24h after learning. Context-dependent extinction memory recall was completely prevented by sleep-manipulation during the resting phase, while impairment was milder during the active phase and extinction memory retained its context-specificity. Importantly, control experiments excluded confounding factors such as differences in baseline locomotion, fear generalization and stress hormone levels. Together, our findings indicate that post-learning sleep supports cued fear extinction memory consolidation in both circadian phases. The lack of correlation between memory efficacy and sleep time suggests that extinction memory may be influenced by specific sleep events in the early consolidation period. Copyright © 2016 Elsevier Inc. All rights reserved.
Contingency Awareness Shapes Acquisition and Extinction of Emotional Responses in a Conditioning Model of Pain-Related Fear

PubMed Central

Labrenz, Franziska; Icenhour, Adriane; Benson, Sven; Elsenbruch, Sigrid

2015-01-01

As a fundamental learning process, fear conditioning promotes the formation of associations between predictive cues and biologically significant signals. In its application to pain, conditioning may provide important insight into mechanisms underlying pain-related fear, although knowledge especially in interoceptive pain paradigms remains scarce. Furthermore, while the influence of contingency awareness on excitatory learning is subject of ongoing debate, its role in pain-related acquisition is poorly understood and essentially unknown regarding extinction as inhibitory learning. Therefore, we addressed the impact of contingency awareness on learned emotional responses to pain- and safety-predictive cues in a combined dataset of two pain-related conditioning studies. In total, 75 healthy participants underwent differential fear acquisition, during which rectal distensions as interoceptive unconditioned stimuli (US) were repeatedly paired with a predictive visual cue (conditioned stimulus; CS+) while another cue (CS−) was presented unpaired. During extinction, both CS were presented without US. CS valence, indicating learned emotional responses, and CS-US contingencies were assessed on visual analog scales (VAS). Based on an integrative measure of contingency accuracy, a median-split was performed to compare groups with low vs. high contingency accuracy regarding learned emotional responses. To investigate predictive value of contingency accuracy, regression analyses were conducted. Highly accurate individuals revealed more pronounced negative emotional responses to CS+ and increased positive responses to CS− when compared to participants with low contingency accuracy. Following extinction, highly accurate individuals had fully extinguished pain-predictive cue properties, while exhibiting persistent positive emotional responses to safety signals. In contrast, individuals with low accuracy revealed equally positive emotional responses to both, CS+ and CS−. Contingency accuracy predicted variance in the formation of positive responses to safety cues while no predictive value was found for danger cues following acquisition and for neither cue following extinction. Our findings underscore specific roles of learned danger and safety in pain-related acquisition and extinction. Contingency accuracy appears to distinctly impact learned emotional responses to safety and danger cues, supporting aversive learning to occur independently from CS-US awareness. The interplay of cognitive and emotional factors in shaping excitatory and inhibitory pain-related learning may contribute to altered pain processing, underscoring its clinical relevance in chronic pain. PMID:26640433
Contingency Awareness Shapes Acquisition and Extinction of Emotional Responses in a Conditioning Model of Pain-Related Fear.

PubMed

Labrenz, Franziska; Icenhour, Adriane; Benson, Sven; Elsenbruch, Sigrid

2015-01-01

As a fundamental learning process, fear conditioning promotes the formation of associations between predictive cues and biologically significant signals. In its application to pain, conditioning may provide important insight into mechanisms underlying pain-related fear, although knowledge especially in interoceptive pain paradigms remains scarce. Furthermore, while the influence of contingency awareness on excitatory learning is subject of ongoing debate, its role in pain-related acquisition is poorly understood and essentially unknown regarding extinction as inhibitory learning. Therefore, we addressed the impact of contingency awareness on learned emotional responses to pain- and safety-predictive cues in a combined dataset of two pain-related conditioning studies. In total, 75 healthy participants underwent differential fear acquisition, during which rectal distensions as interoceptive unconditioned stimuli (US) were repeatedly paired with a predictive visual cue (conditioned stimulus; CS(+)) while another cue (CS(-)) was presented unpaired. During extinction, both CS were presented without US. CS valence, indicating learned emotional responses, and CS-US contingencies were assessed on visual analog scales (VAS). Based on an integrative measure of contingency accuracy, a median-split was performed to compare groups with low vs. high contingency accuracy regarding learned emotional responses. To investigate predictive value of contingency accuracy, regression analyses were conducted. Highly accurate individuals revealed more pronounced negative emotional responses to CS(+) and increased positive responses to CS(-) when compared to participants with low contingency accuracy. Following extinction, highly accurate individuals had fully extinguished pain-predictive cue properties, while exhibiting persistent positive emotional responses to safety signals. In contrast, individuals with low accuracy revealed equally positive emotional responses to both, CS(+) and CS(-). Contingency accuracy predicted variance in the formation of positive responses to safety cues while no predictive value was found for danger cues following acquisition and for neither cue following extinction. Our findings underscore specific roles of learned danger and safety in pain-related acquisition and extinction. Contingency accuracy appears to distinctly impact learned emotional responses to safety and danger cues, supporting aversive learning to occur independently from CS-US awareness. The interplay of cognitive and emotional factors in shaping excitatory and inhibitory pain-related learning may contribute to altered pain processing, underscoring its clinical relevance in chronic pain.

Parental social anxiety disorder prospectively predicts toddlers' fear/avoidance in a social referencing paradigm.

PubMed

Aktar, Evin; Majdandžić, Mirjana; de Vente, Wieke; Bögels, Susan M

2014-01-01

Anxiety runs in families. Observational learning of anxious behavior from parents with anxiety disorders plays an important role in the intergenerational transmission of anxiety. We investigated the link between parental anxiety (parental lifetime anxiety disorders and expressed parental anxiety) and toddler fear/avoidance during social referencing (SR) situations. Toddlers (N = 117) participated with both parents (with lifetime social anxiety disorder, other nonsocial anxiety disorders, lifetime comorbid social and other anxiety disorders, or without anxiety disorders) in a longitudinal study. Behavioral inhibition (BI) was measured at 12 months via observational tasks. At 30 months, children were confronted with a stranger and a remote-control robot in SR situations, separately with each parent. Children's fear and avoidance, and parents' expressions of anxiety, encouragement, and overcontrol were observed. Toddlers of parents with lifetime social anxiety disorder (alone and comorbid with other anxiety disorders) showed more fear/avoidance in SR situations than toddlers of parents without anxiety disorders, while the effect of other anxiety disorders alone was not significant. Although expressed parental anxiety at 30 months in SR situations did not significantly predict toddlers' fear/avoidance, higher levels of expressed anxiety at 12 months in SR situations by parents with comorbid social and other anxiety disorders predicted higher levels of fear/avoidance. BI at 12 months predicted toddlers' fear/avoidance only with mothers, but not with fathers. Parental lifetime social anxiety disorders may be a stronger predictor of children's fear/avoidance than parents' expressions of anxiety in SR situations in toddlerhood. End of infancy may be a sensitive time for learning of anxiety from parents with comorbid lifetime social and nonsocial anxiety disorders in SR situations. Fathers are as important as mothers in the transmission of anxiety via SR. Furthermore, children may act relatively free of their early temperament in SR situations with fathers. © 2013 The Authors. Journal of Child Psychology and Psychiatry © 2013 Association for Child and Adolescent Mental Health.
The ventromedial hypothalamus mediates predator fear memory

PubMed Central

Silva, Bianca A.; Mattucci, Camilla; Kryzwkowski, Piotr; Cuozzo, Rachel; Carbonari, Laura; Gross, Cornelius T.

2016-01-01

The amygdala has been shown to be essential for the processing of acute and learned fear across animal species. However, the downstream neural circuits that mediate these fear responses differ depending on the nature of the threat, with separate pathways identified for predator, conspecific, and physically harmful threats. In particular, the dorsomedial part of the ventromedial hypothalamus (VHMdm) is critical for the expression of defensive responses to predator. Here, we tested the hypothesis that this circuit also participates in predator fear memory by transient pharmacogenetic inhibition of VMHdm and its downstream effector, the dorsal periaqueductal grey, during predator fear learning in the mouse. Our data demonstrate that neural activity in VMHdm is required for both the acquisition and recall of predator fear memory, while that of its downstream effector, the dorsal periaqueductal grey, is required only for the acute expression of fear. These findings are consistent with a role for the medial hypothalamus in encoding an internal emotional state of fear. PMID:26991018
Early handling, but not maternal separation, decreases emotional responses in two paradigms of fear without changes in mesolimbic dopamine.

PubMed

Madruga, Clarice; Xavier, Léder L; Achaval, Matilde; Sanvitto, Gilberto L; Lucion, Aldo B

2006-01-30

This study aimed at identifying the effects of neonatal handling (H) and maternal separation (MS) on two paradigms of fear, learned and innate, and on the tyrosine hydroxylase (TH) immunoreactive cells in adult life. Wistar rats were daily handled with a brief maternal separation, maternal separated for 3 h or left undisturbed during the first 10 days of life. Behavioural responses in the open-field (innate fear) and conditioned fear (learned fear) were evaluated. Moreover, a semi-quantitative analysis of TH immunoreactivity in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNpc) was performed using optical densitometry and confirmed by planar measurements of neuronal density. Early handling decreased behaviour responses of innate and learned fear in adult life, while maternal separation had no significant long-lasting effect on these responses compared to the non-handled group. The behavioural effects of early handling could not be explained by changes in the density of midbrain dopaminergic cells, which were not affected by handling or maternal separation.
Neural population-level memory traces in the mouse hippocampus.

PubMed

Chen, Guifen; Wang, L Phillip; Tsien, Joe Z

2009-12-16

One of the fundamental goals in neurosciences is to elucidate the formation and retrieval of brain's associative memory traces in real-time. Here, we describe real-time neural ensemble transient dynamics in the mouse hippocampal CA1 region and demonstrate their relationships with behavioral performances during both learning and recall. We employed the classic trace fear conditioning paradigm involving a neutral tone followed by a mild foot-shock 20 seconds later. Our large-scale recording and decoding methods revealed that conditioned tone responses and tone-shock association patterns were not present in CA1 during the first pairing, but emerged quickly after multiple pairings. These encoding patterns showed increased immediate-replay, correlating tightly with increased immediate-freezing during learning. Moreover, during contextual recall, these patterns reappeared in tandem six-to-fourteen times per minute, again correlating tightly with behavioral recall. Upon traced tone recall, while various fear memories were retrieved, the shock traces exhibited a unique recall-peak around the 20-second trace interval, further signifying the memory of time for the expected shock. Therefore, our study has revealed various real-time associative memory traces during learning and recall in CA1, and demonstrates that real-time memory traces can be decoded on a moment-to-moment basis over any single trial.
BNDF heterozygosity is associated with memory deficits and alterations in cortical and hippocampal EEG power.

PubMed

Geist, Phillip A; Dulka, Brooke N; Barnes, Abigail; Totty, Michael; Datta, Subimal

2017-08-14

Brain derived neurotrophic factor (BDNF) plays a pivotal role in structural plasticity, learning, and memory. Electroencephalogram (EEG) spectral power in the cortex and hippocampus has also been correlated with learning and memory. In this study, we investigated the effect of globally reduced BDNF levels on learning behavior and EEG power via BDNF heterozygous (KO) rats. We employed several behavioral tests that are thought to depend on cortical and hippocampal plasticity to varying degrees: novel object recognition, a test that is reliant on a variety of cognitive systems; contextual fear, which is highly hippocampal-dependent; and cued fear, which has been shown to be amygdala-dependent. We also examined the effects of BDNF reduction on cortical and hippocampal EEG spectral power via chronically implanted electrodes in the motor cortex and dorsal hippocampus. We found that BDNF KO rats were impaired in novelty recognition and fear memory retention, while hippocampal EEG power was decreased in slow waves and increased in fast waves. Interestingly, our results, for the first time, show sexual dimorphism in each of our tests. These results support the hypothesis that BDNF drives both cognitive plasticity and coordinates EEG activity patterns, potentially serving as a link between the two. Copyright © 2017 Elsevier B.V. All rights reserved.
Neonatal Odor-Shock Conditioning Alters the Neural Network Involved in Odor Fear Learning at Adulthood

ERIC Educational Resources Information Center

Sevelinges, Yannick; Sullivan, Regina M.; Messaoudi, Belkacem; Mouly, Anne-Marie

2008-01-01

Adult learning and memory functions are strongly dependent on neonatal experiences. We recently showed that neonatal odor-shock learning attenuates later life odor fear conditioning and amygdala activity. In the present work we investigated whether changes observed in adults can also be observed in other structures normally involved, namely…
Context Fear Learning Specifically Activates Distinct Populations of Neurons in Amygdala and Hypothalamus

ERIC Educational Resources Information Center

Trogrlic, Lidia; Wilson, Yvette M.; Newman, Andrew G.; Murphy, Mark

2011-01-01

The identity and distribution of neurons that are involved in any learning or memory event is not known. In previous studies, we identified a discrete population of neurons in the lateral amygdala that show learning-specific activation of a c-"fos"-regulated transgene following context fear conditioning. Here, we have extended these studies to…
Developmental aspects of fear: Comparing the acquisition and generalization of conditioned fear in children and adults

PubMed Central

Schiele, Miriam A.; Reinhard, Julia; Reif, Andreas; Domschke, Katharina; Romanos, Marcel; Deckert, Jürgen

2016-01-01

ABSTRACT Most research on human fear conditioning and its generalization has focused on adults whereas only little is known about these processes in children. Direct comparisons between child and adult populations are needed to determine developmental risk markers of fear and anxiety. We compared 267 children and 285 adults in a differential fear conditioning paradigm and generalization test. Skin conductance responses (SCR) and ratings of valence and arousal were obtained to indicate fear learning. Both groups displayed robust and similar differential conditioning on subjective and physiological levels. However, children showed heightened fear generalization compared to adults as indexed by higher arousal ratings and SCR to the generalization stimuli. Results indicate overgeneralization of conditioned fear as a developmental correlate of fear learning. The developmental change from a shallow to a steeper generalization gradient is likely related to the maturation of brain structures that modulate efficient discrimination between danger and (ambiguous) safety cues. © 2016 The Authors. Developmental Psychobiology Published by Wiley Periodicals, Inc. Dev Psychobiol 58: 471–481, 2016. PMID:26798984
Increased anxiety but normal fear and safety learning in orexin-deficient mice.

PubMed

Khalil, Radwa; Fendt, Markus

2017-03-01

The loss of orexin neurons in humans leads to the disease narcolepsy, characterized by daytime sleepiness and cataplexy. Recent data suggest that orexin is also involved in emotional processing. The goal of the present study was to evaluate fear and safety learning as well as unconditioned fear (anxiety) in orexin-deficient animals. Orexin-deficient mice are an established animal model used to investigate the neuropathology and potential treatments for narcolepsy. Here, we present novel data showing that orexin-deficient mice express increased anxiety in the open field, light-dark box test and carnivore odor-induced avoidance, but are normal in fear and safety learning. These findings suggest an important role of orexin in brain areas involved in anxiety. Copyright © 2016 Elsevier B.V. All rights reserved.
Morphine prevents the development of stress-enhanced fear learning.

PubMed

Szczytkowski-Thomson, Jennifer L; Lebonville, Christina L; Lysle, Donald T

2013-01-01

The current study investigates the pharmacotherapeutic use of morphine as a preventative treatment for stress-enhanced fear learning, an animal model that closely mimics symptoms of post-traumatic stress disorder (PTSD). PTSD is a chronic and debilitating anxiety disorder characterized by exaggerated fear and/or anxiety that may develop as a result of exposure to a traumatic event. In this model, rats are exposed to a severe stressor (15 foot shocks) in one environment (Context A) and then subsequently exposed to a milder form of the same stressor (single foot shock) in a different environment (Context B). Animals that did not receive prior shock treatment exhibit fear responsiveness to Context B in line with the severity of the single shock given in this context. Animals that had received prior shock treatment in Context A exhibit an exaggerated learned fear response to Context B. Furthermore, animals receiving a single dose of morphine immediately following the severe stressor in Context A continue to show an enhanced fear response in Context B. However, animals receiving repeated morphine administration (three injections) after exposure to the severe stressor in Context A or a single dose of morphine at 48 h after the severe stressor no longer exhibit an enhancement in fear learning to Context B. These results are consistent with clinical studies suggesting that morphine treatment following a severe stressor may be useful in preventing or reducing the severity of PTSD in at-risk populations. Copyright © 2012 Elsevier Inc. All rights reserved.
Fear conditioning leads to alteration in specific genes expression in cortical and thalamic neurons that project to the lateral amygdala.

PubMed

Katz, Ira K; Lamprecht, Raphael

2015-02-01

RNA transcription is needed for memory formation. However, the ability to identify genes whose expression is altered by learning is greatly impaired because of methodological difficulties in profiling gene expression in specific neurons involved in memory formation. Here, we report a novel approach to monitor the expression of genes after learning in neurons in specific brain pathways needed for memory formation. In this study, we aimed to monitor gene expression after fear learning. We retrogradely labeled discrete thalamic neurons that project to the lateral amygdala (LA) of rats. The labeled neurons were dissected, using laser microdissection microscopy, after fear conditioning learning or unpaired training. The RNAs from the dissected neurons were subjected to microarray analysis. The levels of selected RNAs detected by the microarray analysis to be altered by fear conditioning were also assessed by nanostring analysis. We observed that the expression of genes involved in the regulation of translation, maturation and degradation of proteins was increased 6 h after fear conditioning compared to unpaired or naïve trained rats. These genes were not expressed 24 h after training or in cortical neurons that project to the LA. The expression of genes involved in transcription regulation and neuronal development was altered after fear conditioning learning in the cortical-LA pathway. The present study provides key information on the identity of genes expressed in discrete thalamic and cortical neurons that project to the LA after fear conditioning. Such an approach could also serve to identify gene products as targets for the development of a new generation of therapeutic agents that could be aimed to functionally identified brain circuits to treat memory-related disorders. © 2014 International Society for Neurochemistry.
The time course of location-avoidance learning in fear of spiders.

PubMed

Rinck, Mike; Koene, Marieke; Telli, Sibel; Moerman-van den Brink, Wiltine; Verhoeven, Barbara; Becker, Eni S

2016-01-01

Two experiments were designed to study the time course of avoidance learning in spider fearfuls (SFs) under controlled experimental conditions. To achieve this, we employed an immersive virtual environment (IVE): While walking freely through a virtual art museum to search for specific paintings, the participants were exposed to virtual spiders. Unbeknown to the participants, only two of four museum rooms contained spiders, allowing for avoidance learning. Indeed, the more SF the participants were, the faster they learned to avoid the rooms that contained spiders (Experiment. 1), and within the first six trials, high fearfuls already developed a preference for starting their search task in rooms without spiders (Experiment 2). These results illustrate the time course of avoidance learning in SFs, and they speak to the usefulness of IVEs in fundamental anxiety research.
Increased levels of conditioned fear and avoidance behavior coincide with changes in phosphorylation of the protein kinase B (AKT) within the amygdala in a mouse model of extremes in trait anxiety.

PubMed

Yen, Yi-Chun; Mauch, Christoph P; Dahlhoff, Maik; Micale, Vincenzo; Bunck, Mirjam; Sartori, Simone B; Singewald, Nicolas; Landgraf, Rainer; Wotjak, Carsten T

2012-07-01

Patients diagnosed for anxiety disorders often display faster acquisition and slower extinction of learned fear. To gain further insights into the mechanisms underlying these phenomenona, we studied conditioned fear in mice originating form a bi-directional selective breeding approach, which is based on elevated plus-maze behavior and results in CD1-derived high (HAB), normal (NAB), and low (LAB) anxiety-related behavior mice. HAB mice displayed pronounced cued-conditioned fear compared to NAB/CD1 and LAB mice that coincided with increased phosphorylation of the protein kinase B (AKT) in the basolateral amygdala 45 min after conditioning. No similar changes were observed after non-associative immediate shock presentations. Fear extinction of recent but not older fear memories was preserved. However, HAB mice were more prone to relapse of conditioned fear with the passage of time. HAB mice also displayed higher levels of contextual fear compared to NAB and LAB mice and exaggerated avoidance following step-down avoidance training. Interestingly, HAB mice showed lower and LAB mice higher levels of acoustic startle responses compared to NAB controls. The increase in arousal observed in LAB mice coincided with the general absence of conditioned freezing. Taken together, our results suggest that the genetic predisposition to high anxiety-related behavior may increase the risk of forming traumatic memories, phobic-like fear and avoidance behavior following aversive encounters, with a clear bias towards passive coping styles. In contrast, genetic predisposition to low anxiety-related and high risk-taking behavior seems to be associated with an increase in active coping styles. Our data imply changes in AKT phosphorylation as a therapeutic target for the prevention of exaggerated fear memories. Copyright © 2012 Elsevier Inc. All rights reserved.
Understanding nurses' and physicians' fear of repercussions for reporting errors: clinician characteristics, organization demographics, or leadership factors?

PubMed

Castel, Evan S; Ginsburg, Liane R; Zaheer, Shahram; Tamim, Hala

2015-08-14

Identifying and understanding factors influencing fear of repercussions for reporting and discussing medical errors in nurses and physicians remains an important area of inquiry. Work is needed to disentangle the role of clinician characteristics from those of the organization-level and unit-level safety environments in which these clinicians work and learn, as well as probing the differing reporting behaviours of nurses and physicians. This study examines the influence of clinician demographics (age, gender, and tenure), organization demographics (teaching status, location of care, and province) and leadership factors (organization and unit leadership support for safety) on fear of repercussions, and does so for nurses and physicians separately. A cross-sectional analysis of 2319 nurse and 386 physician responders from three Canadian provinces to the Modified Stanford patient safety climate survey (MSI-06). Data were analyzed using exploratory factor analysis, multiple linear regression, and hierarchical linear regression. Age, gender, tenure, teaching status, and province were not significantly associated with fear of repercussions for nurses or physicians. Mental health nurses had poorer fear responses than their peers outside of these areas, as did community physicians. Strong organization and unit leadership support for safety explained the most variance in fear for both nurses and physicians. The absence of associations between several plausible factors including age, tenure and teaching status suggests that fear is a complex construct requiring more study. Substantially differing fear responses across locations of care indicate areas where interventions may be needed. In addition, since factors affecting fear of repercussions appear to be different for nurses and physicians, tailoring patient safety initiatives to each group may, in some instances, be fruitful. Although further investigation is needed to examine these and other factors in detail, supportive safety leadership appears to be central to reducing fear of reporting errors for both nurses and physicians.
Acute stress impairs the retrieval of extinction memory in humans

PubMed Central

Raio, Candace M.; Brignoni-Perez, Edith; Goldman, Rachel; Phelps, Elizabeth A.

