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Sample records for human fear conditioning

  1. Modeling fear-conditioned bradycardia in humans.

    PubMed

    Castegnetti, Giuseppe; Tzovara, Athina; Staib, Matthias; Paulus, Philipp C; Hofer, Nicolas; Bach, Dominik R

    2016-06-01

    Across species, cued fear conditioning is a common experimental paradigm to investigate aversive Pavlovian learning. While fear-conditioned stimuli (CS+) elicit overt behavior in many mammals, this is not the case in humans. Typically, autonomic nervous system activity is used to quantify fear memory in humans, measured by skin conductance responses (SCR). Here, we investigate whether heart period responses (HPR) evoked by the CS, often observed in humans and small mammals, are suitable to complement SCR as an index of fear memory in humans. We analyze four datasets involving delay and trace conditioning, in which heart beats are identified via electrocardiogram or pulse oximetry, to show that fear-conditioned heart rate deceleration (bradycardia) is elicited and robustly distinguishes CS+ from CS-. We then develop a psychophysiological model (PsPM) of fear-conditioned HPR. This PsPM is inverted to yield estimates of autonomic input into the heart. We show that the sensitivity to distinguish CS+ and CS- (predictive validity) is higher for model-based estimates than peak-scoring analysis, and compare this with SCR. Our work provides a novel tool to investigate fear memory in humans that allows direct comparison between species. © 2016 The Authors. Psychophysiology published by Wiley Periodicals, Inc. on behalf of Society for Psychophysiological Research.

  2. Conditioned Fear Extinction and Reinstatement in a Human Fear-Potentiated Startle Paradigm

    ERIC Educational Resources Information Center

    Norrholm, Seth D.; Jovanovic, Tanja; Vervliet, Bram; Myers, Karyn M.; Davis, Michael; Rothbaum, Barbara O.; Duncan, Erica J.

    2006-01-01

    The purpose of this study was to analyze fear extinction and reinstatement in humans using fear-potentiated startle. Participants were fear conditioned using a simple discrimination procedure with colored lights as the conditioned stimuli (CSs) and an airblast to the throat as the unconditioned stimulus (US). Participants were extinguished 24 h…

  3. Thalamocortical interactions underlying visual fear conditioning in humans.

    PubMed

    Lithari, Chrysa; Moratti, Stephan; Weisz, Nathan

    2015-11-01

    Despite a strong focus on the role of the amygdala in fear conditioning, recent works point to a more distributed network supporting fear conditioning. We aimed to elucidate interactions between subcortical and cortical regions in fear conditioning in humans. To do this, we used two fearful faces as conditioned stimuli (CS) and an electrical stimulation at the left hand, paired with one of the CS, as unconditioned stimulus (US). The luminance of the CS was rhythmically modulated leading to "entrainment" of brain oscillations at a predefined modulation frequency. Steady-state responses (SSR) were recorded by MEG. In addition to occipital regions, spectral analysis of SSR revealed increased power during fear conditioning particularly for thalamus and cerebellum contralateral to the upcoming US. Using thalamus and amygdala as seed-regions, directed functional connectivity was calculated to capture the modulation of interactions that underlie fear conditioning. Importantly, this analysis showed that the thalamus drives the fusiform area during fear conditioning, while amygdala captures the more general effect of fearful faces perception. This study confirms ideas from the animal literature, and demonstrates for the first time the central role of the thalamus in fear conditioning in humans.

  4. Neural mechanisms of human temporal fear conditioning.

    PubMed

    Harnett, Nathaniel G; Shumen, Joshua R; Wagle, Pooja A; Wood, Kimberly H; Wheelock, Muriah D; Baños, James H; Knight, David C

    2016-12-01

    Learning the temporal relationship between a warning cue (conditioned stimulus; CS) and aversive threat (unconditioned stimulus; UCS) is an important aspect of Pavlovian conditioning. Although prior functional magnetic resonance imaging (fMRI) research has identified brain regions that support Pavlovian conditioning, it remains unclear whether these regions support time-related processes important for this type of associative learning. Elucidating the neural substrates of temporal conditioning is important for a complete understanding of the Pavlovian conditioning process. Therefore, the present study used a temporal Pavlovian conditioning procedure to investigate brain activity that mediates the formation of temporal associations. During fMRI, twenty-three healthy volunteers completed a temporal conditioning procedure and a control task that does not support conditioning. Specifically, during the temporal conditioning procedure, the UCS was presented at fixed intervals (ITI: 20s) while in the control condition the UCS was presented at random intervals (Average ITI: 20s, ITI Range: 6-34s). We observed greater skin conductance responses and expectancy of the UCS during fixed (i.e., temporal conditioning) relative to random (i.e., control procedure) interval trials. These findings demonstrate fixed trials support temporal conditioning, while random trials do not. During fixed interval trials, greater conditioned fMRI signal responses were observed within dorsolateral prefrontal cortex, inferior parietal lobule, inferior and middle temporal cortex, hippocampus, and amygdala. The current findings suggest these brain regions constitute a neural circuit that encodes the temporal information necessary for Pavlovian fear conditioning. Copyright © 2016 Elsevier Inc. All rights reserved.

  5. Categories, Concepts, and Conditioning: How Humans Generalize Fear

    PubMed Central

    Dunsmoor, Joseph E.; Murphy, Gregory L.

    2015-01-01

    During the past century, Pavlovian conditioning has served as the predominant experimental paradigm and theoretical framework to understand how humans learn to fear and avoid real or perceived dangers. Animal models for translational research offer insight into basic behavioral and neurophysiological factors mediating the acquisition, expression, inhibition, and generalization of fear. However, it is important to consider the limits of traditional animal models when applied to humans. Here, we focus on the question of how humans generalize fear. We propose that to understand fear generalization in humans requires taking into account research on higher-level cognition such as category-based induction, inferential reasoning, and representation of conceptual knowledge. Doing so will open the door for productive avenues of new research. PMID:25577706

  6. Generalization of Extinguished Skin Conductance Responding in Human Fear Conditioning

    ERIC Educational Resources Information Center

    Vervliet, Bram; Vansteenwegen, Debora; Eelen, Paul

    2004-01-01

    In a human fear conditioning paradigm using the skin conductance response (SCR), participants were assigned to two groups. Following identical acquisition, group ABA (n = 16) was extinguished to a generalization stimulus (GS), whereas group AAB (n = 20) was extinguished to the conditioned stimulus (CS). At test, presenting the CS in group ABA…

  7. Generalization of Extinguished Skin Conductance Responding in Human Fear Conditioning

    ERIC Educational Resources Information Center

    Vervliet, Bram; Vansteenwegen, Debora; Eelen, Paul

    2004-01-01

    In a human fear conditioning paradigm using the skin conductance response (SCR), participants were assigned to two groups. Following identical acquisition, group ABA (n = 16) was extinguished to a generalization stimulus (GS), whereas group AAB (n = 20) was extinguished to the conditioned stimulus (CS). At test, presenting the CS in group ABA…

  8. Versatility of fear-potentiated startle paradigms for assessing human conditioned fear extinction and return of fear.

    PubMed

    Norrholm, Seth D; Anderson, Kemp M; Olin, Ilana W; Jovanovic, Tanja; Kwon, Cliffe; Warren, Victor T; McCarthy, Alexander; Bosshardt, Lauren; Sabree, Justin; Duncan, Erica J; Rothbaum, Barbara O; Bradley, Bekh