2014-01-01

Extinction training is a form of inhibitory learning that allows an organism to associate a previously aversive cue with a new, safe outcome. Extinction does not erase a fear association, but instead creates a competing association that may or may not be retrieved when a cue is subsequently encountered. Characterizing the conditions under which extinction learning is expressed is important to enhancing the treatment of anxiety disorders that rely on extinction-based exposure therapy as a primary treatment technique. The ventromedial prefrontal cortex, which plays an important role in the expression of extinction memory, has been shown to be functionally impaired after stress exposure. Further, recent research in rodents found that exposure to stress led to deficits in extinction retrieval, although this has yet to be tested in humans. To explore how stress might influence extinction retrieval in humans, participants underwent a differential aversive learning paradigm, in which one image was probabilistically paired with an aversive shock while the other image denoted safety. Extinction training directly followed, at which point reinforcement was omitted. A day later, participants returned to the lab and either completed an acute stress manipulation (i.e., cold pressor), or a control task, before undergoing an extinction retrieval test. Skin conductance responses and salivary cortisol concentrations were measured throughout each session as indices of fear arousal and neuroendocrine stress responses, respectively. The efficacy of our stress induction was established by observing significant increases in cortisol for the stress condition only. We examined extinction retrieval by comparing conditioned responses during the last trial of extinction (day 1) with that of the first trial of re-extinction (day 2). Groups did not differ on initial fear acquisition or extinction, however, one day later participants in the stress group (n = 27) demonstrated significantly less extinction retrieval (i.e., greater fear recovery) than those in the control group (n = 25). Our results suggest that acute stress impairs extinction memory retrieval and offers insight into why treatment strategies used in the clinic may be challenging to recruit in daily life where stress is pervasive. PMID:24508065
Extinction of Contextual Fear with Timed Exposure to Enriched Environment: A Differential Effect

PubMed Central

Hegde, Preethi; O'Mara, Shane; Laxmi, Thenkanidiyoor Rao

2017-01-01

Background Extinction of fear memory depends on the environmental and emotional cues. Furthermore, consolidation of extinction is also dependent on the environmental exposure. But, the relationship of the time of the exposure to a variety of environmental cues is not well known. The important region involved in facilitation of extinction of fear memory is through diversion of the flow of information leaving the lateral nucleus of amygdala. Purpose The study aimed to address a question to explain how these brain regions react to environmental stimulation during the retention and extinction of fear memory. Methods An enriched environment (EE) is assumed to mediate extinction of fear memory, we examined the apparent discrepancy between the effects of defensive response, the freezing behavior induced by Pavlovian classical fear conditioning by subjecting them to variance in the timing to EE. The different timing of EE exposure was 10 days of EE either before fear conditioning and/or after extinction training to the rats. The local field potentials was recorded from CA1 hippocampus, lateral nucleus of amygdala and infralimbic region of medial prefrontal cortex (mPFC) during the fear learning and extinction from the control rats and rats exposed to EE before and after fear conditioning. Results Exposure to EE before the fear conditioning and after extinction training was more effective in the extinction fear memory. In addition, we also found switching from exploratory locomotion to freezing during retention of contextual fear memory which was associated with decreased theta power and reduced synchronized theta oscillations in CA1-hippocampus, lateral nucleus of amygdala, and infralimbic region of mPFC. Conclusion Thus, we propose that the timing of exposure to EE play a key role in the extinction of fear memory. PMID:28588364
The prelimbic cortex directs attention toward predictive cues during fear learning.

PubMed

Sharpe, Melissa J; Killcross, Simon

2015-06-01

The prelimbic cortex is argued to promote conditioned fear expression, at odds with appetitive research implicating this region in attentional processing. Consistent with an attentional account, we report that the effect of prelimbic lesions on fear expression depends on the degree of competition between contextual and discrete cues. Further, when competition from contextual cues is low, we found that PL inactivation resulted in animals expressing fear toward irrelevant discrete cues; an effect selective to inactivation during the learning phase and not during retrieval. These data demonstrate that the prelimbic cortex modulates attention toward cues to preferentially direct fear responding on the basis of their predictive value. © 2015 Sharpe and Killcross; Published by Cold Spring Harbor Laboratory Press.
Extinction of Conditioned Fear is Better Learned and Recalled in the Morning than in the Evening

PubMed Central

Pace-Schott, Edward F.; Spencer, Rebecca M.C.; Vijayakumar, Shilpa; Ahmed, Nafis; Verga, Patrick W.; Orr, Scott P.; Pitman, Roger K.; Milad, Mohammed R.

2013-01-01

Sleep helps emotional memories consolidate and may promote generalization of fear extinction memory. We examined whether extinction learning and memory might differ in the morning and evening due, potentially, to circadian and/or sleep-homeostatic factors. Healthy men (N=109) in 6 groups completed a 2-session protocol. In Session 1, fear conditioning was followed by extinction learning. Partial reinforcement with mild electric shock produced conditioned skin conductance responses (SCR) to 2 differently colored lamps (CS+), but not a third color (CS−), within the computer image of a room (conditioning context). One CS+ (CS+E) but not the other (CS+U) was immediately extinguished by un-reinforced presentations in a different room (extinction context). Delay durations of 3 hr (within AM or PM), 12 hr (morning-to-evening or evening-to-morning) or 24 hr (morning-to-morning or evening-to-evening) followed. In Session 2, extinction recall and contextual fear renewal were tested. We observed no significant effects of the delay interval on extinction memory but did observe an effect of time-of-day. Fear extinction was significantly better if learned in the morning (p=.002). Collapsing across CS+ type, there was smaller morning differential SCR at both extinction recall (p=.003) and fear renewal (p=.005). Morning extinction recall showed better generalization from the CS+E to CS+U with the response to the CS+U significantly larger than to the CS+E only in the evening (p=.028). Thus, extinction is learned faster and its memory is better generalized in the morning. Cortisol and testosterone showed the expected greater salivary levels in the morning when higher testosterone/cortisol ratio also predicting better extinction learning. Circadian factors may promote morning extinction. Alternatively, evening homeostatic sleep pressure may impede extinction and favor recall of conditioned fear. PMID:23992769
Extinction of conditioned fear is better learned and recalled in the morning than in the evening.

PubMed

Pace-Schott, Edward F; Spencer, Rebecca M C; Vijayakumar, Shilpa; Ahmed, Nafis A K; Verga, Patrick W; Orr, Scott P; Pitman, Roger K; Milad, Mohammed R

2013-11-01

Sleep helps emotional memories consolidate and may promote generalization of fear extinction memory. We examined whether extinction learning and memory might differ in the morning and evening due, potentially, to circadian and/or sleep-homeostatic factors. Healthy men (N = 109) in 6 groups completed a 2-session protocol. In Session 1, fear conditioning was followed by extinction learning. Partial reinforcement with mild electric shock produced conditioned skin conductance responses (SCRs) to 2 differently colored lamps (CS+), but not a third color (CS-), within the computer image of a room (conditioning context). One CS+ (CS + E) but not the other (CS + U) was immediately extinguished by un-reinforced presentations in a different room (extinction context). Delay durations of 3 h (within AM or PM), 12 h (morning-to-evening or evening-to-morning) or 24 h (morning-to-morning or evening-to-evening) followed. In Session 2, extinction recall and contextual fear renewal were tested. We observed no significant effects of the delay interval on extinction memory but did observe an effect of time-of-day. Fear extinction was significantly better if learned in the morning (p = .002). Collapsing across CS + type, there was smaller morning differential SCR at both extinction recall (p = .003) and fear renewal (p = .005). Morning extinction recall showed better generalization from the CS + E to CS + U with the response to the CS + U significantly larger than to the CS + E only in the evening (p = .028). Thus, extinction is learned faster and its memory is better generalized in the morning. Cortisol and testosterone showed the expected greater salivary levels in the morning when higher testosterone/cortisol ratio also predicted better extinction learning. Circadian factors may promote morning extinction. Alternatively, evening homeostatic sleep pressure may impede extinction and favor recall of conditioned fear. Copyright © 2013 Elsevier Ltd. All rights reserved.
Sex differences in conditioned stimulus discrimination during context-dependent fear learning and its retrieval in humans: the role of biological sex, contraceptives and menstrual cycle phases.

PubMed

Lonsdorf, Tina B; Haaker, Jan; Schümann, Dirk; Sommer, Tobias; Bayer, Janine; Brassen, Stefanie; Bunzeck, Nico; Gamer, Matthias; Kalisch, Raffael

2015-11-01

Anxiety disorders are more prevalent in women than in men. Despite this sexual dimorphism, most experimental studies are conducted in male participants and studies focusing on sex differences are sparse. In addition, the role of hormonal contraceptives and menstrual cycle phase in fear conditioning and extinction processes remain largely unknown. We investigated sex differences in context-dependent fear acquisition and extinction (day 1) and their retrieval/expression (day 2). Skin conductance responses (SCRs), fear and unconditioned stimulus expectancy ratings were obtained. We included 377 individuals (261 women) in our study. Robust sex differences were observed in all dependent measures. Women generally displayed higher subjective ratings but smaller SCRs than men and showed reduced excitatory/inhibitory conditioned stimulus (CS+/CS-) discrimination in all dependent measures. Furthermore, women using hormonal contraceptives showed reduced SCR CS discrimination on day 2 than men and free-cycling women, while menstrual cycle phase had no effect. Possible limitations include the simultaneous testing of up to 4 participants in cubicles, which might have introduced a social component, and not assessing postexperimental contingency awareness. The response pattern in women shows striking similarity to previously reported sex differences in patients with anxiety. Our results suggest that pronounced deficits in associative discrimination learning and subjective expression of safety information (CS- responses) might underlie higher prevalence and higher symptom rates seen in women with anxiety disorders. The data call for consideration of biological sex and hormonal contraceptive use in future studies and may suggest that targeting inhibitory learning during therapy might aid precision medicine.

Fear of causing harm: use of mannequin-based simulation to decrease student anxiety prior to interacting with female teaching associates.

PubMed

Pugh, Carla M; Obadina, Eniola T; Aidoo, Kofi A

2009-01-01

There is a paucity of research assessing the potential benefits of mannequin trainers when preparing students to interact with teaching associates. The goal of this study was to better understand the effects of mannequin-based simulators on student comfort toward learning specific aspects of the clinical female pelvic exam. First-year medical students (N = 344) were surveyed before and after a mannequin-based simulation curriculum to assess their comfort levels toward learning the female pelvic exam. Causing harm was the top cause of student anxiety toward learning the pelvic exam. Although the mannequin-based simulation curriculum was effective in significantly increasing (p < .001) student comfort levels toward learning the pelvic exam, the majority of students progressed from being "very uncomfortable" with the exam to being "somewhat comfortable." We suggest that mannequin-based simulators be used prior to students' learning experience with pelvic exam teaching associates.
Maternal buffering of fear-potentiated startle in children and adolescents with trauma exposure.

PubMed

van Rooij, Sanne J H; Cross, Dorthie; Stevens, Jennifer S; Vance, L Alexander; Kim, Ye Ji; Bradley, Bekh; Tottenham, Nim; Jovanovic, Tanja

2017-02-01

Parental availability influences fear expression and learning across species, but the effect of maternal buffering on fear learning in humans is unknown. Here we investigated the effect of maternal availability during fear conditioning in a group of children (ages 8-10) and adolescents (ages 11-13) from a low-income population with a range of trauma exposure. Acoustic startle response data were collected to measure fear-potentiated startle (FPS) in 104 participants. A total of 62 participants were tested with the mother available and 42 when the mother was not in the testing room. We observed that maternal availability during fear conditioning interacted with age to affect FPS discrimination between CS+ and CS-. In line with previous findings suggesting an absence of maternal buffering in adolescents, fear discrimination was affected by maternal availability only in children. Second, we observed that the effect of maternal buffering on FPS discrimination in children was not influenced by maternally reported warmth. In conclusion, we demonstrated that maternal availability improved discrimination in children, regardless of the quality of the relationship. Adolescents discriminated irrespective of maternal status, suggesting that childhood may be a sensitive period for environmental influences on key processes such as learning of danger and safety signals.
Increased Cortical Gamma-Aminobutyric Acid Precedes Incomplete Extinction of Conditioned Fear and Increased Hippocampal Excitatory Tone in a Mouse Model of Mild Traumatic Brain Injury.

PubMed

Schneider, Brandy L; Ghoddoussi, Farhad; Charlton, Jennifer L; Kohler, Robert J; Galloway, Matthew P; Perrine, Shane A; Conti, Alana C

2016-09-01

Mild traumatic brain injury (mTBI) contributes to development of affective disorders, including post-traumatic stress disorder (PTSD). Psychiatric symptoms typically emerge in a tardive fashion post-TBI, with negative effects on recovery. Patients with PTSD, as well as rodent models of PTSD, demonstrate structural and functional changes in brain regions mediating fear learning, including prefrontal cortex (PFC), amygdala (AMYG), and hippocampus (HC). These changes may reflect loss of top-down control by which PFC normally exhibits inhibitory influence over AMYG reactivity to fearful stimuli, with HC contribution. Considering the susceptibility of these regions to injury, we examined fear conditioning (FC) in the delayed post-injury period, using a mouse model of mTBI. Mice with mTBI displayed enhanced acquisition and delayed extinction of FC. Using proton magnetic resonance spectroscopy ex vivo, we examined PFC, AMYG, and HC levels of gamma-aminobutyric acid (GABA) and glutamate as surrogate measures of inhibitory and excitatory neurotransmission, respectively. Eight days post-injury, GABA was increased in PFC, with no significant changes in AMYG. In animals receiving FC and mTBI, glutamate trended toward an increase and the GABA/glutamate ratio decreased in ventral HC at 25 days post-injury, whereas GABA decreased and GABA/glutamate decreased in dorsal HC. These neurochemical changes are consistent with early TBI-induced PFC hypoactivation facilitating the fear learning circuit and exacerbating behavioral fear responses. The latent emergence of overall increased excitatory tone in the HC, despite distinct plasticity in dorsal and ventral HC fields, may be associated with disordered memory function, manifested as incomplete extinction and enhanced FC recall.
Fear Generalization and Anxiety: Behavioral and Neural Mechanisms.

PubMed

Dunsmoor, Joseph E; Paz, Rony

2015-09-01

Fear can be an adaptive emotion that helps defend against potential danger. Classical conditioning models elegantly describe how animals learn which stimuli in the environment signal danger, but understanding how this learning is generalized to other stimuli that resemble aspects of a learned threat remains a challenge. Critically, the overgeneralization of fear to harmless stimuli or situations is a burden to daily life and characteristic of posttraumatic stress disorder and other anxiety disorders. Here, we review emerging evidence on behavioral and neural mechanisms of generalization of emotional learning with the goal of encouraging further research on generalization in anxiety disorders. We begin by placing research on fear generalization in a rich historical context of stimulus generalization dating back to Pavlov, which lays the foundation for theoretical and experimental approaches used today. We then transition to contemporary behavioral and neurobiological research on generalization of emotional learning in humans and nonhuman animals and discuss the factors that promote generalization on the one hand from discrimination on the other hand. Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
Object-location training elicits an overlapping but temporally distinct transcriptional profile from contextual fear conditioning.

PubMed

Poplawski, Shane G; Schoch, Hannah; Wimmer, Mathieu; Hawk, Joshua D; Walsh, Jennifer L; Giese, Karl P; Abel, Ted

2014-12-01

Hippocampus-dependent learning is known to induce changes in gene expression, but information on gene expression differences between different learning paradigms that require the hippocampus is limited. The bulk of studies investigating RNA expression after learning use the contextual fear conditioning task, which couples a novel environment with a footshock. Although contextual fear conditioning has been useful in discovering gene targets, gene expression after spatial memory tasks has received less attention. In this study, we used the object-location memory task and studied gene expression at two time points after learning in a high-throughput manner using a microfluidic qPCR approach. We found that expression of the classic immediate-early genes changes after object-location training in a fashion similar to that observed after contextual fear conditioning. However, the temporal dynamics of gene expression are different between the two tasks, with object-location memory producing gene expression changes that last at least 2 hours. Our findings indicate that different training paradigms may give rise to distinct temporal dynamics of gene expression after learning. Copyright © 2014 Elsevier Inc. All rights reserved.
Object-Location Training Elicits an Overlapping but Temporally Distinct Transcriptional Profile from Contextual Fear Conditioning

PubMed Central

Wimmer, Mathieu; Hawk, Joshua D.; Walsh, Jennifer L.; Giese, Karl P.; Abel, Ted

2014-01-01

Hippocampus-dependent learning is known to induce changes in gene expression, but information on gene expression differences between different learning paradigms that require the hippocampus is limited. The bulk of studies investigating RNA expression after learning use the contextual fear conditioning task, which couples a novel environment with a footshock. Although contextual fear conditioning has been useful in discovering gene targets, gene expression after spatial memory tasks has received less attention. In this study, we used the object-location memory task and studied gene expression at two time points after learning in a high-throughput manner using a microfluidic qPCR approach. We found that expression of the classic immediate-early genes changes after object-location training in a fashion similar to that observed after contextual fear conditioning. However, the temporal dynamics of gene expression are different between the two tasks, with object-location memory producing gene expression changes that last at least 2 hours. Our findings indicate that different training paradigms may give rise to distinct temporal dynamics of gene expression after learning. PMID:25242102
Aversive Learning Modulates Cortical Representations of Object Categories

PubMed Central

Dunsmoor, Joseph E.; Kragel, Philip A.; Martin, Alex; LaBar, Kevin S.

2014-01-01

Experimental studies of conditioned learning reveal activity changes in the amygdala and unimodal sensory cortex underlying fear acquisition to simple stimuli. However, real-world fears typically involve complex stimuli represented at the category level. A consequence of category-level representations of threat is that aversive experiences with particular category members may lead one to infer that related exemplars likewise pose a threat, despite variations in physical form. Here, we examined the effect of category-level representations of threat on human brain activation using 2 superordinate categories (animals and tools) as conditioned stimuli. Hemodynamic activity in the amygdala and category-selective cortex was modulated by the reinforcement contingency, leading to widespread fear of different exemplars from the reinforced category. Multivariate representational similarity analyses revealed that activity patterns in the amygdala and object-selective cortex were more similar among exemplars from the threat versus safe category. Learning to fear animate objects was additionally characterized by enhanced functional coupling between the amygdala and fusiform gyrus. Finally, hippocampal activity co-varied with object typicality and amygdala activation early during training. These findings provide novel evidence that aversive learning can modulate category-level representations of object concepts, thereby enabling individuals to express fear to a range of related stimuli. PMID:23709642
The key role of extinction learning in anxiety disorders: behavioral strategies to enhance exposure-based treatments.

PubMed

Pittig, Andre; van den Berg, Linda; Vervliet, Bram

2016-01-01

Extinction learning is a major mechanism for fear reduction by means of exposure. Current research targets innovative strategies to enhance fear extinction and thereby optimize exposure-based treatments for anxiety disorders. This selective review updates novel behavioral strategies that may provide cutting-edge clinical implications. Recent studies provide further support for two types of enhancement strategies. Procedural enhancement strategies implemented during extinction training translate to how exposure exercises may be conducted to optimize fear extinction. These strategies mostly focus on a maximized violation of dysfunctional threat expectancies and on reducing context and stimulus specificity of extinction learning. Flanking enhancement strategies target periods before and after extinction training and inform optimal preparation and post-processing of exposure exercises. These flanking strategies focus on the enhancement of learning in general, memory (re-)consolidation, and memory retrieval. Behavioral strategies to enhance fear extinction may provide powerful clinical applications to further maximize the efficacy of exposure-based interventions. However, future replications, mechanistic examinations, and translational studies are warranted to verify long-term effects and naturalistic utility. Future directions also comprise the interplay of optimized fear extinction with (avoidance) behavior and motivational antecedents of exposure.
Neurocircuitry models of posttraumatic stress disorder and extinction: human neuroimaging research--past, present, and future.

PubMed

Rauch, Scott L; Shin, Lisa M; Phelps, Elizabeth A

2006-08-15

The prevailing neurocircuitry models of anxiety disorders have been amygdalocentric in form. The bases for such models have progressed from theoretical considerations, extrapolated from research in animals, to in vivo human imaging data. For example, one current model of posttraumatic stress disorder (PTSD) has been highly influenced by knowledge from rodent fear conditioning research. Given the phenomenological parallels between fear conditioning and the pathogenesis of PTSD, we have proposed that PTSD is characterized by exaggerated amygdala responses (subserving exaggerated acquisition of fear associations and expression of fear responses) and deficient frontal cortical function (mediating deficits in extinction and the capacity to suppress attention/response to trauma-related stimuli), as well as deficient hippocampal function (mediating deficits in appreciation of safe contexts and explicit learning/memory). Neuroimaging studies have yielded convergent findings in support of this model. However, to date, neuroimaging investigations of PTSD have not principally employed conditioning and extinction paradigms per se. The recent development of such imaging probes now sets the stage for directly testing hypotheses regarding the neural substrates of fear conditioning and extinction abnormalities in PTSD.
Differential splicing and glycosylation of Apoer2 alters synaptic plasticity and fear learning

PubMed Central

Wasser, Catherine R.; Masiulis, Irene; Durakoglugil, Murat S.; Lane-Donovan, Courtney; Xian, Xunde; Beffert, Uwe; Agarwala, Anandita; Hammer, Robert E.; Herz, Joachim

2015-01-01

Apoer2 is an essential receptor in the central nervous system that binds to the apolipoprotein ApoE. Various splice variants of Apoer2 are produced. We showed that Apoer2 lacking exon 16, which encodes the O-linked sugar (OLS) domain, altered the proteolytic processing and abundance of Apoer2 in cells and synapse number and function in mice. In cultured cells expressing this splice variant, extracellular cleavage of OLS-deficient Apoer2 was reduced, consequently preventing γ-secretase-dependent release of the intracellular domain of Apoer2. Mice expressing Apoer2 lacking the OLS domain had increased Apoer2 abundance in the brain, hippocampal spine density, and glutamate receptor abundance, but decreased synaptic efficacy. Mice expressing a form of Apoer2 lacking the OLS domain and containing an alternatively spliced cytoplasmic tail region that promotes glutamate receptor signaling showed enhanced hippocampal long-term potentiation (LTP), a phenomenon associated with learning and memory. However, these mice did not display enhanced spatial learning in the Morris water maze, and cued fear conditioning was reduced. Reducing the expression of the mutant Apoer2 allele so that the abundance of the protein was similar to that of Apoer2 in wild-type mice normalized spine density, hippocampal LTP, and cued fear learning. These findings demonstrated a role for ApoE receptors as regulators of synaptic glutamate receptor activity and established differential receptor glycosylation as a potential regulator of synaptic function and memory. PMID:25429077
The Role of Verbal Threat Information in the Development of Childhood Fear. “Beware the Jabberwock!”