    2011-01-01

    Fear conditioning methodologies have often been employed as testable models for assessing learned fear responses in individuals with anxiety disorders such as post-traumatic stress disorder (PTSD) and specific phobia. One frequently used paradigm is measurement of the acoustic startle reflex under conditions that mimic anxiogenic and fear-related conditions. For example, fear-potentiated startle is the relative increase in the frequency or magnitude of the acoustic startle reflex in the presence of a previously neutral cue (e.g., colored shape; termed the conditioned stimulus or CS+) that has been repeatedly paired with an aversive unconditioned stimulus (e.g., airblast to the larynx). Our group has recently used fear-potentiated startle paradigms to demonstrate impaired fear extinction in civilian and combat populations with PTSD. In the current study, we examined the use of either auditory or visual CSs in a fear extinction protocol that we have validated and applied to human clinical conditions. This represents an important translational bridge in that numerous animal studies of fear extinction, upon which much of the human work is based, have employed the use of auditory CSs as opposed to visual CSs. Participants in both the auditory and visual groups displayed robust fear-potentiated startle to the CS+, clear discrimination between the reinforced CS+ and non-reinforced CS-, significant extinction to the previously reinforced CS+, and marked spontaneous recovery. We discuss the current results as they relate to future investigations of PTSD-related impairments in fear processing in populations with diverse medical and psychiatric histories.

  9. Contextual fear conditioning in humans using feature-identical contexts.

    PubMed

    Baeuchl, Christian; Meyer, Patric; Hoppstädter, Michael; Diener, Carsten; Flor, Herta

    2015-05-01

    Contextual fear conditioning studies in animals and humans found an involvement of the hippocampus and amygdala during fear learning. To exclude a focus on elements of the context we employed a paradigm, which uses two feature-identical contexts that only differ in the arrangement of the features and requires configural processing. We employed functional magnetic resonance imaging to determine the role of the hippocampus and neocortical areas during the acquisition of contextual fear in humans. For contextual fear acquisition, we paired one context (CS+) with an aversive electrical stimulus, whereas the other (CS-) was never followed by aversive stimulation. Blood oxygen level dependent activation to the CS+ was present in the insula, inferior frontal gyrus, inferior parietal lobule, superior medial gyrus and caudate nucleus. Furthermore, the amygdala and hippocampus were involved in a time-dependent manner. Psychophysiological interaction analyses revealed functional connectivity of a more posterior hippocampal seed region with the anterior hippocampus, posterior cingulate cortex and superior parietal lobule. The anterior hippocampus was functionally coupled with the amygdala and postcentral gyrus. This study complements previous findings in contextual fear conditioning in humans and provides a paradigm which might be useful for studying patients with hippocampal impairment.

  10. Fear conditioning, safety learning, and sleep in humans.

    PubMed

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

    2014-08-27

    Fear conditioning is considered an animal model of post-traumatic stress disorder. Such models have shown fear conditioning disrupts subsequent rapid eye movement sleep (REM). Here, we provide a translation of these models into humans. Using the fear potentiated startle (FPS) procedure, we examined the effects of fear conditioning and safety signal learning on subsequent REM sleep in healthy adults. We also examined the effects of changes in REM sleep on retention of fear and safety learning. Participants (n = 42 normal controls) spent 3 consecutive nights in the laboratory. The first was an adaptation night. Following the second night, we administered a FPS procedure that included pairing a wrist shock with a threat signal and a safety signal never paired with a shock. The next day, we administered the FPS procedure again, with no wrist shocks to any stimulus, to measure retention of fear and safety. Canonical correlations assessed the relationship between FPS response and REM sleep. Results demonstrated that increased safety signal learning during the initial acquisition phase was associated with increased REM sleep consolidation that night, with 28.4% of the variance in increased REM sleep consolidation from baseline accounted for by safety signal learning. Overnight REM sleep was, in turn, related to overnight retention of fear and safety learning, with 22.5% of the variance in startle retention accounted for by REM sleep. These data suggest that sleep difficulties, specifically REM sleep fragmentation, may play a mechanistic role in post-traumatic stress disorder via an influence on safety signal learning and/or threat-safety discrimination.