PubMed Central

Field, Andy P.

2010-01-01

Rachman’s (Behaviour Research and Therapy 15:372–387, 1977; Clinical Psychology Review 11:155–173, 1991) three pathways theory proposed that childhood fears not only arise as a consequence of direct learning experiences, but can also be elicited by means of threat information transmission. This review looks at the scientific evidence for this idea, which has accumulated during the past three decades. We review research on the influences of media exposure on children’s fears, retrospective parent and child reports on the role of threat information in fear acquisition, and experimental studies that explored the causal effects of threat information on childhood fears. We also discuss possible mechanisms by which threat information exerts its influence and the processes relevant to understand the role of this type of learning experience in the origins of fear. Finally, implications for the prevention and intervention of childhood fears are briefly explored, and potential leads for future research will be highlighted. PMID:20198423
Tracking the fear memory engram: discrete populations of neurons within amygdala, hypothalamus, and lateral septum are specifically activated by auditory fear conditioning

PubMed Central

Wilson, Yvette M.; Gunnersen, Jenny M.; Murphy, Mark

2015-01-01

Memory formation is thought to occur via enhanced synaptic connectivity between populations of neurons in the brain. However, it has been difficult to localize and identify the neurons that are directly involved in the formation of any specific memory. We have previously used fos-tau-lacZ (FTL) transgenic mice to identify discrete populations of neurons in amygdala and hypothalamus, which were specifically activated by fear conditioning to a context. Here we have examined neuronal activation due to fear conditioning to a more specific auditory cue. Discrete populations of learning-specific neurons were identified in only a small number of locations in the brain, including those previously found to be activated in amygdala and hypothalamus by context fear conditioning. These populations, each containing only a relatively small number of neurons, may be directly involved in fear learning and memory. PMID:26179231
Origins of common fears in South African children.

PubMed

Muris, Peter; du Plessis, Michelle; Loxton, Helene

2008-12-01

The present study examined the origins of common childhood fears within a South African context. Six-hundred-and-fifty-five 10- to 14-year-old children were given a brief fear list that helped them to identify their most intense fear and then completed a brief questionnaire for assessing the origins of fears that was based on Rachman's [Rachman, S. (1977). The conditioning theory of fear acquisition: A critical examination. Behaviour Research and Therapy, 15, 375-387; Rachman, S. (1991). Neoconditioning and the classical theory of fear acquisition. Clinical Psychology Review, 17, 47-67] three-pathways theory. More precisely, children were asked to report whether they had experienced conditioning, modeling, and negative information experiences in relation to their most feared stimulus or situation, and also had to indicate to what extent such experiences had actually played a role in the onset and/or intensification of their fears. Results showed that children most frequently reported indirect learning experiences (i.e., modeling and negative information) in relation to their fears, whereas conditioning was clearly less often mentioned. The majority of the children had no precise idea of how their fear had actually begun, but a substantial proportion of them reported various learning experiences in relation to the onset and intensification of fears. Significant cultural differences were not only observed in the prevalence of common fears, but also in the pathways reported for the origins of fears. The results are briefly discussed in terms of the living conditions of South African children from various cultural backgrounds.
Corticosterone facilitates extinction of fear memory in BALB/c mice but strengthens cue related fear in C57BL/6 mice.

PubMed

Brinks, V; de Kloet, E R; Oitzl, M S

2009-04-01

Corticosterone, the naturally occurring glucocorticoid of rodents is secreted in response to stressors and is known for its facilitating and detrimental effects on emotional learning and memory. The large variability in the action of corticosterone on processing of emotional memories is postulated to depend on genetic background and the spatio-temporal domain in which the hormone operates. To address this hypothesis, mice of two strains with distinct corticosterone secretory patterns and behavioural phenotype (BALB/c and C57BL/6J) were treated with corticosterone (250 microg/kg, i.p.), either 5 min before or directly after acquisition in a fear conditioning task. As the paradigm allowed assessing in one experimental procedure both context- and cue-related fear behaviour, we were able to detect generalization and specificity of fear. BALB/c showed generalized strong fear memory, while C57BL/6J mice discriminated between freezing during context- and cue episodes. Corticosterone had opposite effects on fear memory depending on the strain and time of injection. Corticosterone after acquisition did not affect C57BL/6J mice, but destabilized consolidation and facilitated extinction in BALB/c. Corticosterone 5 min before acquisition strengthened stress-associated signals: BALB/c no longer showed lower fear memory, while C57BL/6J mice displayed increased fear memory and impaired extinction in cue episodes. We propose that corticosterone-induced facilitation of fear memory in C57BL/6J mice can be used to study the development of fear memories, corticosterone administration in BALB/c mice presents a model to examine treatment. We conclude that genetic background and time of corticosterone action are modifiers of fear memory with interesting translational implications for anxiety-related diseases.
Biologically based neural circuit modelling for the study of fear learning and extinction

NASA Astrophysics Data System (ADS)

Nair, Satish S.; Paré, Denis; Vicentic, Aleksandra

2016-11-01

The neuronal systems that promote protective defensive behaviours have been studied extensively using Pavlovian conditioning. In this paradigm, an initially neutral-conditioned stimulus is paired with an aversive unconditioned stimulus leading the subjects to display behavioural signs of fear. Decades of research into the neural bases of this simple behavioural paradigm uncovered that the amygdala, a complex structure comprised of several interconnected nuclei, is an essential part of the neural circuits required for the acquisition, consolidation and expression of fear memory. However, emerging evidence from the confluence of electrophysiological, tract tracing, imaging, molecular, optogenetic and chemogenetic methodologies, reveals that fear learning is mediated by multiple connections between several amygdala nuclei and their distributed targets, dynamical changes in plasticity in local circuit elements as well as neuromodulatory mechanisms that promote synaptic plasticity. To uncover these complex relations and analyse multi-modal data sets acquired from these studies, we argue that biologically realistic computational modelling, in conjunction with experiments, offers an opportunity to advance our understanding of the neural circuit mechanisms of fear learning and to address how their dysfunction may lead to maladaptive fear responses in mental disorders.
2-arachidonoylglycerol signaling impairs short-term fear extinction

PubMed Central

Hartley, N D; Gunduz-Cinar, O; Halladay, L; Bukalo, O; Holmes, A; Patel, S

2016-01-01

Impairments in fear extinction are thought to be central to the psychopathology of posttraumatic stress disorder, and endocannabinoid (eCB) signaling has been strongly implicated in extinction learning. Here we utilized the monoacylglycerol lipase inhibitor JZL184 to selectively augment brain 2-AG levels combined with an auditory cue fear-conditioning paradigm to test the hypothesis that 2-AG-mediated eCB signaling modulates short-term fear extinction learning in mice. We show that systemic JZL184 impairs short-term extinction learning in a CB1 receptor-dependent manner without affecting non-specific freezing behavior or the acquisition of conditioned fear. This effect was also observed in over-conditioned mice environmentally manipulated to re-acquire fear extinction. Cumulatively, the effects of JZL184 appear to be partly due to augmentation of 2-AG signaling in the basolateral nucleus of the amygdala (BLA), as direct microinfusion of JZL184 into the BLA produced similar results. Moreover, we elucidate a short ~3-day temporal window during which 2-AG augmentation impairs extinction behavior, suggesting a preferential role for 2-AG-mediated eCB signaling in the modulation of short-term behavioral sequelae to acute traumatic stress exposure. PMID:26926885
Perceptions of College Students on Successful Strategies for Reducing Mathematics Anxiety

ERIC Educational Resources Information Center

Allen, Amelia Ann

2011-01-01

Despite more than 50 years of attempts to improve mathematics education and the simultaneous prevalence of fears associated with learning mathematics in the United States, the problem of mathematics anxiety among students still remains. This qualitative phenomenological study was focused on understanding college students' perceptions regarding the…
Social learning of fear and safety is determined by the demonstrator's racial group.

PubMed

Golkar, Armita; Castro, Vasco; Olsson, Andreas

2015-01-01

Social learning offers an efficient route through which humans and other animals learn about potential dangers in the environment. Such learning inherently relies on the transmission of social information and should imply selectivity in what to learn from whom. Here, we conducted two observational learning experiments to assess how humans learn about danger and safety from members ('demonstrators') of an other social group than their own. We show that both fear and safety learning from a racial in-group demonstrator was more potent than learning from a racial out-group demonstrator. © 2015 The Author(s) Published by the Royal Society. All rights reserved.
Extending Social Learning Theory to Explain Victimization Among Gang and Ex-Gang Offenders.

PubMed

Gagnon, Analisa

2018-03-01

This study is among the first to extend and test social learning theory's ability to understand property and violent victimization. It specifically tests whether aspects of definitions, differential reinforcement, and differential association/modeling can explain the three types of victimization of gang members: actual experience, perception of likelihood, and fear. The sample consists of over 300 male and female gang members incarcerated in jails throughout Florida. The results show that all three types of victimization can be explained by the three aspects of social learning theory.
Extinction learning is slower, weaker and less context specific after alcohol

PubMed Central

Bisby, James A.; King, John A.; Sulpizio, Valentina; Degeilh, Fanny; Valerie Curran, H.; Burgess, Neil

2015-01-01

Alcohol is frequently involved in psychological trauma and often used by individuals to reduce fear and anxiety. We examined the effects of alcohol on fear acquisition and extinction within a virtual environment. Healthy volunteers were administered alcohol (0.4 g/kg) or placebo and underwent acquisition and extinction from different viewpoints of a virtual courtyard, in which the conditioned stimulus, paired with a mild electric shock, was centrally located. Participants returned the following day to test fear recall from both viewpoints of the courtyard. Skin conductance responses were recorded as an index of conditioned fear. Successful fear acquisition under alcohol contrasted with impaired extinction learning evidenced by persistent conditioned responses (Experiment 1). Participants’ impairments in extinction under alcohol correlated with impairments in remembering object-locations in the courtyard seen from one viewpoint when tested from the other viewpoint. Alcohol-induced extinction impairments were overcome by increasing the number of extinction trials (Experiment 2). However, a test of fear recall the next day showed persistent fear in the alcohol group across both viewpoints. Thus, alcohol impaired extinction rather than acquisition of fear, suggesting that extinction is more dependent than acquisition on alcohol-sensitive representations of spatial context. Overall, extinction learning under alcohol was slower, weaker and less context-specific, resulting in persistent fear at test that generalized to the extinction viewpoint. The selective effect on extinction suggests an effect of alcohol on prefrontal involvement, while the reduced context-specificity implicates the hippocampus. These findings have important implications for the use of alcohol by individuals with clinical anxiety disorders. PMID:26234587

A hippocampal insulin-growth factor 2 pathway regulates the extinction of fear memories

PubMed Central

Agis-Balboa, Roberto Carlos; Arcos-Diaz, Dario; Wittnam, Jessica; Govindarajan, Nambirajan; Blom, Kim; Burkhardt, Susanne; Haladyniak, Ulla; Agbemenyah, Hope Yao; Zovoilis, Athanasios; Salinas-Riester, Gabriella; Opitz, Lennart; Sananbenesi, Farahnaz; Fischer, Andre

2011-01-01

Extinction learning refers to the phenomenon that a previously learned response to an environmental stimulus, for example, the expression of an aversive behaviour upon exposure to a specific context, is reduced when the stimulus is repeatedly presented in the absence of a previously paired aversive event. Extinction of fear memories has been implicated with the treatment of anxiety disease but the molecular processes that underlie fear extinction are only beginning to emerge. Here, we show that fear extinction initiates upregulation of hippocampal insulin-growth factor 2 (Igf2) and downregulation of insulin-growth factor binding protein 7 (Igfbp7). In line with this observation, we demonstrate that IGF2 facilitates fear extinction, while IGFBP7 impairs fear extinction in an IGF2-dependent manner. Furthermore, we identify one cellular substrate of altered IGF2 signalling during fear extinction. To this end, we show that fear extinction-induced IGF2/IGFBP7 signalling promotes the survival of 17–19-day-old newborn hippocampal neurons. In conclusion, our data suggest that therapeutic strategies that enhance IGF2 signalling and adult neurogenesis might be suitable to treat disease linked to excessive fear memory. PMID:21873981
Enhanced Extinction of Aversive Memories by High-Frequency Stimulation of the Rat Infralimbic Cortex

PubMed Central

Maroun, Mouna; Kavushansky, Alexandra; Holmes, Andrew; Wellman, Cara; Motanis, Helen

2012-01-01

Electrical stimulation of the rodent medial prefrontal cortex (mPFC), including the infralimbic cortex (IL), immediately prior to or during fear extinction training facilitates extinction memory. Here we examined the effects of high-frequency stimulation (HFS) of the rat IL either prior to conditioning or following retrieval of the conditioned memory, on extinction of Pavlovian fear and conditioned taste aversion (CTA). IL-HFS applied immediately after fear memory retrieval, but not three hours after retrieval or prior to conditioning, subsequently reduced freezing during fear extinction. Similarly, IL-HFS given immediately, but not three hours after, retrieval of a CTA memory reduced aversion during extinction. These data indicate that HFS of the IL may be an effective method for reducing both learned fear and learned aversion. PMID:22586453
Hippocampal Arc (Arg3.1) expression is induced by memory recall and required for memory reconsolidation in trace fear conditioning.

PubMed

Chia, Chester; Otto, Tim

2013-11-01

Mounting evidence suggests that long-lasting, protein synthesis-dependent changes in synaptic strength accompany both the initial acquisition and subsequent recall of specific memories. Within brain areas thought to be important for learning and memory, including the hippocampus, learning-related plasticity is likely mediated in part by NMDA receptor activation and experience-dependent changes in gene expression. In the present study, we examined the role of activity-regulated cytoskeletal-associated protein (Arc/Arg3.1) expression in the acquisition, recall, and reconsolidation of memory in a trace fear conditioning paradigm. First, we show that the expression of Arc protein in ventral hippocampus (VH) is dramatically enhanced by memory recall 24h after the acquisition of trace fear conditioning, and that both memory recall and the associated recall-induced enhancement of Arc expression are blocked by pre-training administration of 2-amino-5-phosphonovaleric acid (APV). Next, we show that while infusion of Arc antisense oligodeoxynucleotides (ODNs) into VH prior to testing had little effect on memory recall, it significantly reduced both Arc protein expression and freezing behavior during subsequent testing sessions. Collectively, these results suggest that Arc/Arg3.1 protein plays an important functional role in both the initial acquisition of hippocampal-dependent memory and the reconsolidation of these memories after recall. Copyright © 2013 Elsevier Inc. All rights reserved.
NPY controls fear conditioning and fear extinction by combined action on Y₁ and Y₂ receptors.

PubMed

Verma, D; Tasan, R O; Herzog, H; Sperk, G

2012-06-01

Neuropeptide Y (NPY) and its receptors have been implicated in the control of emotional-affective processing, but the mechanism is unclear. While it is increasingly evident that stimulation of Y₁ and inhibition of Y₂ receptors produce prominent anxiolytic and antidepressant effects, the contribution of the individual NPY receptor subtypes in the acquisition and extinction of learned fear are unknown. Here we performed Pavlovian fear conditioning and extinction in NPY knockout (KO) and in NPY receptor KO mice. NPY KO mice display a dramatically accelerated acquisition of conditioned fear. Deletion of Y₁ receptors revealed only a moderately accelerated acquisition of conditioned fear, while lack of Y₂ receptors was without any effect on fear learning. However, the strong phenotype seen in NPY KO mice was reproduced in mice lacking both Y₁ and Y₂ receptors. In addition, NPY KO mice showed excessive recall of conditioned fear and impaired fear extinction. This behaviour was replicated only after deletion of both Y₁ and Y₂ receptors. In Y₁ receptor single KO mice, fear extinction was delayed and was unchanged in Y₂ receptor KO mice. Deletion of NPY and particularly Y₂ receptors resulted in a generalization of conditioned fear. Our data demonstrate that NPY delays the acquisition, reduces the expression of conditioned fear while promoting fear extinction. Although these effects appear to be primarily mediated by Y₁ receptors, the pronounced phenotype of Y₁Y₂ receptor double KO mice suggests a synergistic role of Y₂ receptors in fear acquisition and in fear extinction. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.
Stress and Fear Extinction

PubMed Central

Maren, Stephen; Holmes, Andrew

2016-01-01

Stress has a critical role in the development and expression of many psychiatric disorders, and is a defining feature of posttraumatic stress disorder (PTSD). Stress also limits the efficacy of behavioral therapies aimed at limiting pathological fear, such as exposure therapy. Here we examine emerging evidence that stress impairs recovery from trauma by impairing fear extinction, a form of learning thought to underlie the suppression of trauma-related fear memories. We describe the major structural and functional abnormalities in brain regions that are particularly vulnerable to stress, including the amygdala, prefrontal cortex, and hippocampus, which may underlie stress-induced impairments in extinction. We also discuss some of the stress-induced neurochemical and molecular alterations in these brain regions that are associated with extinction deficits, and the potential for targeting these changes to prevent or reverse impaired extinction. A better understanding of the neurobiological basis of stress effects on extinction promises to yield novel approaches to improving therapeutic outcomes for PTSD and other anxiety and trauma-related disorders. PMID:26105142
Change--how to remove the fear, resentment, and resistance.

PubMed

Weitz, A J

1995-11-01

This article introduces active learning, which is an innovative education methodology for the workplace classroom. It is used to help people remove their fear, resentment, and resistance to the change process itself. Active learning makes education more effective compared with the predominantly used traditional lecture-type teaching methodology.
Learning Induces Sonic Hedgehog Signaling in the Amygdala which Promotes Neurogenesis and Long-Term Memory Formation

PubMed Central

Hung, Hui-Chi; Hsiao, Ya-Hsin

2015-01-01

Background: It is known that neurogenesis occurs throughout the life mostly in the subgranular zone of the hippocampus and the subventricular zone of the lateral ventricle. We investigated whether neurogenesis occurred in the amygdala and its function in fear memory formation. Methods: For detection of newborn neurons, mice were injected intraperitoneally with 5-bromo-2’-deoxyuridine (BrdU) 2h before receiving 15 tone–footshock pairings, and newborn neurons were analyzed 14 and 42 days after training. To determine the relationship between neurogenesis and memory formation, mice were given a proliferation inhibitor methylazoxymethanol (MAM) or a DNA synthesis inhibitor cytosine arabinoside (Ara-C). To test whether sonic hedgehog (Shh) signaling was required for neurogenesis, Shh-small hairpin–interfering RNA (shRNA) was inserted into a retroviral vector (Retro-Shh-shRNA). Results: The number of BrdU+/Neuronal nuclei (NeuN)+ cells was significantly higher in the conditioned mice, suggesting that association of tone with footshock induced neurogenesis. MAM and Ara-C markedly reduced neurogenesis and impaired fear memory formation. Shh, its receptor patched 1 (Ptc1), and transcription factor Gli1 protein levels increased at 1 day and returned to baseline at 7 days after fear conditioning. Retro-Shh-shRNA, which knocked down Shh specifically in the mitotic neurons, reduced the number of BrdU+/NeuN+ cells and decreased freezing responses. Conclusions: These results suggest that fear learning induces Shh signaling activation in the amygdala, which promotes neurogenesis and fear memory formation. PMID:25522410
Evidence for Hippocampus-Dependent Contextual Learning at Postnatal Day 17 in the Rat

ERIC Educational Resources Information Center

Foster, Jennifer A.; Burman, Michael A.

2010-01-01

Long-term memory for fear of an environment (contextual fear conditioning) emerges later in development (postnatal day; PD 23) than long-term memory for fear of discrete stimuli (PD 17). As contextual, but not explicit cue, fear conditioning relies on the hippocampus; this has been interpreted as evidence that the hippocampus is not fully…
Childhood Fears: What Children Are Afraid of and Why.

ERIC Educational Resources Information Center

Crosser, Sandra

1995-01-01

It is important for early childhood professionals to learn about childhood fears so that they can help children cope with them. Children's fears are normal, the nature of preschoolers' fears is related to their cognitive development, and a child's temperament and sense of autonomy may influence the extent of and manner of reaction to a fearful…
An "egr-1" ("zif268") Antisense Oligodeoxynucleotide Infused into the Amygdala Disrupts Fear Conditioning

ERIC Educational Resources Information Center

Donley, Melanie P.; Rosen, Jeffrey B.; Malkani, Seema; Wallace, Karin J.

2004-01-01

Studies of gene expression following fear conditioning have demonstrated that the inducible transcription factor, "egr-1," is increased in the lateral nucleus of the amygdala shortly following fear conditioning. These studies suggest that "egr-1" and its protein product Egr-1 in the amygdala are important for learning and memory of fear. To…
Activation of BDNF Signaling Prevents the Return of Fear in Female Mice

ERIC Educational Resources Information Center

Baker-Andresen, Danay; Flavell, Charlotte R.; Li, Xiang; Bredy, Timothy W.

2013-01-01

There are significant sex differences in vulnerability to develop fear-related anxiety disorders. Females exhibit twice the rate of post-traumatic stress disorder (PTSD) as males and sex differences have been observed in fear extinction learning in both humans and rodents, with a failure to inhibit fear emerging as a precipitating factor in the…
Long-term effects of controllability or the lack of it on coping abilities and stress resilience in the rat.

PubMed

Lucas, Morgan; Ilin, Yana; Anunu, Rachel; Kehat, Orli; Xu, Lin; Desmedt, Aline; Richter-Levin, Gal

2014-09-01

Findings suggest that stress-induced impaired learning and coping abilities may be attributed more to the psychological nature of the stressor, rather than its physical properties. It has been proposed that establishing controllability over stressors can ameliorate some of its effects on cognition and behavior. Gaining controllability was suggested to be associated with the development of stress resilience. Based on repeated exposure to the two-way shuttle avoidance task, we previously developed and validated a behavioral task that leads to a strict dissociation between gaining controllability (to the level that the associated fear is significantly reduced) and a fearful state of uncontrollability. Employing this protocol, we investigated here the impact of gaining or failing to gain emotional controllability on indices of anxiety and depression and on subsequent abilities to cope with positively or negatively reinforcing learning experiences. In agreement with previous studies, rats exposed to the uncontrollable protocol demonstrated high concentration of sera corticosterone, increased immobility, reduced duration of struggling in the forced swim test and impaired ability to acquire subsequent learning tasks. Achieving emotional controllability resulted in resilience to stress as was indicated by longer duration of struggling in the forced swim test, and enhanced learning abilities. Our prolonged training protocol, with the demonstrated ability of rats to gain emotional controllability, is proposed as a useful tool to study the neurobiological mechanisms of stress resilience.
Dexamethasone Treatment Leads to Enhanced Fear Extinction and Dynamic Fkbp5 Regulation in Amygdala

PubMed Central

Sawamura, Takehito; Klengel, Torsten; Armario, Antonio; Jovanovic, Tanja; Norrholm, Seth D; Ressler, Kerry J; Andero, Raül

2016-01-01

Posttraumatic stress disorder (PTSD) is both a prevalent and debilitating trauma-related disorder associated with dysregulated fear learning at the core of many of its signs and symptoms. Improvements in the currently available psychological and pharmacological treatments are needed in order to improve PTSD treatment outcomes and to prevent symptom relapse. In the present study, we used a putative animal model of PTSD that included presentation of immobilization stress (IMO) followed by fear conditioning (FC) a week later. We then investigated the acute effects of GR receptor activation on the extinction (EXT) of conditioned freezing, using dexamethasone administered systemically which is known to result in suppression of the HPA axis. In our previous work, IMO followed by tone-shock-mediated FC was associated with impaired fear EXT. In this study, we administered dexamethasone 4 h before EXT training and then examined EXT retention (RET) 24 h later to determine whether dexamethasone suppression rescued EXT deficits. Dexamethasone treatment produced dose-dependent enhancement of both EXT and RET. Dexamethasone was also associated with reduced amygdala Fkbp5 mRNA expression following EXT and after RET. Moreover, DNA methylation of the Fkbp5 gene occurred in a dose-dependent and time course-dependent manner within the amygdala. Additionally, we found dynamic changes in epigenetic regulation, including Dnmt and Tet gene pathways, as a function of both fear EXT and dexamethasone suppression of the HPA axis. Together, these data suggest that dexamethasone may serve to enhance EXT by altering Fkbp5-mediated glucocorticoid sensitivity via epigenetic regulation of Fkbp5 expression. PMID:26174596
Dexamethasone Treatment Leads to Enhanced Fear Extinction and Dynamic Fkbp5 Regulation in Amygdala.

PubMed

Sawamura, Takehito; Klengel, Torsten; Armario, Antonio; Jovanovic, Tanja; Norrholm, Seth D; Ressler, Kerry J; Andero, Raül

2016-02-01

Posttraumatic stress disorder (PTSD) is both a prevalent and debilitating trauma-related disorder associated with dysregulated fear learning at the core of many of its signs and symptoms. Improvements in the currently available psychological and pharmacological treatments are needed in order to improve PTSD treatment outcomes and to prevent symptom relapse. In the present study, we used a putative animal model of PTSD that included presentation of immobilization stress (IMO) followed by fear conditioning (FC) a week later. We then investigated the acute effects of GR receptor activation on the extinction (EXT) of conditioned freezing, using dexamethasone administered systemically which is known to result in suppression of the HPA axis. In our previous work, IMO followed by tone-shock-mediated FC was associated with impaired fear EXT. In this study, we administered dexamethasone 4 h before EXT training and then examined EXT retention (RET) 24 h later to determine whether dexamethasone suppression rescued EXT deficits. Dexamethasone treatment produced dose-dependent enhancement of both EXT and RET. Dexamethasone was also associated with reduced amygdala Fkbp5 mRNA expression following EXT and after RET. Moreover, DNA methylation of the Fkbp5 gene occurred in a dose-dependent and time course-dependent manner within the amygdala. Additionally, we found dynamic changes in epigenetic regulation, including Dnmt and Tet gene pathways, as a function of both fear EXT and dexamethasone suppression of the HPA axis. Together, these data suggest that dexamethasone may serve to enhance EXT by altering Fkbp5-mediated glucocorticoid sensitivity via epigenetic regulation of Fkbp5 expression.
Administration of riluzole to the basolateral amygdala facilitates fear extinction in rats.

PubMed

Sugiyama, Azusa; Yamada, Misa; Saitoh, Akiyoshi; Oka, Jun-Ichiro; Yamada, Mitsuhiko

2018-01-15

A general understanding exists that inhibition of glutamatergic neurotransmission in the basolateral amygdala (BLA) impairs fear extinction in rodents. Surprisingly, we recently found that systemic administration of riluzole, which has been shown to inhibit the glutamatergic system, facilitates extinction learning in rats with a preconditioned contextual fear response. However, the mechanisms underlying this paradoxical effect of riluzole remain unclear. In this study, adult male Wistar rats were bilaterally cannulated in the BLA to examine the effects of intra-BLA administration of riluzole. We also compared the effects of riluzole with those of d-cycloserine, a partial agonist at the glycine-binding region of the N-methyl-d-aspartate (NMDA) receptor. In this study, intra-BLA administration of either riluzole or d-cycloserine facilitated extinction learning of contextual fear in conditioned rats. In addition, both riluzole and d-cycloserine enhanced the acquisition of recognition memory in the same model. However, intra-BLA injections of riluzole, but not d-cycloserine, had a potent anxiolytic-like effect when investigated using an elevated plus-maze test. Our findings suggest that riluzole-induced facilitation of extinction learning in rats with a preconditioned contextual fear reflects an indirect effect, resulting from the intra-BLA administration of the drug, and might not be directly related to inhibition of glutamatergic signaling. Further research is needed to clarify the mechanisms underlying the paradoxical effect of riluzole on fear extinction learning observed in this study. Copyright © 2017 Elsevier B.V. All rights reserved.
Sex differences in fear discrimination do not manifest as differences in conditioned inhibition.

PubMed

Foilb, Allison R; Bals, Julia; Sarlitto, Mary C; Christianson, John P

2018-01-01

Distinguishing safety from danger is necessary for survival, but is aberrant in individuals with post-traumatic stress disorder (PTSD). While PTSD is more prevalent in women than men, research on sex differences in safety learning is limited. Here, female rats demonstrated greater fear discrimination than males in a CS+/CS- paradigm. To determine if this sex difference transferred to fear inhibition, rats were tested for conditioned inhibition in a summation test with the CS+ and CS- presented in compound; no sex difference emerged. The results suggest sex differences in the neural mechanisms of discrimination learning but not recall of a fear inhibitor. © 2018 Foilb et al.; Published by Cold Spring Harbor Laboratory Press.
Lead exposure and fear-potentiated startle in the VA Normative Aging Study: a pilot study of a novel physiological approach to investigating neurotoxicant effects.

PubMed

Grashow, Rachel; Miller, Mark W; McKinney, Ann; Nie, Linda H; Sparrow, David; Hu, Howard; Weisskopf, Marc G

2013-01-01

Physiologically-based indicators of neural plasticity in humans could provide mechanistic insights into toxicant actions on learning in the brain, and perhaps prove more objective and sensitive measures of such effects than other methods. We explored the association between lead exposure and classical conditioning of the acoustic startle reflex (ASR)-a simple form of associative learning in the brain-in a population of elderly men. Fifty-one men from the VA Normative Aging Study with cumulative bone lead exposure measurements made with K-X-Ray-Fluorescence participated in a fear-conditioning protocol. The mean age of the men was 75.5years (standard deviation [sd]=5.9) and mean patella lead concentration was 22.7μg/g bone (sd=15.9). Baseline ASR eyeblink response decreased with age, but was not associated with subsequent conditioning. Among 37 men with valid responses at the end of the protocol, higher patella lead was associated with decreased awareness of the conditioning contingency (declarative learning; adjusted odds ratio [OR] per 20μg/g patella lead=0.91, 95% confidence interval [CI]: 0.84, 0.99, p=0.03). Eyeblink conditioning (non-declarative learning) was 0.44sd less (95% CI: -0.91, 0.02; p=0.06) per 20μg/g patella lead after adjustment. Each result was stronger when correcting for the interval between lead measurement and startle testing (awareness: OR=0.88, 95% CI: 0.78, 0.99, p=0.04; conditioning: -0.79sd less, 95% CI: -1.56, 0.03, p=0.04). This initial exploration suggests that lead exposure interferes with specific neural mechanisms of learning and offers the possibility that the ASR may provide a new approach to physiologically explore the effects of neurotoxicant exposures on neural mechanisms of learning in humans with a paradigm that is directly comparable to animal models. Copyright © 2013 Elsevier Inc. All rights reserved.
Nicotine Ameliorates NMDA Receptor Antagonist-Induced Deficits in Contextual Fear Conditioning through High Affinity Nicotinic Acetylcholine Receptors in the Hippocampus

PubMed Central

André, Jessica M.; Leach, Prescott T.; Gould, Thomas J.

2011-01-01

NMDA glutamate receptors (NMDARs) and nicotinic acetylcholine receptors (nAChRs) are both involved in learning and synaptic plasticity. Increasing evidence suggests processes mediated by these receptors may interact to modulate learning; however, little is known about the neural substrates involved in these interactive processes. The present studies investigated the effects of nicotine on MK-801 hydrogen maleate (MK-801) and DL-2-Amino-5-phosphonovaleric acid (APV) induced disruption of contextual fear conditioning in male C57BL/6J mice, using direct drug infusion and selective nAChR antagonists to define the brain regions and the nAChR subtypes involved. Mice treated with MK-801 showed a deficit in contextual fear conditioning that was ameliorated by nicotine. Direct drug infusion demonstrated that the NMDAR antagonists disrupted hippocampal function and that nicotine acted in the dorsal hippocampus to ameliorate the deficit in learning. The high-affinity nAChR antagonist Dihydro-β-erythroidine hydrobromide (DhβE) blocked the effects of nicotine on MK-801-induced deficits while the α7 nAChR antagonist methyllycaconitine citrate salt hydrate (MLA) did not. These results suggest that NMDARs and nAChRs may mediate similar hippocampal processes involved in contextual fear conditioning. Furthermore, these results may have implications for developing effective therapeutics for the cognitive deficits associated with schizophrenia because a large subset of patients with schizophrenia exhibit cognitive deficits that may be related to NMDAR dysfunction and smoke at much higher rates than the healthy population, which may be an attempt to ameliorate cognitive deficits. PMID:21167848
Sex differences in conditioned stimulus discrimination during context-dependent fear learning and its retrieval in humans: the role of biological sex, contraceptives and menstrual cycle phases

PubMed Central

Lonsdorf, Tina B.; Haaker, Jan; Schümann, Dirk; Sommer, Tobias; Bayer, Janine; Brassen, Stefanie; Bunzeck, Nico; Gamer, Matthias; Kalisch, Raffael

2015-01-01

Background Anxiety disorders are more prevalent in women than in men. Despite this sexual dimorphism, most experimental studies are conducted in male participants, and studies focusing on sex differences are sparse. In addition, the role of hormonal contraceptives and menstrual cycle phase in fear conditioning and extinction processes remain largely unknown. Methods We investigated sex differences in context-dependent fear acquisition and extinction (day 1) and their retrieval/expression (day 2). Skin conductance responses (SCRs), fear and unconditioned stimulus expectancy ratings were obtained. Results We included 377 individuals (261 women) in our study. Robust sex differences were observed in all dependent measures. Women generally displayed higher subjective ratings but smaller SCRs than men and showed reduced excitatory/inhibitory conditioned stimulus (CS+/CS−) discrimination in all dependent measures. Furthermore, women using hormonal contraceptives showed reduced SCR CS discrimination on day 2 than men and free-cycling women, while menstrual cycle phase had no effect. Limitations Possible limitations include the simultaneous testing of up to 4 participants in cubicles, which might have introduced a social component, and not assessing postexperimental contingency awareness. Conclusion The response pattern in women shows striking similarity to previously reported sex differences in patients with anxiety. Our results suggest that pronounced deficits in associative discrimination learning and subjective expression of safety information (CS− responses) might underlie higher prevalence and higher symptom rates seen in women with anxiety disorders. The data call for consideration of biological sex and hormonal contraceptive use in future studies and may suggest that targeting inhibitory learning during therapy might aid precision medicine. PMID:26107163
Estradiol shifts interactions between the infralimbic cortex and central amygdala to enhance fear extinction memory in female rats.

PubMed

Maeng, Lisa Y; Cover, Kara K; Taha, Mohamad B; Landau, Aaron J; Milad, Mohammed R; Lebrón-Milad, Kelimer

2017-01-02

There is growing evidence that estradiol (E2) enhances fear extinction memory consolidation. However, it is unclear how E2 influences the nodes of the fear extinction network to enhance extinction memory. This study begins to delineate the neural circuits underlying the influence of E2 on fear extinction acquisition and consolidation in female rats. After fear conditioning (day 1), naturally cycling female rats underwent extinction learning (day 2) in a low-E2 state, receiving a systemic administration of either E2 or vehicle prior to extinction training. Extinction memory recall was then tested 24 hr later (day 3). We measured immediate early gene c-fos expression within the extinction network during fear extinction learning and extinction recall. During extinction learning, E2 treatment increased centrolateral amygdala c-fos activity and reduced lateral amygdala activity relative to vehicle. During extinction recall, E2-treated rats exhibited reduced c-fos expression in the centromedial amygdala. There were no group differences in c-fos expression within the medial prefrontal cortex or dorsal hippocampus. Examining c-fos ratios with the infralimbic cortex (IL) revealed that, despite the lack of group differences within the IL, E2 treatment induced greater IL activity relative to both prelimbic cortex and central amygdala (CeA) activity during extinction memory recall. Only the relationship between IL and CeA activity positively correlated with extinction retention. In conclusion, E2 appears to modify interactions between the IL and the CeA in females, shifting from stronger amygdalar modulation of fear during extinction learning to stronger IL control during extinction recall. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Prior Learning of Relevant Nonaversive Information Is a Boundary Condition for Avoidance Memory Reconsolidation in the Rat Hippocampus.

PubMed

Radiske, Andressa; Gonzalez, Maria Carolina; Conde-Ocazionez, Sergio A; Feitosa, Anatildes; Köhler, Cristiano A; Bevilaqua, Lia R; Cammarota, Martín

2017-10-04

Reactivated memories can be modified during reconsolidation, making this process a potential therapeutic target for posttraumatic stress disorder (PTSD), a mental illness characterized by the recurring avoidance of situations that evoke trauma-related fears. However, avoidance memory reconsolidation depends on a set of still loosely defined boundary conditions, limiting the translational value of basic research. In particular, the involvement of the hippocampus in fear-motivated avoidance memory reconsolidation remains controversial. Combining behavioral and electrophysiological analyses in male Wistar rats, we found that previous learning of relevant nonaversive information is essential to elicit the participation of the hippocampus in avoidance memory reconsolidation, which is associated with an increase in theta- and gamma-oscillation power and cross-frequency coupling in dorsal CA1 during reactivation of the avoidance response. Our results indicate that the hippocampus is involved in memory reconsolidation only when reactivation results in contradictory representations regarding the consequences of avoidance and suggest that robust nesting of hippocampal theta-gamma rhythms at the time of retrieval is a specific reconsolidation marker. SIGNIFICANCE STATEMENT Posttraumatic stress disorder (PTSD) is characterized by maladaptive avoidance responses to stimuli or behaviors that represent or bear resemblance to some aspect of a traumatic experience. Disruption of reconsolidation, the process by which reactivated memories become susceptible to modifications, is a promising approach for treating PTSD patients. However, much of what is known about fear-motivated avoidance memory reconsolidation derives from studies based on fear conditioning instead of avoidance-learning paradigms. Using a step-down inhibitory avoidance task in rats, we found that the hippocampus is involved in memory reconsolidation only when the animals acquired the avoidance response in an environment that they had previously learned as safe and showed that increased theta- and gamma-oscillation coupling during reactivation is an electrophysiological signature of this process. Copyright © 2017 the authors 0270-6474/17/379675-11$15.00/0.
It's time to fear! Interval timing in odor fear conditioning in rats

PubMed Central

Shionoya, Kiseko; Hegoburu, Chloé; Brown, Bruce L.; Sullivan, Regina M.; Doyère, Valérie; Mouly, Anne-Marie

2013-01-01

Time perception is crucial to goal attainment in humans and other animals, and interval timing also guides fundamental animal behaviors. Accumulating evidence has made it clear that in associative learning, temporal relations between events are encoded, and a few studies suggest this temporal learning occurs very rapidly. Most of these studies, however, have used methodologies that do not permit investigating the emergence of this temporal learning. In the present study we monitored respiration, ultrasonic vocalization (USV) and freezing behavior in rats in order to perform fine-grain analysis of fear responses during odor fear conditioning. In this paradigm an initially neutral odor (the conditioned stimulus, CS) predicted the arrival of an aversive unconditioned stimulus (US, footshock) at a fixed 20-s time interval. We first investigated the development of a temporal pattern of responding related to CS-US interval duration. The data showed that during acquisition with odor-shock pairings, a temporal response pattern of respiration rate was observed. Changing the CS-US interval duration from 20-s to 30-s resulted in a shift of the temporal response pattern appropriate to the new duration thus demonstrating that the pattern reflected the learning of the CS-US interval. A temporal pattern was also observed during a retention test 24 h later for both respiration and freezing measures, suggesting that the animals had stored the interval duration in long-term memory. We then investigated the role of intra-amygdalar dopaminergic transmission in interval timing. For this purpose, the D1 dopaminergic receptors antagonist SCH23390 was infused in the basolateral amygdala before conditioning. This resulted in an alteration of timing behavior, as reflected in differential temporal patterns between groups observed in a 24 h retention test off drug. The present data suggest that D1 receptor dopaminergic transmission within the amygdala is involved in temporal processing. PMID:24098277
Sustained conditioned responses in prelimbic prefrontal neurons are correlated with fear expression and extinction failure.

PubMed

Burgos-Robles, Anthony; Vidal-Gonzalez, Ivan; Quirk, Gregory J

2009-07-01

During auditory fear conditioning, it is well established that lateral amygdala (LA) neurons potentiate their response to the tone conditioned stimulus, and that this potentiation is required for conditioned fear behavior. Conditioned tone responses in LA, however, last only a few hundred milliseconds and cannot be responsible for sustained fear responses to a tone lasting tens of seconds. Recent evidence from inactivation and stimulation studies suggests that the prelimbic (PL) prefrontal cortex is necessary for expression of learned fears, but the timing of PL tone responses and correlations with fear behavior have not been studied. Using multichannel unit recording techniques in behaving rats, we observed sustained conditioned tone responses in PL that were correlated with freezing behavior on a second-to-second basis during the presentation of a 30 s tone. PL tone responses were also correlated with conditioned freezing across different experimental phases (habituation, conditioning, extinction). Moreover, the persistence of PL responses after extinction training was associated with failure to express extinction memory. Together with previous inactivation findings, the present results suggest that PL transforms transient amygdala inputs to a sustained output that drives conditioned fear responses and gates the expression of extinction. Given the relatively long latency of conditioned responses we observed in PL (approximately 100 ms after tone onset), we propose that PL integrates inputs from the amygdala, hippocampus, and other cortical sources to regulate the expression of fear memories.
Phosphodiesterase 10A inhibition attenuates sleep deprivation-induced deficits in long-term fear memory.

PubMed

Guo, Lengqiu; Guo, Zhuangli; Luo, Xiaoqing; Liang, Rui; Yang, Shui; Ren, Haigang; Wang, Guanghui; Zhen, Xuechu

2016-12-02

Sleep, particularly rapid eye movement (REM) sleep, is implicated in the consolidation of emotional memories. In the present study, we investigated the protective effects of a phosphodiesterase 10A (PDE10A) inhibitor MP-10 on deficits in long-term fear memory induced by REM sleep deprivation (REM-SD). REM-SD caused deficits in long-term fear memory, however, MP-10 administration ameliorated the deleterious effects of REM-SD on long term fear memory. Brain-derived neurotropic factor (BDNF) and phosphorylated cAMP response element-binding protein (pCREB) were altered in specific brain regions associated with learning and memory in REM-SD rats. Accordingly, REM-SD caused a significant decrease of pCREB in hippocampus and striatum and a significant decrease of BDNF in the hippocampus, striatum and amygdala, however, MP-10 reversed the effects of REM-SD in a dose-dependent manner. Our findings suggest that REM-SD disrupts the consolidation of long-term fear memory and that administration of MP-10 protects the REM-SD-induced deficits in fear memory, which may be due to the MP-10-induced expression of BDNF in the hippocampus, striatum and amygdala, and phosphorylation of CREB in the hippocampus and striatum. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.
Interoceptive fear conditioning and panic disorder: the role of conditioned stimulus-unconditioned stimulus predictability.