  11. Fear-Conditioning Mechanisms Associated with Trait Vulnerability to Anxiety in Humans

    PubMed Central

    Indovina, Iole; Robbins, Trevor W.; Núñez-Elizalde, Anwar O.; Dunn, Barnaby D.; Bishop, Sonia J.

    2011-01-01

    Summary Investigations of fear conditioning in rodents and humans have illuminated the neural mechanisms underlying cued and contextual fear. A critical question is how personality dimensions such as trait anxiety act through these mechanisms to confer vulnerability to anxiety disorders, and whether humans' ability to overcome acquired fears depends on regulatory skills not characterized in animal models. In a neuroimaging study of fear conditioning in humans, we found evidence for two independent dimensions of neurocognitive function associated with trait vulnerability to anxiety. The first entailed increased amygdala responsivity to phasic fear cues. The second involved impoverished ventral prefrontal cortical (vPFC) recruitment to downregulate both cued and contextual fear prior to omission (extinction) of the aversive unconditioned stimulus. These two dimensions may contribute to symptomatology differences across anxiety disorders; the amygdala mechanism affecting the development of phobic fear and the frontal mechanism influencing the maintenance of both specific fears and generalized anxiety. PMID:21315265

  12. Don't fear 'fear conditioning': Methodological considerations for the design and analysis of studies on human fear acquisition, extinction, and return of fear.

    PubMed

    Lonsdorf, Tina B; Menz, Mareike M; Andreatta, Marta; Fullana, Miguel A; Golkar, Armita; Haaker, Jan; Heitland, Ivo; Hermann, Andrea; Kuhn, Manuel; Kruse, Onno; Drexler, Shira Meir; Meulders, Ann; Nees, Frauke; Pittig, Andre; Richter, Jan; Römer, Sonja; Shiban, Youssef; Schmitz, Anja; Straube, Benjamin; Vervliet, Bram; Wendt, Julia; Baas, Johanna M P; Merz, Christian J

    2017-03-03

    The so-called 'replicability crisis' has sparked methodological discussions in many areas of science in general, and in psychology in particular. This has led to recent endeavours to promote the transparency, rigour, and ultimately, replicability of research. Originating from this zeitgeist, the challenge to discuss critical issues on terminology, design, methods, and analysis considerations in fear conditioning research is taken up by this work, which involved representatives from fourteen of the major human fear conditioning laboratories in Europe. This compendium is intended to provide a basis for the development of a common procedural and terminology framework for the field of human fear conditioning. Whenever possible, we give general recommendations. When this is not feasible, we provide evidence-based guidance for methodological decisions on study design, outcome measures, and analyses. Importantly, this work is also intended to raise awareness and initiate discussions on crucial questions with respect to data collection, processing, statistical analyses, the impact of subtle procedural changes, and data reporting specifically tailored to the research on fear conditioning.

  13. Cross-US reinstatement of human conditioned fear: return of old fears or emergence of new ones?

    PubMed

    Sokol, Nicole; Lovibond, Peter F

    2012-05-01

    Re-exposure to the unconditioned stimulus (US) following fear extinction in the laboratory produces reinstatement of fear. Similarly in clinical situations, anxiety patients may experience adverse events that reinstate fear following successful exposure therapy. The current study employed two USs, shock and loud noise, to examine whether a US that is qualitatively different but of the same valence as the original acquisition US can produce reinstatement in human fear conditioning. Both standard and cross-US reinstatement manipulations led to elevated fear as indexed by skin conductance. However, cross-US reinstatement was accompanied by elevated expectancy of the US that had been presented during the reinstatement manipulation, not the US that had been used to establish fear in acquisition. This result implies that reinstatement may involve the development of new fears. Context conditioning and cognitive processes were implicated as possible mechanisms. The current findings suggest that clinical relapse attributed to reinstatement may not always reflect the reactivation of old fears but may instead represent new fears worthy of clinical examination. Copyright © 2012. Published by Elsevier Ltd.