PubMed

Acheson, Dean T; Forsyth, John P; Moses, Erica

2012-03-01

Interoceptive fear conditioning is at the core of contemporary behavioral accounts of panic disorder. Yet, to date only one study has attempted to evaluate interoceptive fear conditioning in humans (see Acheson, Forsyth, Prenoveau, & Bouton, 2007). That study used brief (physiologically inert) and longer-duration (panicogenic) inhalations of 20% CO(2)-enriched air as an interoceptive conditioned (CS) and unconditioned (US) stimulus and evaluated fear learning in three conditions: CS only, CS-US paired, and CS-US unpaired. Results showed fear conditioning in the paired condition, and fearful responding and resistance to extinction in an unpaired condition. The authors speculated that such effects may be due to difficulty discriminating between the CS and the US. The aims of the present study are to (a) replicate and expand this line of work using an improved methodology, and (b) clarify the role of CS-US discrimination difficulties in either potentiating or depotentiating fear learning. Healthy participants (N=104) were randomly assigned to one of four conditions: (a) CS only, (b) contingent CS-US pairings, (c) unpaired CS and US presentations, or (d) an unpaired "discrimination" contingency, which included an exteroceptive discrimination cue concurrently with CS onset. Electrodermal and self-report ratings served as indices of conditioned responding. Consistent with expectation, the paired contingency and unpaired contingencies yielded elevated fearful responding to the CS alone. Moreover, adding a discrimination cue to the unpaired contingency effectively attenuated fearful responding. Overall, findings are consistent with modern learning theory accounts of panic and highlight the role of interoceptive conditioning and unpredictability in the etiology of panic disorder. Copyright © 2011. Published by Elsevier Ltd.
Enduring abolishment of remote but not recent expression of conditioned fear by the blockade of calcium-permeable AMPA receptors before extinction training.

PubMed

Zelena, Dóra; Mikics, Éva; Balázsfi, Diána; Varga, János; Klausz, Barbara; Urbán, Eszter; Sipos, Eszter; Biró, László; Miskolczi, Christina; Kovács, Krisztina; Ferenczi, Szilamér; Haller, József

2016-06-01

Calcium-permeable (GluA2 subunit-free) AMPA receptors (CP-AMPAR) play prominent roles in fear extinction; however, no blockers of these receptors were studied in tests relevant to extinction learning so far. The CP-AMPAR antagonist IEM-1460 was administered once before extinction trainings, which were started either 1 or 28 days after fear conditioning (FC). We used a mild extinction protocol that durably decreased but did not abolish conditioned fear. The messenger RNA (mRNA) expression of GluA1 and GluA2 subunits were investigated at both time points in the ventromedial prefrontal cortex (vmPFC) and amygdala. IEM-1460 transiently facilitated extinction 1 day after conditioning, but learned fear spontaneously recovered 4 weeks later. When the extinction protocol was applied 28 days after training, IEM-1460 enhanced extinction memory, moreover abolished conditioned fear for at least a month. The expression of GluA1 and GluA2 mRNAs was increased at both time points in the vmPFC. In the basolateral and central amygdala, the GluA1/GluA2 mRNA ratio increased, suggesting a shift towards the preponderance of GluA1 over GluA2 expression. AMPAR blockade lastingly enhanced the extinction of remote but not recent fear memories. Time-dependent changes in AMPA receptor subunit mRNA expression may explain the differential effects of CP-AMPAR blockade on recent and remote conditioned fear, further supporting the notion that the mechanisms maintaining learned fear change over time. Our findings suggest clinical implications for CP-AMPAR blockers, particularly for acquired anxieties (e.g., post-traumatic stress disorder) which have a slow onset and are durable.
Impaired fear extinction learning in adult heterozygous BDNF knock-out mice.

PubMed

Psotta, Laura; Lessmann, Volkmar; Endres, Thomas

2013-07-01

Brain-derived neurotrophic factor (BDNF) is a crucial regulator of neuroplasticity, which underlies learning and memory processes in different brain areas. To investigate the role of BDNF in the extinction of amygdala-dependent cued fear memories, we analyzed fear extinction learning in heterozygous BDNF knock-out mice, which possess a reduction of endogenous BDNF protein levels to ~50% of wild-type animals. Since BDNF expression has been shown to decline with aging of animals, we tested the performance in extinction learning of these mice at 2 months (young adults) and 7 months (older adults) of age. The present study shows that older adult heterozygous BDNF knock-out mice, which have a chronic 50% lack of BDNF, also possess a deficit in the acquisition of extinction memory, while extinction learning remains unaffected in young adult heterozygous BDNF knock-out mice. This deficit in extinction learning is accompanied by a reduction of BDNF protein in the hippocampus, amygdala and the prefrontal cortex. Copyright © 2013 Elsevier Inc. All rights reserved.
The Amygdala Is Not Necessary for Unconditioned Stimulus Inflation after Pavlovian Fear Conditioning in Rats

ERIC Educational Resources Information Center

Rabinak, Christine A.; Orsini, Caitlin A.; Zimmerman, Joshua M.; Maren, Stephen

2009-01-01

The basolateral complex (BLA) and central nucleus (CEA) of the amygdala play critical roles in associative learning, including Pavlovian conditioning. However, the precise role for these structures in Pavlovian conditioning is not clear. Recent work in appetitive conditioning paradigms suggests that the amygdala, particularly the BLA, has an…
Prediction Error and Trace Dominance Determine the Fate of Fear Memories after Post-Training Manipulations

ERIC Educational Resources Information Center

Alfei, Joaquín M.; Monti, Roque I. Ferrer; Molina, Victor A.; Bueno, Adrián M.; Urcelay, Gonzalo P.

2015-01-01

Different mnemonic outcomes have been observed when associative memories are reactivated by CS exposure and followed by amnestics. These outcomes include mere retrieval, destabilization-reconsolidation, a transitional period (which is insensitive to amnestics), and extinction learning. However, little is known about the interaction between initial…
A Genomic Response to Trace Fear Conditioning in the Amygdala of Female Rats After Developmental Exposure to Manganese

EPA Science Inventory

Increases in brain-derived neurotrophic factor (Bdnf), Ca2+/calmodulin-dependent protein kinase II alpha (Camk2a), and cyclic adenosine monophosphate (cAMP) response element binding (Creb1) gene expression have been associated with learning in a variety of different rodent studie...
Activation of the Infralimbic Cortex in a Fear Context Enhances Extinction Learning

ERIC Educational Resources Information Center

Thompson, Brittany M.; Baratta, Michael V.; Biedenkapp, Joseph C.; Rudy, Jerry W.; Watkins, Linda R.; Maier, Steven F.

2010-01-01

Activation of the infralimbic region (IL) of the medial prefrontal cortex (mPFC) reduces conditioned fear in a variety of situations, and the IL is thought to play an important role in the extinction of conditioned fear. Here we report a series of experiments using contextual fear conditioning in which the IL is activated with the GABAa antagonist…
The Class I HDAC Inhibitor RGFP963 Enhances Consolidation of Cued Fear Extinction

ERIC Educational Resources Information Center

Bowers, Mallory E.; Xia, Bing; Carreiro, Samantha; Ressler, Kerry J.

2015-01-01

Evidence indicates that broad, nonspecific histone deacetylase (HDAC) inhibition enhances learning and memory, however, the contribution of the various HDACs to specific forms of learning is incompletely understood. Here, we show that the Class I HDAC inhibitor, RGFP963, enhances consolidation of cued fear extinction. However, RGFP966, a strong…
GABA and NMDA receptors in CRF neurons have opposing effects in fear acquisition and anxiety in central amygdala vs. bed nucleus of the stria terminalis

PubMed Central

Gafford, Georgette M.; Ressler, Kerry J.

2016-01-01

Beginning with Vale and Colleagues in 1981, corticotropin releasing factor (CRF) also called corticotropin releasing hormone (CRH) has repeatedly been identified as an important contributor to fear and anxiety behavior. These findings have proven useful to further our understanding of disorders that have significant fear-dysregulation, such as post-traumatic stress, as well as other stress- and anxiety-related disorders. Unfortunately, the data are not all in agreement. In particular the role of CRF in fear learning is controversial, with studies pointing to contradictory effects from CRF manipulation even within the same brain structure. Further, very few studies address the potentially promising role of CRF manipulation in fear extinction behavior. Here, we briefly review the role of CRF in anxiety, fear learning and extinction, focusing on recent cell-type and neurotransmitter-specific studies in the amygdala and bed nucleus of the stria terminalis (BNST) that may help to synthesize the available data on the role of CRF in fear and anxiety-related behaviors. PMID:25888455
The neural circuits of innate fear: detection, integration, action, and memorization

PubMed Central

Silva, Bianca A.; Gross, Cornelius T.

2016-01-01

How fear is represented in the brain has generated a lot of research attention, not only because fear increases the chances for survival when appropriately expressed but also because it can lead to anxiety and stress-related disorders when inadequately processed. In this review, we summarize recent progress in the understanding of the neural circuits processing innate fear in rodents. We propose that these circuits are contained within three main functional units in the brain: a detection unit, responsible for gathering sensory information signaling the presence of a threat; an integration unit, responsible for incorporating the various sensory information and recruiting downstream effectors; and an output unit, in charge of initiating appropriate bodily and behavioral responses to the threatful stimulus. In parallel, the experience of innate fear also instructs a learning process leading to the memorization of the fearful event. Interestingly, while the detection, integration, and output units processing acute fear responses to different threats tend to be harbored in distinct brain circuits, memory encoding of these threats seems to rely on a shared learning system. PMID:27634145
Contextual fear conditioning in zebrafish.

PubMed

Kenney, Justin W; Scott, Ian C; Josselyn, Sheena A; Frankland, Paul W

2017-10-01

Zebrafish are a genetically tractable vertebrate that hold considerable promise for elucidating the molecular basis of behavior. Although numerous recent advances have been made in the ability to precisely manipulate the zebrafish genome, much less is known about many aspects of learning and memory in adult fish. Here, we describe the development of a contextual fear conditioning paradigm using an electric shock as the aversive stimulus. We find that contextual fear conditioning is modulated by shock intensity, prevented by an established amnestic agent (MK-801), lasts at least 14 d, and exhibits extinction. Furthermore, fish of various background strains (AB, Tu, and TL) are able to acquire fear conditioning, but differ in fear extinction rates. Taken together, we find that contextual fear conditioning in zebrafish shares many similarities with the widely used contextual fear conditioning paradigm in rodents. Combined with the amenability of genetic manipulation in zebrafish, we anticipate that our paradigm will prove to be a useful complementary system in which to examine the molecular basis of vertebrate learning and memory. © 2017 Kenney et al.; Published by Cold Spring Harbor Laboratory Press.
How trait anxiety, interpretation bias and memory affect acquired fear in children learning about new animals.

PubMed

Field, Zoë C; Field, Andy P

2013-06-01

Cognitive models of vulnerability to anxiety propose that information processing biases such as interpretation bias play a part in the etiology and maintenance of anxiety disorders. However, at present little is known about the role of memory in information processing accounts of child anxiety. The current study investigates the relationships between interpretation biases, memory and fear responses when learning about new stimuli. Children (aged 8-11 years) were presented with ambiguous information regarding a novel animal, and their fear, interpretation bias, and memory for the information was measured. The main findings were: (1) trait anxiety and interpretation bias significantly predicted acquired fear; (2) interpretation bias did not significantly mediate the relationship between trait anxiety and acquired fear; (3) interpretation bias appeared to be a more important predictor of acquired fear than trait anxiety per se; and (4) the relationship between interpretation bias and acquired fear was not mediated by the number of negative memories but was mediated by the number of positive and false-positive memories. The findings suggest that information processing models of child anxiety need to explain the role of positive memory in the formation of fear responses.
Serotonin 2C receptor antagonist improves fear discrimination and subsequent safety signal recall

PubMed Central

Foilb, Allison R.; Christianson, John P.

2015-01-01

The capacity to discriminate between safety and danger is fundamental for survival, but is disrupted in individuals with posttraumatic stress disorder (PTSD). Acute stressors cause a release of serotonin (5-HT) in the forebrain, which is one mechanism for enhanced fear and anxiety; these effects are mediated by the 5-HT2C receptor. Using a fear discrimination paradigm where a danger signal conditioned stimulus (CS+) coterminates with a mild footshock and a safety signal (CS-) indicates the absence of shock, we demonstrate that danger/safety discrimination and fear inhibition develops over the course of 4 daily conditioning sessions. Systemic administration of the 5-HT2C receptor antagonist SB 242084 (0.25 or 1.0 mg/kg) prior to conditioning reduced behavioral freezing during conditioning, improved learning and subsequent inhibition of fear by the safety signal. Discrimination was apparent in the first recall test, and discrimination during training was evident after 3 days of conditioning versus 5 days in the vehicle treated controls. These results suggest a novel therapeutic use for 5-HT2C receptor antagonists to improve learning under stressful circumstances. Potential anatomical loci for 5-HT2C receptor modulation of fear discrimination learning and cognitive performance enhancement are discussed. PMID:26344640
Protein synthesis in the basolateral amygdala complex is required for consolidation of a first-order fear memory, but not for consolidation of a higher-order fear memory.

PubMed

Leidl, Dana M; Lay, Belinda P P; Chakouch, Cassandra; Westbrook, R Frederick; Holmes, Nathan M

2018-04-12

The present series of experiments pursued our recent findings that consolidation of a second-order fear memory requires neuronal activity, but not de novo protein synthesis, in the basolateral amygdala complex (BLA). It used a modified second-order conditioning protocol in which rats were exposed to S1-shock pairings in stage 1 and pairings of the serial S2-S1 compound and shock in stage 2. Experiment 1 showed that responding (freezing) to S2 in this protocol is conditional on its compounding with S1 in stage 2 (Experiment 1), and therefore, the result of associative formation. The remaining experiments then showed that the protein synthesis requirement for consolidation of new learning about S2 varied with the training afforded S1. When S1 was trained in stage 1 and present in stage 2, consolidation of the new S2 fear memory was unaffected by pre- or post-stage 2 infusions of the protein synthesis inhibitor, cycloheximide, into the BLA (Experiments 2 and 5). This result was observed independently of the number of S1-shock pairings in stage 1 (even a single pairing produced the result), and alongside demonstrations that cycloheximide infusions disrupt consolidation of a first-order fear memory (Experiments 2 and 5). However, when S1 was not conditioned in stage 1 (Experiment 3) or was omitted from conditioning in stage 2 (Experiment 4), consolidation of the new S2 fear memory was disrupted by post-stage 2 cycloheximide infusions into the BLA. These results were taken to imply that the consolidation of a higher-order fear memory exploits molecular events associated with consolidation of a reactivated first-order fear memory; hence it occurs independently of de novo protein synthesis in the BLA. Alternatively, the nature of the association formed in higher-order conditioning may be such as to not require de novo protein synthesis for its consolidation. Copyright © 2018 Elsevier Inc. All rights reserved.
Differential influence of social versus isolate housing on vicarious fear learning in adolescent mice.

PubMed

Panksepp, Jules B; Lahvis, Garet P

2016-04-01

Laboratory rodents can adopt the pain or fear of nearby conspecifics. This phenotype conceptually lies within the domain of empathy, a bio-psycho-social process through which individuals come to share each other's emotion. Using a model of cue-conditioned fear, we show here that the expression of vicarious fear varies with respect to whether mice are raised socially or in solitude during adolescence. The impact of the adolescent housing environment was selective: (a) vicarious fear was more influenced than directly acquired fear, (b) "long-term" (24-h postconditioning) vicarious fear memories were stronger than "short-term" (15-min postconditioning) memories in socially reared mice whereas the opposite was true for isolate mice, and (c) females were more fearful than males. Housing differences during adolescence did not alter the general mobility of mice or their vocal response to receiving the unconditioned stimulus. Previous work with this mouse model underscored a genetic influence on vicarious fear learning, and the present study complements these findings by elucidating an interaction between the adolescent social environment and vicarious experience. Collectively, these findings are relevant to developing models of empathy amenable to mechanistic exploitation in the laboratory. (PsycINFO Database Record (c) 2016 APA, all rights reserved).
Emotional trait and memory associates of sleep timing and quality

PubMed Central

Pace-Schott, Edward F.; Rubin, Zoe S.; Tracy, Lauren E.; Spencer, Rebecca M.C.; Orr, Scott P.; Verga, Patrick W.

2015-01-01

Poor ability to remember the extinction of conditioned fear, elevated trait anxiety, and delayed or disrupted nocturnal sleep are reported in anxiety disorders. The current study examines the interrelationship of these factors in healthy young-adult males. Skin- conductance response was conditioned to two differently colored lamps. One color but not the other was then extinguished. After varying delays, both colors were presented to determine extinction recall and generalization. Questionnaires measured sleep quality, morningness - eveningness, neuroticism and trait anxiety. A subset produced a mean 7.0 nights of actigraphy and sleep diaries. Median split of mean sleep midpoint defined early-and late-”sleep timers”. Extinction was more rapidly learned in the morning than evening only in early-timers, who also better generalized extinction recall. Extinction recall was greater with higher sleep efficiency. Sleep efficiency and morningness were negatively associated with neuroticism and anxiety. However, neuroticism and anxiety did not predict extinction learning, recall or generalization. Therefore, neuroticism/anxiety and deficient fear extinction, although both associated with poor quality and late timing of sleep, are not directly associated with each other. Elevated trait anxiety, in addition to predisposing directly to anxiety disorders, may thus also indirectly promote such disorders by impairing sleep and, consequently, extinction memory. PMID:26257092

Emotional trait and memory associates of sleep timing and quality.

PubMed

Pace-Schott, Edward F; Rubin, Zoe S; Tracy, Lauren E; Spencer, Rebecca M C; Orr, Scott P; Verga, Patrick W

2015-10-30

Poor ability to remember the extinction of conditioned fear, elevated trait anxiety, and delayed or disrupted nocturnal sleep are reported in anxiety disorders. The current study examines the interrelationship of these factors in healthy young-adult males. Skin-conductance response was conditioned to two differently colored lamps. One color but not the other was then extinguished. After varying delays, both colors were presented to determine extinction recall and generalization. Questionnaires measured sleep quality, morningness-eveningness, neuroticism and trait anxiety. A subset produced a mean 7.0 nights of actigraphy and sleep diaries. Median split of mean sleep midpoint defined early- and late-"sleep timers". Extinction was more rapidly learned in the morning than evening only in early timers who also better generalized extinction recall. Extinction recall was greater with higher sleep efficiency. Sleep efficiency and morningness were negatively associated with neuroticism and anxiety. However, neuroticism and anxiety did not predict extinction learning, recall or generalization. Therefore, neuroticism/anxiety and deficient fear extinction, although both associated with poor quality and late timing of sleep, are not directly associated with each other. Elevated trait anxiety, in addition to predisposing directly to anxiety disorders, may thus also indirectly promote such disorders by impairing sleep and, consequently, extinction memory. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
Tracking the fear memory engram: discrete populations of neurons within amygdala, hypothalamus, and lateral septum are specifically activated by auditory fear conditioning.

PubMed

Butler, Christopher W; Wilson, Yvette M; Gunnersen, Jenny M; Murphy, Mark

2015-08-01

Memory formation is thought to occur via enhanced synaptic connectivity between populations of neurons in the brain. However, it has been difficult to localize and identify the neurons that are directly involved in the formation of any specific memory. We have previously used fos-tau-lacZ (FTL) transgenic mice to identify discrete populations of neurons in amygdala and hypothalamus, which were specifically activated by fear conditioning to a context. Here we have examined neuronal activation due to fear conditioning to a more specific auditory cue. Discrete populations of learning-specific neurons were identified in only a small number of locations in the brain, including those previously found to be activated in amygdala and hypothalamus by context fear conditioning. These populations, each containing only a relatively small number of neurons, may be directly involved in fear learning and memory. © 2015 Butler et al.; Published by Cold Spring Harbor Laboratory Press.
The birth, death and resurrection of avoidance: a reconceptualization of a troubled paradigm.

PubMed

LeDoux, J E; Moscarello, J; Sears, R; Campese, V

2017-01-01

Research on avoidance conditioning began in the late 1930s as a way to use laboratory experiments to better understand uncontrollable fear and anxiety. Avoidance was initially conceived of as a two-factor learning process in which fear is first acquired through Pavlovian aversive conditioning (so-called fear conditioning), and then behaviors that reduce the fear aroused by the Pavlovian conditioned stimulus are reinforced through instrumental conditioning. Over the years, criticisms of both the avoidance paradigm and the two-factor fear theory arose. By the mid-1980s, avoidance had fallen out of favor as an experimental model relevant to fear and anxiety. However, recent progress in understanding the neural basis of Pavlovian conditioning has stimulated a new wave of research on avoidance. This new work has fostered new insights into contributions of not only Pavlovian and instrumental learning but also habit learning, to avoidance, and has suggested that the reinforcing event underlying the instrumental phase should be conceived in terms of cellular and molecular events in specific circuits rather than in terms of vague notions of fear reduction. In our approach, defensive reactions (freezing), actions (avoidance) and habits (habitual avoidance) are viewed as being controlled by unique circuits that operate nonconsciously in the control of behavior, and that are distinct from the circuits that give rise to conscious feelings of fear and anxiety. These refinements, we suggest, overcome older criticisms, justifying the value of the new wave of research on avoidance, and offering a fresh perspective on the clinical implications of this work.
The birth, death and resurrection of avoidance: a reconceptualization of a troubled paradigm

PubMed Central

LeDoux, J E; Moscarello, J; Sears, R; Campese, V

2017-01-01

Research on avoidance conditioning began in the late 1930s as a way to use laboratory experiments to better understand uncontrollable fear and anxiety. Avoidance was initially conceived of as a two-factor learning process in which fear is first acquired through Pavlovian aversive conditioning (so-called fear conditioning), and then behaviors that reduce the fear aroused by the Pavlovian conditioned stimulus are reinforced through instrumental conditioning. Over the years, criticisms of both the avoidance paradigm and the two-factor fear theory arose. By the mid-1980s, avoidance had fallen out of favor as an experimental model relevant to fear and anxiety. However, recent progress in understanding the neural basis of Pavlovian conditioning has stimulated a new wave of research on avoidance. This new work has fostered new insights into contributions of not only Pavlovian and instrumental learning but also habit learning, to avoidance, and has suggested that the reinforcing event underlying the instrumental phase should be conceived in terms of cellular and molecular events in specific circuits rather than in terms of vague notions of fear reduction. In our approach, defensive reactions (freezing), actions (avoidance) and habits (habitual avoidance) are viewed as being controlled by unique circuits that operate nonconsciously in the control of behavior, and that are distinct from the circuits that give rise to conscious feelings of fear and anxiety. These refinements, we suggest, overcome older criticisms, justifying the value of the new wave of research on avoidance, and offering a fresh perspective on the clinical implications of this work. PMID:27752080
The L-type voltage-gated calcium channel CaV1.2 mediates fear extinction and modulates synaptic tone in the lateral amygdala.

PubMed

Temme, Stephanie J; Murphy, Geoffrey G

2017-11-01

L-type voltage-gated calcium channels (LVGCCs) have been implicated in both the formation and the reduction of fear through Pavlovian fear conditioning and extinction. Despite the implication of LVGCCs in fear learning and extinction, studies of the individual LVGCC subtypes, Ca V 1.2 and Ca V 1.3, using transgenic mice have failed to find a role of either subtype in fear extinction. This discontinuity between the pharmacological studies of LVGCCs and the studies investigating individual subtype contributions could be due to the limited neuronal deletion pattern of the Ca V 1.2 conditional knockout mice previously studied to excitatory neurons in the forebrain. To investigate the effects of deletion of Ca V 1.2 in all neuronal populations, we generated Ca V 1.2 conditional knockout mice using the synapsin1 promoter to drive Cre recombinase expression. Pan-neuronal deletion of Ca V 1.2 did not alter basal anxiety or fear learning. However, pan-neuronal deletion of Ca V 1.2 resulted in a significant deficit in extinction of contextual fear, implicating LVGCCs, specifically Ca V 1.2, in extinction learning. Further exploration on the effects of deletion of Ca V 1.2 on inhibitory and excitatory input onto the principle neurons of the lateral amygdala revealed a significant shift in inhibitory/excitatory balance. Together these data illustrate an important role of Ca V 1.2 in fear extinction and the synaptic regulation of activity within the amygdala. © 2017 Temme and Murphy; Published by Cold Spring Harbor Laboratory Press.
Body temperature as a conditional response measure for pavlovian fear conditioning.

PubMed

Godsil, B P; Quinn, J J; Fanselow, M S

2000-01-01

On six days rats were exposed to each of two contexts. They received an electric shock in one context and nothing in the other. Rats were tested later in each environment without shock. The rats froze and defecated more often in the shock-paired environment; they also exhibited a significantly larger elevation in rectal temperature in that environment. The rats discriminated between each context, and we suggest that the elevation in temperature is the consequence of associative learning. Thus, body temperature can be used as a conditional response measure in Pavlovian fear conditioning experiments that use footshock as the unconditional stimulus.
Modulation of hippocampal NCAM polysialylation and spatial memory consolidation by fear conditioning.

PubMed

Sandi, Carmen; Merino, José J; Cordero, M Isabel; Kruyt, Nyika D; Murphy, Keith J; Regan, Ciaran M

2003-09-15

Cell adhesion molecule function is involved in hippocampal synaptic plasticity and associated with memory consolidation. At the infragranular zone of the dentate gyrus, neurons expressing the polysialylated form of the neural cell adhesion molecule (NCAM PSA) transiently increase their frequency 12 hours after training in different tasks. Using immunohistochemical procedures, we investigated NCAM polysialylation following training in a contextual fear conditioning paradigm that employed increasing shock intensities to separately model stressful and traumatic experiences in adult male Wistar rats. Fear conditioning with a stressful.4-mA stimulus resulted in an increased frequency of dentate polysialylated neurons, the magnitude of which was indistinguishable from that observed following water maze training. By contrast, training with a traumatic 1-mA stimulus resulted in a significant decrease in the frequency of polysialylated neurons at the 12 hours posttraining time. Whereas sequential training in the water maze paradigm followed by fear conditioning resulted in potentiated consolidation of spatial information when conditioning involved a.4-mA stimulus, amnesia for spatial learning occurred when conditioning was performed with a 1-mA stimulus. These results suggest traumatic fear conditioning suppresses NCAM-PSA-mediated plasticity and the concomitant inability to store the trace of recently acquired information.
Extinction of Fear Generalization: A Comparison Between Fibromyalgia Patients and Healthy Control Participants.

PubMed

Meulders, Ann; Meulders, Michel; Stouten, Iris; De Bie, Jozef; Vlaeyen, Johan W S

2017-01-01

Fear learning deficiencies might contribute to the development and maintenance of chronic pain disability. Fear is often not restricted to movements (conditioned stimulus [CS+]) originally associated with pain (unconditioned stimulus), but expands to similar movements (generalization stimuli [GSs]). This spreading of fear becomes dysfunctional when overgeneralization to safe stimuli occurs. More importantly, persistence of pain-related fear to GSs despite corrective feedback might even be more debilitating and maintain long-term chronic pain disability. Yet, research on this topic is lacking. Using a voluntary joystick movement paradigm, we examined (extinction of) pain-related fear generalization in fibromyalgia patients (FM) and healthy control participants (HC). During acquisition, one movement (CS+) predicted pain; another did not (CS-). We tested (extinction of) fear generalization to 5 GSs varying in similarity with the CS+ and CS-. Results revealed flatter pain expectancy generalization gradients in FM than in HC due to elevated responses to GSs more similar to the CS-; the fear generalization gradients did not differ. Although pain-related fear and expectancy to the GSs decreased during extinction, responses to the GSs remained higher for FM than HC, suggesting that extinction of generalization is impaired in chronic pain patients. Persistence of excessive protective responses may contribute to maintaining long-term chronic pain disability. Pain-related fear and expectancy to movements-varying in similarity with the original painful and nonpainful movement-decrease during extinction in HC and FM. Yet, conditioned responses remain elevated in patients despite corrective feedback, indicating impaired extinction of generalization. Persistent excessive protective responses may contribute to preserving pain disability. Copyright © 2016 American Pain Society. Published by Elsevier Inc. All rights reserved.
Adiponectin regulates contextual fear extinction and intrinsic excitability of dentate gyrus granule neurons through AdipoR2 receptors

PubMed Central

Zhang, D; Wang, X; Wang, B; Garza, J C; Fang, X; Wang, J; Scherer, P E; Brenner, R; Zhang, W; Lu, X-Y

2017-01-01

Post-traumatic stress disorder (PTSD) is characterized by exaggerated fear expression and impaired fear extinction. The underlying molecular and cellular mechanisms of PTSD are largely unknown. The current pharmacological and non-pharmacological treatments for PTSD are either ineffective or temporary with high relapse rates. Here we report that adiponectin-deficient mice exhibited normal contextual fear conditioning but displayed slower extinction learning. Infusions of adiponectin into the dentate gyrus (DG) of the hippocampus in fear-conditioned mice facilitated extinction of contextual fear. Whole-cell patch-clamp recordings in brain slices revealed that intrinsic excitability of DG granule neurons was enhanced by adiponectin deficiency and suppressed after treatment with the adiponectin mimetic AdipoRon, which were associated with increased input resistance and hyperpolarized resting membrane potential, respectively. Moreover, deletion of AdipoR2, but not AdipoR1 in the DG, resulted in augmented fear expression and reduced extinction, accompanied by intrinsic hyperexcitability of DG granule neurons. Adiponectin and AdipoRon failed to induce facilitation of fear extinction and elicit inhibition of intrinsic excitability of DG neurons in AdipoR2 knockout mice. These results indicated that adiponectin action via AdipoR2 was both necessary and sufficient for extinction of contextual fear and intrinsic excitability of DG granule neurons, implying that enhancing or dampening DG neuronal excitability may cause resistance to or facilitation of extinction. Therefore, our findings provide a functional link between adiponectin/AdipoR2 activation, DG neuronal excitability and contextual fear extinction, and suggest that targeting adiponectin/AdipoR2 may be used to strengthen extinction-based exposure therapies for PTSD. PMID:27137743
Adiponectin regulates contextual fear extinction and intrinsic excitability of dentate gyrus granule neurons through AdipoR2 receptors.

PubMed

Zhang, D; Wang, X; Wang, B; Garza, J C; Fang, X; Wang, J; Scherer, P E; Brenner, R; Zhang, W; Lu, X-Y

2017-07-01

Post-traumatic stress disorder (PTSD) is characterized by exaggerated fear expression and impaired fear extinction. The underlying molecular and cellular mechanisms of PTSD are largely unknown. The current pharmacological and non-pharmacological treatments for PTSD are either ineffective or temporary with high relapse rates. Here we report that adiponectin-deficient mice exhibited normal contextual fear conditioning but displayed slower extinction learning. Infusions of adiponectin into the dentate gyrus (DG) of the hippocampus in fear-conditioned mice facilitated extinction of contextual fear. Whole-cell patch-clamp recordings in brain slices revealed that intrinsic excitability of DG granule neurons was enhanced by adiponectin deficiency and suppressed after treatment with the adiponectin mimetic AdipoRon, which were associated with increased input resistance and hyperpolarized resting membrane potential, respectively. Moreover, deletion of AdipoR2, but not AdipoR1 in the DG, resulted in augmented fear expression and reduced extinction, accompanied by intrinsic hyperexcitability of DG granule neurons. Adiponectin and AdipoRon failed to induce facilitation of fear extinction and elicit inhibition of intrinsic excitability of DG neurons in AdipoR2 knockout mice. These results indicated that adiponectin action via AdipoR2 was both necessary and sufficient for extinction of contextual fear and intrinsic excitability of DG granule neurons, implying that enhancing or dampening DG neuronal excitability may cause resistance to or facilitation of extinction. Therefore, our findings provide a functional link between adiponectin/AdipoR2 activation, DG neuronal excitability and contextual fear extinction, and suggest that targeting adiponectin/AdipoR2 may be used to strengthen extinction-based exposure therapies for PTSD.
Prepared stimuli enhance aversive learning without weakening the impact of verbal instructions

PubMed Central

2018-01-01

Fear-relevant stimuli such as snakes and spiders are thought to capture attention due to evolutionary significance. Classical conditioning experiments indicate that these stimuli accelerate learning, while instructed extinction experiments suggest they may be less responsive to instructions. We manipulated stimulus type during instructed aversive reversal learning and used quantitative modeling to simultaneously test both hypotheses. Skin conductance reversed immediately upon instruction in both groups. However, fear-relevant stimuli enhanced dynamic learning, as measured by higher learning rates in participants conditioned with images of snakes and spiders. Results are consistent with findings that dissociable neural pathways underlie feedback-driven and instructed aversive learning. PMID:29339561
Behavioral Mechanisms of Context Fear Generalization in Mice

ERIC Educational Resources Information Center

Huckleberry, Kylie A.; Ferguson, Laura B.; Drew, Michael R.

2016-01-01

There is growing interest in generalization of learned contextual fear, driven in part by the hypothesis that mood and anxiety disorders stem from impaired hippocampal mechanisms of fear generalization and discrimination. However, there has been relatively little investigation of the behavioral and procedural mechanisms that might control…
Prior fear conditioning does not impede enhanced active avoidance in serotonin transporter knockout rats.

PubMed

Schipper, Pieter; Henckens, Marloes J A G; Borghans, Bart; Hiemstra, Marlies; Kozicz, Tamas; Homberg, Judith R

2017-05-30

Stressors can be actively or passively coped with, and adequate adaption of the coping response to environmental conditions can reduce their potential deleterious effects. One major factor influencing stress coping behaviour is serotonin transporter (5-HTT) availability. Abolishment of 5-HTT is known to impair fear extinction but facilitates acquisition of signalled active avoidance (AA), a behavioural task in which an animal learns to avoid an aversive stimulus that is predicted by a cue. Flexibility in adapting coping behaviour to the nature of the stressor shapes resilience to stress-related disorders. Therefore, we investigated the relation between 5-HTT expression and ability to adapt a learned coping response to changing environmental conditions. To this end, we first established and consolidated a cue-conditioned passive fear response in 5-HTT -/- and wildtype rats. Next, we used the conditioned stimulus (CS) to signal oncoming shocks during signalled AA training in 5-HTT -/- and wildtype rats to study their capability to acquire an active coping response to the CS following fear conditioning. Finally, we investigated the behavioural response to the CS in a novel environment and measured freezing, exploration and self-grooming, behaviours reflective of stress coping strategy. We found that fear conditioned and sham conditioned 5-HTT -/- animals acquired the signalled AA response faster than wildtypes, while prior conditioning briefly delayed AA learning similarly in both genotypes. Subsequent exposure to the CS in the novel context reduced freezing and increased locomotion in 5-HTT -/- compared to wildtype rats. This indicates that improved AA performance in 5-HTT -/- rats resulted in a weaker residual passive fear response to the CS in a novel context. Fear conditioning prior to AA training did not affect freezing upon re-encountering the CS, although it did reduce locomotion in 5-HTT -/- rats. We conclude that independent of 5-HTT signalling, prior fear conditioning does not greatly impair the acquisition of subsequent active coping behaviour when the situation allows for it. Abolishment of 5-HTT results in a more active coping style in case of novelty-induced fear and upon CS encounter in a novel context after AA learning. Copyright © 2017 Elsevier B.V. All rights reserved.
The Effect of D-Cycloserine on Immediate vs. Delayed Extinction of Learned Fear

ERIC Educational Resources Information Center

Langton, Julia M.; Richardson, Rick

2010-01-01

We compared the effect of D-cycloserine (DCS) on immediate (10 min after conditioning) and delayed (24 h after conditioning) extinction of learned fear in rats. DCS facilitated both immediate and delayed extinction when the drug was administered after extinction training. However, DCS did not facilitate immediate extinction when administered prior…
Blockade of Dopamine Activity in the Nucleus Accumbens Impairs Learning Extinction of Conditioned Fear

ERIC Educational Resources Information Center

Holtzman-Assif, Orit; Laurent, Vincent; Westbrook, R. Frederick

2010-01-01

Three experiments used rats to investigate the role of dopamine activity in learning to inhibit conditioned fear responses (freezing) in extinction. In Experiment 1, rats systemically injected with the D2 dopamine antagonist, haloperidol, froze more across multiple extinction sessions and on a drug-free retention test than control rats. In…
Sensitive periods in affective development: nonlinear maturation of fear learning.

PubMed

Hartley, Catherine A; Lee, Francis S

2015-01-01

At specific maturational stages, neural circuits enter sensitive periods of heightened plasticity, during which the development of both brain and behavior are highly receptive to particular experiential information. A relatively advanced understanding of the regulatory mechanisms governing the initiation, closure, and reinstatement of sensitive period plasticity has emerged from extensive research examining the development of the visual system. In this article, we discuss a large body of work characterizing the pronounced nonlinear changes in fear learning and extinction that occur from childhood through adulthood, and their underlying neural substrates. We draw upon the model of sensitive period regulation within the visual system, and present burgeoning evidence suggesting that parallel mechanisms may regulate the qualitative changes in fear learning across development.
Sensitive Periods in Affective Development: Nonlinear Maturation of Fear Learning

PubMed Central

Hartley, Catherine A; Lee, Francis S

2015-01-01

At specific maturational stages, neural circuits enter sensitive periods of heightened plasticity, during which the development of both brain and behavior are highly receptive to particular experiential information. A relatively advanced understanding of the regulatory mechanisms governing the initiation, closure, and reinstatement of sensitive period plasticity has emerged from extensive research examining the development of the visual system. In this article, we discuss a large body of work characterizing the pronounced nonlinear changes in fear learning and extinction that occur from childhood through adulthood, and their underlying neural substrates. We draw upon the model of sensitive period regulation within the visual system, and present burgeoning evidence suggesting that parallel mechanisms may regulate the qualitative changes in fear learning across development. PMID:25035083
Neural circuitry of abdominal pain-related fear learning and reinstatement in irritable bowel syndrome.

PubMed

Icenhour, A; Langhorst, J; Benson, S; Schlamann, M; Hampel, S; Engler, H; Forsting, M; Elsenbruch, S

2015-01-01

Altered pain anticipation likely contributes to disturbed central pain processing in chronic pain conditions like irritable bowel syndrome (IBS), but the learning processes shaping the expectation of pain remain poorly understood. We assessed the neural circuitry mediating the formation, extinction, and reactivation of abdominal pain-related memories in IBS patients compared to healthy controls (HC) in a differential fear conditioning paradigm. During fear acquisition, predictive visual cues (CS(+)) were paired with rectal distensions (US), while control cues (CS(-)) were presented unpaired. During extinction, only CSs were presented. Subsequently, memory reactivation was assessed with a reinstatement procedure involving unexpected USs. Using functional magnetic resonance imaging, group differences in neural activation to CS(+) vs CS(-) were analyzed, along with skin conductance responses (SCR), CS valence, CS-US contingency, state anxiety, salivary cortisol, and alpha-amylase activity. The contribution of anxiety symptoms was addressed in covariance analyses. Fear acquisition was altered in IBS, as indicated by more accurate contingency awareness, greater CS-related valence change, and enhanced CS(+)-induced differential activation of prefrontal cortex and amygdala. IBS patients further revealed enhanced differential cingulate activation during extinction and greater differential hippocampal activation during reinstatement. Anxiety affected neural responses during memory formation and reinstatement. Abdominal pain-related fear learning and memory processes are altered in IBS, mediated by amygdala, cingulate cortex, prefrontal areas, and hippocampus. Enhanced reinstatement may contribute to hypervigilance and central pain amplification, especially in anxious patients. Preventing a 'relapse' of learned fear utilizing extinction-based interventions may be a promising treatment goal in IBS. © 2014 John Wiley & Sons Ltd.
Thyroid Receptor β Involvement in the Effects of Acute Nicotine on Hippocampus-Dependent Memory

PubMed Central

Leach, Prescott T.; Kenney, Justin W.; Connor, David; Gould, Thomas J.

2015-01-01

Cigarette smoking is common despite adverse health effects. Nicotine’s effects on learning may contribute to addiction by enhancing drug-context associations. Effects of nicotine on learning could be direct or could occur by altering systems that modulate cognition. Because thyroid signaling can alter cognition and nicotine/smoking may change thyroid function, nicotine could affect learning through changes in thyroid signaling. These studies investigate the functional contributions of thyroid receptor (TR) subtypes β and α1 to nicotine-enhanced learning and characterize the effects of acute nicotine and learning on thyroid hormone levels. We conducted a high throughput screen of transcription factor activity to identify novel targets that may contribute to the effects of nicotine on learning. Based on these results, which showed that combined nicotine and learning uniquely acted to increase TR activation, we identified TRs as potential targets of nicotine. Further analyses were conducted to determine the individual and combined effects of nicotine and learning on thyroid hormone levels, but no changes were seen. Next, to determine the role of TRβ and TRα1 in the effects of nicotine on learning, mice lacking the TRβ or TRα1 gene and wildtype littermates were administered acute nicotine prior to fear conditioning. Nicotine enhanced contextual fear conditioning in TRα1 knockout mice and wildtypes from both lines but TRβ knockout mice did not show nicotine-enhanced learning. This finding supports involvement of TRβ signaling in the effect of acute nicotine on hippocampus-dependent memory. Acute nicotine enhances learning and these effects may involve processes regulated by the transcription factor TRβ. PMID:25666034
Prefrontal NMDA receptors expressed in excitatory neurons control fear discrimination and fear extinction.

PubMed

Vieira, Philip A; Corches, Alex; Lovelace, Jonathan W; Westbrook, Kevin B; Mendoza, Michael; Korzus, Edward

2015-03-01

N-methyl-D-aspartate receptors (NMDARs) are critically involved in various learning mechanisms including modulation of fear memory, brain development and brain disorders. While NMDARs mediate opposite effects on medial prefrontal cortex (mPFC) interneurons and excitatory neurons, NMDAR antagonists trigger profound cortical activation. The objectives of the present study were to determine the involvement of NMDARs expressed specifically in excitatory neurons in mPFC-dependent adaptive behaviors, specifically fear discrimination and fear extinction. To achieve this, we tested mice with locally deleted Grin1 gene encoding the obligatory NR1 subunit of the NMDAR from prefrontal CamKIIα positive neurons for their ability to distinguish frequency modulated (FM) tones in fear discrimination test. We demonstrated that NMDAR-dependent signaling in the mPFC is critical for effective fear discrimination following initial generalization of conditioned fear. While mice with deficient NMDARs in prefrontal excitatory neurons maintain normal responses to a dangerous fear-conditioned stimulus, they exhibit abnormal generalization decrement. These studies provide evidence that NMDAR-dependent neural signaling in the mPFC is a component of a neural mechanism for disambiguating the meaning of fear signals and supports discriminative fear learning by retaining proper gating information, viz. both dangerous and harmless cues. We also found that selective deletion of NMDARs from excitatory neurons in the mPFC leads to a deficit in fear extinction of auditory conditioned stimuli. These studies suggest that prefrontal NMDARs expressed in excitatory neurons are involved in adaptive behavior. Copyright © 2015 Elsevier Inc. All rights reserved.

Generalization of Fear Inhibition by Disrupting Hippocampal Protein Synthesis-Dependent Reconsolidation Process

PubMed Central

Yang, Chih-Hao; Huang, Chiung-Chun; Hsu, Kuei-Sen

2011-01-01

Repetitive replay of fear memories may precipitate the occurrence of post-traumatic stress disorder and other anxiety disorders. Hence, the suppression of fear memory retrieval may help prevent and treat these disorders. The formation of fear memories is often linked to multiple environmental cues and these interconnected cues may act as reminders for the recall of traumatic experiences. However, as a convenience, a simple paradigm of one cue pairing with the aversive stimulus is usually used in studies of fear conditioning in animals. Here, we built a more complex fear conditioning model by presenting several environmental stimuli during fear conditioning and characterize the effectiveness of extinction training and the disruption of reconsolidation process on the expression of learned fear responses. We demonstrate that extinction training with a single-paired cue resulted in cue-specific attenuation of fear responses but responses to other cures were unchanged. The cue-specific nature of the extinction persisted despite training sessions combined with -cycloserine treatment reveals a significant weakness in extinction-based treatment. In contrast, the inhibition of the dorsal hippocampus (DH) but not the basolateral amygdala (BLA)-dependent memory reconsolidation process using either protein synthesis inhibitors or genetic disruption of cAMP-response-element-binding protein-mediated transcription comprehensively disrupted the learned connections between fear responses and all paired environmental cues. These findings emphasize the distinct role of the DH and the BLA in the reconsolidation process of fear memories and further indicate that the disruption of memory reconsolidation process in the DH may result in generalization of fear inhibition. PMID:21593730
Generalization of fear inhibition by disrupting hippocampal protein synthesis-dependent reconsolidation process.

PubMed

Yang, Chih-Hao; Huang, Chiung-Chun; Hsu, Kuei-Sen

2011-09-01

Repetitive replay of fear memories may precipitate the occurrence of post-traumatic stress disorder and other anxiety disorders. Hence, the suppression of fear memory retrieval may help prevent and treat these disorders. The formation of fear memories is often linked to multiple environmental cues and these interconnected cues may act as reminders for the recall of traumatic experiences. However, as a convenience, a simple paradigm of one cue pairing with the aversive stimulus is usually used in studies of fear conditioning in animals. Here, we built a more complex fear conditioning model by presenting several environmental stimuli during fear conditioning and characterize the effectiveness of extinction training and the disruption of reconsolidation process on the expression of learned fear responses. We demonstrate that extinction training with a single-paired cue resulted in cue-specific attenuation of fear responses but responses to other cures were unchanged. The cue-specific nature of the extinction persisted despite training sessions combined with D-cycloserine treatment reveals a significant weakness in extinction-based treatment. In contrast, the inhibition of the dorsal hippocampus (DH) but not the basolateral amygdala (BLA)-dependent memory reconsolidation process using either protein synthesis inhibitors or genetic disruption of cAMP-response-element-binding protein-mediated transcription comprehensively disrupted the learned connections between fear responses and all paired environmental cues. These findings emphasize the distinct role of the DH and the BLA in the reconsolidation process of fear memories and further indicate that the disruption of memory reconsolidation process in the DH may result in generalization of fear inhibition.
Differential expression of the immediate early genes c-Fos, Arc, Egr-1, and Npas4 during long-term memory formation in the context preexposure facilitation effect (CPFE).

PubMed

Heroux, Nicholas A; Osborne, Brittany F; Miller, Lauren A; Kawan, Malak; Buban, Katelyn N; Rosen, Jeffrey B; Stanton, Mark E

2018-01-01

The context preexposure facilitation effect (CPFE) is a contextual fear conditioning paradigm in which learning about the context, acquiring the context-shock association, and retrieving/expressing contextual fear are temporally dissociated into three distinct phases (context preexposure, immediate-shock training, and retention). The current study examined changes in the expression of plasticity-associated immediate early genes (IEGs) during context and contextual fear memory formation on the preexposure and training days of the CPFE, respectively. Using adolescent Long-Evans rats, preexposure and training day expression of the IEGs c-Fos, Arc, Egr-1, and Npas4 in the medial prefrontal cortex (mPFC), dorsal hippocampus (dHPC), and basolateral amygdala (BLA) was analyzed using qPCR as an extension of previous studies from our lab examining Egr-1 via in situ hybridization (Asok, Schreiber, Jablonski, Rosen, & Stanton, 2013; Schreiber, Asok, Jablonski, Rosen, & Stanton, 2014). In Expt. 1, context preexposure induced expression of c-Fos, Arc, Egr-1 and Npas4 significantly above that of home-cage (HC) controls in all three regions. In Expt. 2, immediate-shock was followed by a post-shock freezing test, resulting in increased mPFC c-Fos expression in a group preexposed to the training context but not a control group preexposed to an alternate context, indicating expression related to associative learning. This was not seen with other IEGs in mPFC or with any IEG in dHPC or BLA. Finally, when the post-shock freezing test was omitted in Expt. 3, training-related increases were observed in prefrontal c-Fos, Arc, Egr-1, and Npas4, hippocampal c-Fos, and amygdalar Egr-1 expression. These results indicate that context exposure in a post-shock freezing test re-engages IEG expression that may obscure associatively-induced expression during contextual fear conditioning. Additionally, these studies suggest a key role for long-term synaptic plasticity in the mPFC in supporting the CPFE. Copyright © 2017. Published by Elsevier Inc.
NF-κB mediates Gadd45β expression and DNA demethylation in the hippocampus during fear memory formation.

PubMed

Jarome, Timothy J; Butler, Anderson A; Nichols, Jessica N; Pacheco, Natasha L; Lubin, Farah D

2015-01-01

Gadd45-mediated DNA demethylation mechanisms have been implicated in the process of memory formation. However, the transcriptional mechanisms involved in the regulation of Gadd45 gene expression during memory formation remain unexplored. NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) controls transcription of genes in neurons and is a critical regulator of synaptic plasticity and memory formation. In silico analysis revealed several NF-κB (p65/RelA and cRel) consensus sequences within the Gadd45β gene promoter. Whether NF-κB activity regulates Gadd45 expression and associated DNA demethylation in neurons during memory formation is unknown. Here, we found that learning in a fear conditioning paradigm increased Gadd45β gene expression and brain-derivedneurotrophic factor (BDNF) DNA demethylation in area CA1 of the hippocampus, both of which were prevented with pharmacological inhibition of NF-κB activity. Further experiments found that conditional mutations in p65/RelA impaired fear memory formation but did not alter changes in Gadd45β expression. The learning-induced increases in Gadd45β mRNA levels, Gadd45β binding at the BDNF gene and BDNF DNA demethylation were blocked in area CA1 of the c-rel knockout mice. Additionally, local siRNA-mediated knockdown of c-rel in area CA1 prevented fear conditioning-induced increases in Gadd45β expression and BDNF DNA demethylation, suggesting that c-Rel containing NF-κB transcription factor complex is responsible for Gadd45β regulation during memory formation. Together, these results support a novel transcriptional role for NF-κB in regulation of Gadd45β expression and DNA demethylation in hippocampal neurons during fear memory.
The role of calsenilin/DREAM/KChIP3 in contextual fear conditioning.

PubMed

Alexander, Jon C; McDermott, Carmel M; Tunur, Tumay; Rands, Vicky; Stelly, Claire; Karhson, Debra; Bowlby, Mark R; An, W Frank; Sweatt, J David; Schrader, Laura A

2009-03-01

Potassium channel interacting proteins (KChIPs) are members of a family of calcium binding proteins that interact with Kv4 potassium (K(+)) channel primary subunits and also act as transcription factors. The Kv4 subunit is a primary K(+) channel pore-forming subunit, which contributes to the somatic and dendritic A-type currents throughout the nervous system. These A-type currents play a key role in the regulation of neuronal excitability and dendritic processing of incoming synaptic information. KChIP3 is also known as calsenilin and as the transcription factor, downstream regulatory element antagonist modulator (DREAM), which regulates a number of genes including prodynorphin. KChIP3 and Kv4 primary channel subunits are highly expressed in hippocampus, an area of the brain important for learning and memory. Through its various functions, KChIP3 may play a role in the regulation of synaptic plasticity and learning and memory. We evaluated the role of KChIP3 in a hippocampus-dependent memory task, contextual fear conditioning. Male KChIP3 knockout (KO) mice showed significantly enhanced memory 24 hours after training as measured by percent freezing. In addition, we found that membrane association and interaction with Kv4.2 of KChIP3 protein was significantly decreased and nuclear KChIP3 expression was increased six hours after the fear conditioning training paradigm with no significant change in KChIP3 mRNA. In addition, prodynorphin mRNA expression was significantly decreased six hours after fear conditioning training in wild-type (WT) but not in KO animals. These data suggest a role for regulation of gene expression by KChIP3/DREAM/calsenilin in consolidation of contextual fear conditioning memories.
HDAC inhibitors as cognitive enhancers in fear, anxiety and trauma therapy: where do we stand?

PubMed Central

Whittle, Nigel; Singewald, Nicolas

2014-01-01

A novel strategy to treat anxiety and fear-related disorders such as phobias, panic and PTSD (post-traumatic stress disorder) is combining CBT (cognitive behavioural therapy), including extinction-based exposure therapy, with cognitive enhancers. By targeting and boosting mechanisms underlying learning, drug development in this field aims at designing CBT-augmenting compounds that help to overcome extinction learning deficits, promote long-term fear inhibition and thus support relapse prevention. Progress in revealing the role of epigenetic regulation of specific genes associated with extinction memory generation has opened new avenues in this direction. The present review examines recent evidence from pre-clinical studies showing that increasing histone acetylation, either via genetic or pharmacological inhibition of HDACs (histone deacetylases) by e.g. vorinostat/SAHA (suberoylanilide hydroxamic acid), entinostat/MS-275, sodium butyrate, TSA (trichostatin A) or VPA (valproic acid), or by targeting HATs (histone acetyltransferases), augments fear extinction and, importantly, generates a long-term extinction memory that can protect from return of fear phenomena. The molecular mechanisms and pathways involved including BDNF (brain-derived neurotrophic factor) and NMDA (N-methyl-D-aspartate) receptor signalling are just beginning to be revealed. First studies in healthy humans are in support of extinction-facilitating effects of HDAC inhibitors. Very recent evidence that HDAC inhibitors can rescue deficits in extinction-memory-impaired rodents indicates a potential clinical utility of this approach also for exposure therapy-resistant patients. Important future work includes investigation of the long-term safety aspects of HDAC inhibitor treatment, as well as design of isotype(s)-specific inhibitors. Taken together, HDAC inhibitors display promising potential as pharmacological adjuncts to augment the efficacy of exposure-based approaches in anxiety and trauma therapy. PMID:24646280
Does Fear Reactivity during Exposure Predict Panic Symptom Reduction?

ERIC Educational Resources Information Center

Meuret, Alicia E.; Seidel, Anke; Rosenfield, Benjamin; Hofmann, Stefan G.; Rosenfield, David

2012-01-01

Objective: Fear reactivity during exposure is a commonly used indicator of learning and overall therapy outcome. The objective of this study was to assess the predictive value of fear reactivity during exposure using multimodal indicators and an advanced analytical design. We also investigated the degree to which treatment condition (cognitive…
Fear in the Palestinian Classroom: Pedagogy, Authoritarianism and Transformation

ERIC Educational Resources Information Center

Affouneh, Saida; Hargreaves, Eleanore

2015-01-01

Drawing on pictures, written sentences and interview contributions, this article explores some Palestinian children's perspectives in order to gain insights into some children's classroom fear in the light of its potential influence on learning. After presenting some existing research indicating a negative relationship between fear and young…
DCS facilitation of fear extinction and exposure-based therapy may rely on lower-level, automatic mechanisms

PubMed Central

Grillon, Christian

2009-01-01

Exposure-based therapy (EBT), a leading technique in the treatment of a range of anxiety disorders, is facilitated by D-cycloserine (DCS), a partial N-methyl-D-aspartate (NMDA) receptor agonist. This review discusses the potential mechanisms involved in this facilitation, and its implications for developing theories of fear conditioning in humans. Basic research in rodents suggests that DCS acts by speeding up extinction. However, several lab-based investigations found that DCS had no effect on extinction in humans. This paper proposes that these observations can be accounted for by a dual-model theory of fear conditioning in humans that engages two complementary defensive systems: a reflexive lower-order system independent of conscious awareness and a higher-order cognitive system associated with conscious awareness of danger and expectation. DCS studies in animals appear to have explored lower-order conditioning mechanisms, whereas human studies have explored higher-order cognitive processes. These observations suggest that DCS may act preferentially on lower- rather than higher-order learning. This paper presents evidence suggesting that, in humans, DCS may similarly affect lower-order learning during EBT and, consequently, may be less effective during cognitive therapy (e.g., cognitive restructuring). Finally, it is recommended that extinction studies using DCS in humans be conducted using fear-relevant stimuli (e.g., snakes), short conditional stimulus-unconditioned stimulus (CS-US) intervals, and intense US in order to promote lower-order conditioning processes. PMID:19520359
The Type 3 Adenylyl Cyclase is Required for Novel Object Learning and Extinction of Contextual Memory: Role of cAMP Signaling in Primary Cilia

PubMed Central

Wang, Zhenshan; Phan, Trongha; Storm, Daniel R.

2011-01-01

Although primary cilia are found on neurons throughout the brain, their physiological function remains elusive. Human ciliopathies are associated with cognition defects and transgenic mice lacking proteins expressed in primary cilia exhibit defects in learning and memory. Recently, it was reported that mice lacking the G-protein coupling receptor somatostatin receptor-3 (SSTR3), a protein expressed predominately in the primary cilia of neurons, have defective memory for novel object recognition and lower cAMP levels in the brain. Since SSTR3 is coupled to regulation of adenylyl cyclase this suggests that adenylyl cyclase activity in primary cilia of CNS neurons may be critical for some forms of learning and memory. Because the type 3 adenylyl cyclase (AC3) is expressed in primary cilia of hippocampal neurons, we examined AC3−/− mice for several forms of learning and memory. Here, we report that AC3−/− mice show no short-term memory for novel objects and fail to exhibit extinction of contextual fear conditioning. They also show impaired learning and memory for temporally dissociated passive avoidance (TDPA). Since AC3 is exclusively expressed in primary cilia we conclude that cAMP signals generated within primary cilia contribute to some forms of learning and memory including extinction of contextual fear conditioning. PMID:21490195
The type 3 adenylyl cyclase is required for novel object learning and extinction of contextual memory: role of cAMP signaling in primary cilia.

PubMed

Wang, Zhenshan; Phan, Trongha; Storm, Daniel R

2011-04-13

Although primary cilia are found on neurons throughout the brain, their physiological function remains elusive. Human ciliopathies are associated with cognition defects, and transgenic mice lacking proteins expressed in primary cilia exhibit defects in learning and memory. Recently, it was reported that mice lacking the G-protein-coupling receptor somatostatin receptor-3 (SSTR3), a protein expressed predominately in the primary cilia of neurons, have defective memory for novel object recognition and lower cAMP levels in the brain. Since SSTR3 is coupled to regulation of adenylyl cyclase, this suggests that adenylyl cyclase activity in primary cilia of CNS neurons may be critical for some forms of learning and memory. Because the type 3 adenylyl cyclase (AC3) is expressed in primary cilia of hippocampal neurons, we examined AC3(-/-) mice for several forms of learning and memory. Here, we report that AC3(-/-) mice show no short-term memory for novel objects and fail to exhibit extinction of contextual fear conditioning. They also show impaired learning and memory for temporally dissociative passive avoidance. Since AC3 is exclusively expressed in primary cilia, we conclude that cAMP signals generated within primary cilia contribute to some forms of learning and memory, including extinction of contextual fear conditioning.
Selective and Protracted Effect of Nifedipine on Fear Memory Extinction Correlates with Induced Stress Response

ERIC Educational Resources Information Center

Waltereit, Robert; Mannhardt, Sonke; Nescholta, Sabine; Maser-Gluth, Christiane; Bartsch, Dusan

2008-01-01

Memory extinction, defined as a decrease of a conditioned response as a function of a non-reinforced conditioned stimulus presentation, has high biological and clinical relevance. Extinction is not a passive reversing or erasing of the plasticity associated with acquisition, but a novel, active learning process. Nifedipine blocks L-type voltage…
Like China in the Bull Shop: Classroom Accidents Waiting To Happen and Downshifting into Boredom.

ERIC Educational Resources Information Center

Kastelic, Robert L.; McLinn, Kathleen

1997-01-01

Suggests that students come to school with an enthusiasm for learning only to discover the confusion and frustration associated with schooling. Proposes that educators must reframe their conceptual understandings and philosophy of the educational process, reduce the use of fear as a student motivator, and work toward eliminating the "bull" or…
Retrosplenial Cortex Is Required for the Retrieval of Remote Memory for Auditory Cues

ERIC Educational Resources Information Center

Todd, Travis P.; Mehlman, Max L.; Keene, Christopher S.; DeAngeli, Nicole E.; Bucci, David J.

2016-01-01

The retrosplenial cortex (RSC) has a well-established role in contextual and spatial learning and memory, consistent with its known connectivity with visuo-spatial association areas. In contrast, RSC appears to have little involvement with delay fear conditioning to an auditory cue. However, all previous studies have examined the contribution of…
Fears about antiretroviral therapy among users of the internet forum for people living with HIV/AIDS in Russia.

PubMed

Dudina, Victoria I; Judina, Darja I; King, Elizabeth J

2017-02-01

The purpose of this research was to identify different types of fear related to starting and adhering to antiretroviral therapy (ART) among people living with HIV (PLHIV) in Russia. Data were collected from the Russian-language internet forum for PLHIV (hivlife.info). Qualitative data analysis focused on the sections of the forum where users discussed health-related issues in order to identify fears related to HIV treatment. The following types of fear were revealed: fear of the illness, fear to learn negative information about one's health, fear of side effects, fear of therapy to be ineffective, fear that the appropriate medications will become unavailable, fear of lifestyle changes, and fear for the well-being of significant others. Efforts to increase the uptake of and adherence to ART should take into account the fears of PLHIV.
Dissociation of learned helplessness and fear conditioning in mice: a mouse model of depression.

PubMed

Landgraf, Dominic; Long, Jaimie; Der-Avakian, Andre; Streets, Margo; Welsh, David K

2015-01-01

The state of being helpless is regarded as a central aspect of depression, and therefore the learned helplessness paradigm in rodents is commonly used as an animal model of depression. The term 'learned helplessness' refers to a deficit in escaping from an aversive situation after an animal is exposed to uncontrollable stress specifically, with a control/comparison group having been exposed to an equivalent amount of controllable stress. A key feature of learned helplessness is the transferability of helplessness to different situations, a phenomenon called 'trans-situationality'. However, most studies in mice use learned helplessness protocols in which training and testing occur in the same environment and with the same type of stressor. Consequently, failures to escape may reflect conditioned fear of a particular environment, not a general change of the helpless state of an animal. For mice, there is no established learned helplessness protocol that includes the trans-situationality feature. Here we describe a simple and reliable learned helplessness protocol for mice, in which training and testing are carried out in different environments and with different types of stressors. We show that with our protocol approximately 50% of mice develop learned helplessness that is not attributable to fear conditioning.
Acquisition of CS-US contingencies during Pavlovian fear conditioning and extinction in social anxiety disorder and posttraumatic stress disorder.

PubMed

Rabinak, Christine A; Mori, Shoko; Lyons, Maryssa; Milad, Mohammed R; Phan, K Luan

2017-01-01

Fear-based disorders, like social anxiety disorder (SAD) and posttraumatic stress disorder (PTSD), are characterized by an exaggerated fear response and avoidance to trigger cues, suggesting a transdiagnostic mechanism of psychopathology. Current theories suggest that abnormalities in conditioned fear is a primary contributor to the pathophysiology of these disorders. The primary goal of this study was to compare acquisition of conditioned stimulus (CS) and aversive unconditioned stimulus (US) contingencies during fear learning and extinction in individuals with SAD and PTSD. In a standard Pavlovian fear conditioning-extinction paradigm we measured subjective US expectancy ratings to different CSs in patients with SAD (n=16) compared to patients with PTSD (n=13) and healthy controls (n=15) RESULTS: Both patient groups (SAD, PTSD) acquired differential conditioning between a CS that predicted US (CS+) and a CS that never predicted the US (CS-), however, both groups reported an increased expectancy that the US would occur following the CS-. Additionally, the PTSD group overestimated that the US would occur in general. Neither patient group showed evidence of successful extinction of the CS+-US contingency nor differentiated their expectation of US occurrence between the CS+ and CS- during extinction learning. Group sample sizes were small and we did not include a trauma-exposed group without PTSD CONCLUSIONS: Both SAD and PTSD generalize expectations of an aversive outcome across CSs, even when a CS never signals an aversive outcome and PTSD may tend to over-expect threat. Fear learning and extinction abnormalities may be a core feature underlying shared symptoms across fear-based disorders. Copyright © 2016 Elsevier B.V. All rights reserved.
Adolescent social defeat alters N-methyl-D-aspartic acid receptor expression and impairs fear learning in adulthood.

PubMed

Novick, Andrew M; Mears, Mackenzie; Forster, Gina L; Lei, Yanlin; Tejani-Butt, Shanaz M; Watt, Michael J

2016-05-01

Repeated social defeat of adolescent male rats results in adult mesocortical dopamine hypofunction, impaired working memory, and increased contextual anxiety-like behavior. Given the role of glutamate in dopamine regulation, cognition, and fear and anxiety, we investigated potential changes to N-methyl-D-aspartic acid (NMDA) receptors following adolescent social defeat. As both NMDA receptors and mesocortical dopamine are implicated in the expression and extinction of conditioned fear, a separate cohort of rats was challenged with a classical fear conditioning paradigm to investigate whether fear learning is altered by adolescent defeat. Quantitative autoradiography was used to measure 3H-MK-801 binding to NMDA receptors in regions of the medial prefrontal cortex, caudate putamen, nucleus accumbens, amygdala and hippocampus. Assessment of fear learning was achieved using an auditory fear conditioning paradigm, with freezing toward the auditory tone used as a measure of conditioned fear. Compared to controls, adolescent social defeat decreased adult NMDA receptor expression in the infralimbic region of the prefrontal cortex and central amygdala, while increasing expression in the CA3 region of the hippocampus. Previously defeated rats also displayed decreased conditioned freezing during the recall and first extinction periods, which may be related to the observed decreases and increases in NMDA receptors within the central amygdala and CA3, respectively. The alteration in NMDA receptors seen following adolescent social defeat suggests that dysfunction of glutamatergic systems, combined with mesocortical dopamine deficits, likely plays a role in the some of the long-term behavioral consequences of social stressors in adolescence seen in both preclinical and clinical studies. Copyright © 2016 Elsevier B.V. All rights reserved.
The L-Type Voltage-Gated Calcium Channel Ca [subscript V] 1.2 Mediates Fear Extinction and Modulates Synaptic Tone in the Lateral Amygdala

ERIC Educational Resources Information Center

Temme, Stephanie J.; Murphy, Geoffrey G.

2017-01-01

L-type voltage-gated calcium channels (LVGCCs) have been implicated in both the formation and the reduction of fear through Pavlovian fear conditioning and extinction. Despite the implication of LVGCCs in fear learning and extinction, studies of the individual LVGCC subtypes, Ca[subscript V]1.2 and Ca[subscript V] 1.3, using transgenic mice have…
A novel perceptual discrimination training task: Reducing fear overgeneralization in the context of fear learning.

PubMed

Ginat-Frolich, Rivkah; Klein, Zohar; Katz, Omer; Shechner, Tomer

2017-06-01

Generalization is an adaptive learning mechanism, but it can be maladaptive when it occurs in excess. A novel perceptual discrimination training task was therefore designed to moderate fear overgeneralization. We hypothesized that improvement in basic perceptual discrimination would translate into lower fear overgeneralization in affective cues. Seventy adults completed a fear-conditioning task prior to being allocated into training or placebo groups. Predesignated geometric shape pairs were constructed for the training task. A target shape from each pair was presented. Thereafter, participants in the training group were shown both shapes and asked to identify the image that differed from the target. Placebo task participants only indicated the location of each shape on the screen. All participants then viewed new geometric pairs and indicated whether they were identical or different. Finally, participants completed a fear generalization test consisting of perceptual morphs ranging from the CS + to the CS-. Fear-conditioning was observed through physiological and behavioural measures. Furthermore, the training group performed better than the placebo group on the assessment task and exhibited decreased fear generalization in response to threat/safety cues. The findings offer evidence for the effectiveness of the novel discrimination training task, setting the stage for future research with clinical populations. Copyright © 2017 Elsevier Ltd. All rights reserved.

Enhanced extinction of contextual fear conditioning in ClockΔ19 mutant mice.

PubMed

Bernardi, Rick E; Spanagel, Rainer

2014-08-01

Clock genes have been implicated in several disorders, such as schizophrenia, bipolar disorder, autism spectrum disorders, and drug dependence. However, few studies to date have examined the role of clock genes in fear-related behaviors. The authors used mice with the ClockΔ19 mutation to assess the involvement of this gene in contextual fear conditioning. Male wild-type (WT) and ClockΔ19 mutant mice underwent a single session of contextual fear conditioning (12 min, 4 unsignaled shocks), followed by daily 12-min retention trials. There were no differences between mutant and WT mice in the acquisition of contextual fear, and WT and mutant mice demonstrated similar freezing during the first retention session. However, extinction of contextual fear was accelerated in mutant mice across the remaining retention sessions, as compared to WT mice, suggesting a role for Clock in extinction following aversive learning. Because the ClockΔ19 mutation has previously been demonstrated to result in an increase in dopamine signaling, the authors confirmed the role of dopamine in extinction learning using preretention session administration of a low dose of the dopamine transport reuptake inhibitor modafinil (0.75 mg/kg), which resulted in decreased freezing across retention sessions. These findings are consistent with an emerging portrayal of the importance of Clock genes in noncircadian functions, as well as the important role of dopamine in extinction learning.
GABA and NMDA receptors in CRF neurons have opposing effects in fear acquisition and anxiety in central amygdala vs. bed nucleus of the stria terminalis.

PubMed

Gafford, Georgette M; Ressler, Kerry J

2015-11-01

This article is part of a Special Issue "SBN 2014". Beginning with Vale and Colleagues in 1981, corticotropin releasing factor (CRF) also called corticotropin releasing hormone (CRH) has repeatedly been identified as an important contributor to fear and anxiety behavior. These findings have proven useful to further our understanding of disorders that have significant fear-dysregulation, such as post-traumatic stress, as well as other stress- and anxiety-related disorders. Unfortunately, the data are not all in agreement. In particular the role of CRF in fear learning is controversial, with studies pointing to contradictory effects from CRF manipulation even within the same brain structure. Further, very few studies address the potentially promising role of CRF manipulation in fear extinction behavior. Here, we briefly review the role of CRF in anxiety, fear learning and extinction, focusing on recent cell-type and neurotransmitter-specific studies in the amygdala and bed nucleus of the stria terminalis (BNST) that may help to synthesize the available data on the role of CRF in fear and anxiety-related behaviors. Copyright © 2015. Published by Elsevier Inc.
Delay and trace fear conditioning in C57BL/6 and DBA/2 mice: issues of measurement and performance.

PubMed

Tipps, Megan E; Raybuck, Jonathan D; Buck, Kari J; Lattal, K Matthew

2014-08-01

Strain comparison studies have been critical to the identification of novel genetic and molecular mechanisms in learning and memory. However, even within a single learning paradigm, the behavioral data for the same strain can vary greatly, making it difficult to form meaningful conclusions at both the behavioral and cellular level. In fear conditioning, there is a high level of variability across reports, especially regarding responses to the conditioned stimulus (CS). Here, we compare C57BL/6 and DBA/2 mice using delay fear conditioning, trace fear conditioning, and a nonassociative condition. Our data highlight both the significant strain differences apparent in these fear conditioning paradigms and the significant differences in conditioning type within each strain. We then compare our data to an extensive literature review of delay and trace fear conditioning in these two strains. Finally, we apply a number of commonly used baseline normalization approaches to compare how they alter the reported differences. Our findings highlight three major sources of variability in the fear conditioning literature: CS duration, number of CS presentations, and data normalization to baseline measures. © 2014 Tipps et al.; Published by Cold Spring Harbor Laboratory Press.
The Role of BDNF in the Development of Fear Learning.

PubMed

Dincheva, Iva; Lynch, Niccola B; Lee, Francis S

2016-10-01

Brain-derived neurotrophic factor (BDNF) is a growth factor that is dynamically expressed in the brain across postnatal development, regulating neuronal differentiation and synaptic plasticity. The neurotrophic hypothesis of psychiatric mood disorders postulates that in the adult brain, decreased BDNF levels leads to altered neural plasticity, contributing to disease. Although BDNF has been established as a key factor regulating the critical period plasticity in the developing visual system, it has recently been shown to also play a role in fear circuitry maturation, which has implications for the emergence of fear-related mood disorders. This review provides a detailed overview of developmental changes in expression of BDNF isoforms, as well as their receptors across postnatal life. In addition, recent developmental studies utilizing a genetic BDNF single nucleotide polymorphism (Val66Met) knock-in mouse highlight the impact of BDNF on fear learning during a sensitive period spanning the transition into adolescent time frame. We hypothesize that BDNF in the developing brain regulates fear circuit plasticity during a sensitive period in early adolescence, and alterations in BDNF expression (genetic or environmental) have a persistent impact on fear behavior and fear-related disorders. © 2016 Wiley Periodicals, Inc.
Effects of prenatal chronic mild stress exposure on hippocampal cell proliferation, expression of GSK-3α, β and NR2B in adult offspring during fear extinction in rats.

PubMed

Li, Min; Li, Xiaobai; Zhang, Xinxin; Ren, Jintao; Jiang, Han; Wang, Yan; Ma, Yuchao; Cheng, Wenwen

2014-06-01

Stress during pregnancy has been implicated as a risk factor for the development of many mental disorders; however, the influence of prenatal stress on the fear or anxiety-related behaviors, especially the fear extinction in adult offspring has been little investigated. In order to investigate how prenatal stress affects fear extinction, which is regarded as a form of new learning that counteracts the expression of Pavlovian's conditioned fear, a rat model of prenatal chronic mild stress (PNS) was used to evaluate the effects of PNS on fear extinction in adult offspring. The expression of hippocampal glycogen synthase kinase-3s (GSK-3α, β), N-methyl-d-aspartic acid receptors (NMDARs)-2B and the hippocampal cell proliferation in dentate gyrus in the adult offspring during fear extinction were studied. Our results showed that PNS significantly reduced body weight of pups, indicating PNS might induce growth retardation in offspring. Moreover, PNS significantly enhanced the freezing behavior of offspring at the phase of extinction, suggesting PNS impaired the abilities of fear extinction learning. In addition, PNS significantly increased the levels of GSK-3α, β and NR2B, but reduced hippocampal cell proliferation during fear extinction. Taken together, our findings suggest that maternal stress during pregnancy can impair the fear extinction of adult offspring, probably by affecting the neural plasticity of brain. Copyright © 2014 ISDN. Published by Elsevier Ltd. All rights reserved.
Contextual Information Drives the Reconsolidation-Dependent Updating of Retrieved Fear Memories

PubMed Central

Jarome, Timothy J; Ferrara, Nicole C; Kwapis, Janine L; Helmstetter, Fred J

2015-01-01

Stored memories enter a temporary state of vulnerability following retrieval known as ‘reconsolidation', a process that can allow memories to be modified to incorporate new information. Although reconsolidation has become an attractive target for treatment of memories related to traumatic past experiences, we still do not know what new information triggers the updating of retrieved memories. Here, we used biochemical markers of synaptic plasticity in combination with a novel behavioral procedure to determine what was learned during memory reconsolidation under normal retrieval conditions. We eliminated new information during retrieval by manipulating animals' training experience and measured changes in proteasome activity and GluR2 expression in the amygdala, two established markers of fear memory lability and reconsolidation. We found that eliminating new contextual information during the retrieval of memories for predictable and unpredictable fear associations prevented changes in proteasome activity and glutamate receptor expression in the amygdala, indicating that this new information drives the reconsolidation of both predictable and unpredictable fear associations on retrieval. Consistent with this, eliminating new contextual information prior to retrieval prevented the memory-impairing effects of protein synthesis inhibitors following retrieval. These results indicate that under normal conditions, reconsolidation updates memories by incorporating new contextual information into the memory trace. Collectively, these results suggest that controlling contextual information present during retrieval may be a useful strategy for improving reconsolidation-based treatments of traumatic memories associated with anxiety disorders such as post-traumatic stress disorder. PMID:26062788
Agency in the Darkness: 'Fear of the Unknown', Learning Disability and Teacher Education for Inclusion

ERIC Educational Resources Information Center

Robinson, Deborah; Goodey, Chris

2018-01-01

This paper proposes inclusion phobia as a sharper and more operative definition of the 'fear of the unknown' often cited as an explanation for resistance to inclusive education. Using 'severe and profound learning disability' as the paradigm case, we situate the phobia surrounding this label in its social and historical context. Our hypothesis is…
Persistent Fear and Anxiety Can Affect Young Children's Learning and Development. Working Paper #9

ERIC Educational Resources Information Center

National Scientific Council on the Developing Child, 2010

2010-01-01

Ensuring that young children have safe, secure environments in which to grow, learn, and develop healthy brains and bodies is not only good for the children themselves but also builds a strong foundation for a thriving, prosperous society. Science shows that early exposure to circumstances that produce persistent fear and chronic anxiety can have…
Distinct Contributions of the Basolateral Amygdala and the Medial Prefrontal Cortex to Learning and Relearning Extinction of Context Conditioned Fear

ERIC Educational Resources Information Center

Laurent, Vincent; Westbrook, R. Frederick

2008-01-01

We studied the roles of the basolateral amygdala (BLA) and the medial prefrontal cortex (mPFC) in learning and relearning to inhibit context conditioned fear (freezing) in extinction. In Experiment 1, pre-extinction BLA infusion of the NMDA receptor (NMDAr) antagonist, ifenprodil, impaired the development and retention of inhibition but…
Aniracetam improves contextual fear conditioning and increases hippocampal gamma-PKC activation in DBA/2J mice.

PubMed

Smith, Amy M; Wehner, Jeanne M

2002-01-01

DBA/2J (D2) mice display poor contextual learning and have less membrane-bound hippocampal protein kinase C (PKC) compared with C57BL/6 (B6) mice. Aniracetam and oxiracetam were previously shown to improve contextual learning in D2 mice and increase PKC activity. This study investigated a possible mechanism for learning enhancement by examining the effects of aniracetam on contextual fear conditioning and activation of the y isoform of PKC (gamma-PKC) in male D2 mice. In comparison to animals treated with vehicle only (10% 2-hydroxypropyl-beta-cyclodextrin), mice treated with aniracetam (100 mg/kg) 30 min prior to fear conditioning training demonstrated significantly improved contextual learning when tested 30 min and 24 h after training. This corresponded with a significant increase in activated, membrane-bound hippocampal gamma-PKC 30 min after training. No increase in learning or gamma-PKC was found 5 min after training. These results suggest an altered time course of activation of gamma-PKC in response to treatment with aniracetam, which improves learning in D2 mice.
Alpha1-adrenergic receptor blockade in the VTA modulates fear memories and stress responses.

PubMed

Solecki, Wojciech B; Szklarczyk, Klaudia; Klasa, Adam; Pradel, Kamil; Dobrzański, Grzegorz; Przewłocki, Ryszard

2017-08-01

Activity of the ventral tegmental area (VTA) and its terminals has been implicated in the Pavlovian associative learning of both stressful and rewarding stimuli. However, the role of the VTA noradrenergic signaling in fear responses remains unclear. We aimed to examine how alpha 1 -adrenergic receptor (α 1 -AR) signaling in the VTA affects conditioned fear. The role of α 1 -AR was assessed using the micro-infusions into the VTA of the selective antagonists (0.1-1µg/0.5µl prazosin and 1µg/0.5µl terazosin) in acquisition and expression of fear memory. In addition, we performed control experiments with α 1 -AR blockade in the mammillary bodies (MB) - a brain region with α 1 -AR expression adjacent to the VTA. Intra-VTA but not intra-MB α 1 -AR blockade prevented formation and retrieval of fear memories. Importantly, local administration of α 1 -AR antagonists did not influence footshock sensitivity, locomotion or anxiety-like behaviors. Similarly, α 1 -AR blockade in the VTA had no effects on negative affect measured as number of 22kHz ultrasonic vocalizations during fear conditioning training. We propose that noradrenergic signaling in the VTA via α 1 -AR regulates formation and retrieval of fear memories but not other behavioral responses to stressful environmental stimuli. It enhances the encoding of environmental stimuli by the VTA to form and retrieve conditioned fear memories and to predict future behavioral outcomes. Our results provide novel insight into the role of the VTA α 1 -AR signaling in the regulation of stress responsiveness and fear memory. Copyright © 2017 Elsevier B.V. and ECNP. All rights reserved.
Early Social Fear Predicts Kindergarteners' Socially Anxious Behaviors: Direct Associations, Moderation by Inhibitory Control, and Differences from Nonsocial Fear

PubMed Central

Brooker, Rebecca J.; Kiel, Elizabeth J.; Buss, Kristin A.

2015-01-01

Although social and nonsocial fear are discernable as early as preschool, little is known about their distinct associations with developmental outcomes. For example, fear has been identified as a predictor of social anxiety problems, but no work has examined whether social and nonsocial fear make independent contributions to risk. We investigated the extent to which early social and non-social fear were associated with socially anxious behaviors during kindergarten. To do this, we identified distinct trajectories of social and nonsocial fear across toddlerhood and preschool. Only social fear was associated with socially anxious behaviors at ages 2 and 5. Because the ability to regulate fear contributes to the degree to which fearful children are at risk for anxiety problems, we also tested whether an early-developing aspect of self-regulation modulated associations between early fear and kindergarten socially anxious behaviors. Specifically, we tested whether inhibitory control differentially modulated associations between early levels of social and nonsocial fear and socially anxious behaviors during kindergarten. Associations between trajectories of early social fear and age 5 socially anxious behaviors were moderated by individual differences in inhibitory control. Consistent with previous research showing associations between overcontrol and anxiety symptoms, more negative outcomes were observed when stable, high levels of social fear across childhood were coupled with high levels of inhibitory control. Results suggest that the combination of social fear and overcontrol reflect a profile of early risk for the development of social inhibition and social anxiety problems. PMID:27213729
Tour Through the Solar System: A Hands-On Planetary Geology Course for High School Students

NASA Astrophysics Data System (ADS)

Sherman, S. B.; Gillis-Davis, J. J.

2011-09-01

We have developed a course in planetary geology for high school students, the primary goals of which are to help students learn how to learn, to reduce the fear and anxiety associated with learning science and math, and to encourage an interest in science, technology, engineering, and mathematics (STEM) fields. Our emphasis in this course is on active learning in a learner-centered environment. All students scored significantly higher on the post-knowledge survey compared with the pre-knowledge survey, and there is a good correlation between the post-knowledge survey and the final exam. Student evaluations showed an increased interest in STEM fields as a result of this course.
Threatening social context facilitates pain-related fear learning.

PubMed

Karos, Kai; Meulders, Ann; Vlaeyen, Johan W S

2015-03-01

This study investigated the effects of a threatening and a safe social context on learning pain-related fear, a key factor in the development and maintenance of chronic pain. We measured self-reported pain intensity, pain expectancy, pain-related fear (verbal ratings and eyeblink startle responses), and behavioral measures of avoidance (movement-onset latency and duration) using an established differential voluntary movement fear conditioning paradigm. Participants (N = 42) performed different movements with a joystick: during fear acquisition, movement in one direction (CS+) was followed by a painful stimulus (pain-US) whereas movement in another direction (CS-) was not. For participants in the threat group, an angry face was continuously presented in the background during the task, whereas in the safe group, a happy face was presented. During the extinction phase the pain-US was omitted. As compared to the safe social context, a threatening social context led to increased contextual fear and facilitated differentiation between CS+ and CS- movements regarding self-reported pain expectancy, fear of pain, eyeblink startle responses, and movement-onset latency. In contrast, self-reported pain intensity was not affected by social context. These data support the modulation of pain-related fear by social context. A threatening social context leads to stronger acquisition of (pain-related) fear and simultaneous contextual fear but does not affect pain intensity ratings. This knowledge may aid in the prevention of chronic pain and anxiety disorders and shows that social context might modulate pain-related fear without immediately affecting pain intensity itself. Copyright © 2015 American Pain Society. Published by Elsevier Inc. All rights reserved.
Phobias and Preparedness - Republished Article.

PubMed

Seligman, Martin E P

2016-09-01

Some inadequacies of the classical conditioning analysis of phobias are discussed: phobias are highly resistant to extinction, whereas laboratory fear conditioning, unlike avoidance conditioning, extinguishes rapidly; phobias comprise a nonarbitrary and limited set of objects, whereas fear conditioning is thought to occur to an unlimited range of conditioned stimuli. Furthermore, phobias, unlike laboratory fear conditioning, are often acquired in one trial and seem quite resistant to change by "cognitive" means. An analysis of phobias using a more contemporary model of fear conditioning is proposed. In this view, phobias are seen as instances of highly "prepared" learning (Seligman, 1970). Such prepared learning is selective, highly resistant to extinction, probably noncognitive and can be acquired in one trial. A reconstruction of the notion of symbolism is suggested. Copyright © 2016 Elsevier Ltd. All rights reserved.
Impairments in Fear Conditioning in Mice Lacking the nNOS Gene

ERIC Educational Resources Information Center

Kelley, Jonathan B.; Balda, Mara A.; Anderson, Karen L.; Itzhak, Yossef

2009-01-01

The fear conditioning paradigm is used to investigate the roles of various genes, neurotransmitters, and substrates in the formation of fear learning related to contextual and auditory cues. In the brain, nitric oxide (NO) produced by neuronal nitric oxide synthase (nNOS) functions as a retrograde neuronal messenger that facilitates synaptic…
The Prelimbic Cortex Directs Attention toward Predictive Cues during Fear Learning

ERIC Educational Resources Information Center

Sharpe, Melissa J.; Killcross, Simon

2015-01-01

The prelimbic cortex is argued to promote conditioned fear expression, at odds with appetitive research implicating this region in attentional processing. Consistent with an attentional account, we report that the effect of prelimbic lesions on fear expression depends on the degree of competition between contextual and discrete cues. Further, when…
Effects of Stress and Sex on Acquisition and Consolidation of Human Fear Conditioning

ERIC Educational Resources Information Center

Kuhn, Cynthia M.; LaBar, Kevin S.; Zorawski, Michael; Blanding, Nineequa Q.

2006-01-01

We examined the relationship between stress hormone (cortisol) release and acquisition and consolidation of conditioned fear learning in healthy adults. Participants underwent acquisition of differential fear conditioning, and consolidation was assessed in a 24-h delayed extinction test. The acquisition phase was immediately followed by an 11-min…
Olfactory Fear Conditioning Induces Field Potential Potentiation in Rat Olfactory Cortex and Amygdala

ERIC Educational Resources Information Center

Messaoudi, Belkacem; Granjon, Lionel; Mouly, Anne-Marie; Sevelinges, Yannick; Gervais, Remi

2004-01-01

The widely used Pavlovian fear-conditioning paradigms used for studying the neurobiology of learning and memory have mainly used auditory cues as conditioned stimuli (CS). The present work assessed the neural network involved in olfactory fear conditioning, using olfactory bulb stimulation-induced field potential signal (EFP) as a marker of…
Flexibility in the face of fear: Hippocampal-prefrontal regulation of fear and avoidance.

PubMed

Moscarello, Justin M; Maren, Stephen

2018-02-01

Generating appropriate defensive behaviors in the face of threat is essential to survival. Although many of these behaviors are 'hard-wired', they are also flexible. For example, Pavlovian fear conditioning generates learned defensive responses, such as conditioned freezing, that can be suppressed through extinction. The expression of extinguished responses is highly context-dependent, allowing animals to engage behavioral responses appropriate to the contexts in which threats are encountered. Likewise, animals and humans will avoid noxious outcomes if given the opportunity. In instrumental avoidance learning, for example, animals overcome conditioned defensive responses, including freezing, in order to actively avoid aversive stimuli. Recent work has greatly advanced understanding of the neural basis of these phenomena and has revealed common circuits involved in the regulation of fear. Specifically, the hippocampus and medial prefrontal cortex play pivotal roles in gating fear reactions and instrumental actions, mediated by the amygdala and nucleus accumbens, respectively. Because an inability to adaptively regulate fear and defensive behavior is a central component of many anxiety disorders, the brain circuits that promote flexible responses to threat are of great clinical significance.

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