  14. Reconsolidation in a human fear conditioning study: a test of extinction as updating mechanism.

    PubMed

    Kindt, Merel; Soeter, Marieke

    2013-01-01

    Disrupting reconsolidation seems to be a promising approach to dampen the expression of fear memory. Recently, we demonstrated that disrupting reconsolidation by a pharmacological manipulation specifically targeted the emotional expression of memory (i.e., startle response). Here we test in a human differential fear-conditioning paradigm with fear-relevant stimuli whether the spacing of a single unreinforced retrieval trial relative to extinction learning allows for "rewriting" the original fear association, thereby preventing the return of fear. In contrast to previous findings reported by Schiller et al. (2010), who used a single-method for indexing fear (skin conductance response) and fear-irrelevant stimuli, we found that extinction learning within the reconsolidation window did not prevent the recovery of fear on multiple indices of conditioned responding (startle response, skin conductance response and US-expectancy). These conflicting results ask for further critical testing given the potential impact on the field of emotional memory and its application to clinical practice.

  15. 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.

  16. 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

  17. Serotonergic Modulation of Conditioned Fear

    PubMed Central

    Homberg, Judith R.

    2012-01-01

    Conditioned fear plays a key role in anxiety disorders as well as depression and other neuropsychiatric conditions. Understanding how neuromodulators drive the associated learning and memory processes, including memory consolidation, retrieval/expression, and extinction (recall), is essential in the understanding of (individual differences in vulnerability to) these disorders and their treatment. The human and rodent studies I review here together reveal, amongst others, that acute selective serotonin reuptake inhibitor (SSRI) treatment facilitates fear conditioning, reduces contextual fear, and increases cued fear, chronic SSRI treatment reduces both contextual and cued fear, 5-HT1A receptors inhibit the acquisition and expression of contextual fear, 5-HT2A receptors facilitates the consolidation of cued and contextual fear, inactivation of 5-HT2C receptors facilitate the retrieval of cued fear memory, the 5-HT3 receptor mediates contextual fear, genetically induced increases in serotonin levels are associated with increased fear conditioning, impaired cued fear extinction, or impaired extinction recall, and that genetically induced 5-HT depletion increases fear conditioning and contextual fear. Several explanations are presented to reconcile seemingly paradoxical relationships between serotonin levels and conditioned fear. PMID:24278743

  18. Rule-based generalisation in single-cue and differential fear conditioning in humans.

    PubMed

    Wong, Alex H K; Lovibond, Peter F

    2017-09-01

    Fear generalisation refers to the spread of conditioned fear to stimuli similar but distinct from the original conditioned stimulus. In this study, participants were presented with repeated pairings of a conditioned stimulus with a shock, in either a single-cue or differential conditioning paradigm. Generalisation of fear was then tested by presenting stimuli that were novel, but similar to the conditioned stimulus along a spatial stimulus dimension. Dependent measures were online shock expectancy ratings and skin conductance level. A diverse range of generalisation gradients was observed, and the shape of the gradients for both expectancy ratings and skin conductance responses corresponded with participants' verbally reported rules. The findings point to an important role for cognitively controlled processes in human fear generalisation, and provide support for a single-system learning model. They also highlight the potential importance of cognitive reappraisal in clinical treatments for over-generalised fear. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. 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

  20. Assessment of social transmission of threats in humans using observational fear conditioning.

    PubMed

    Haaker, Jan; Golkar, Armita; Selbing, Ida; Olsson, Andreas

    2017-07-01

    Across the human life span, fear is often acquired indirectly by observation of the emotional expressions of others. The observational fear conditioning protocol was previously developed as a laboratory model for investigating socially acquired threat responses. This protocol serves as a suitable alternative to the widely used Pavlovian fear conditioning, in which threat responses are acquired through direct experiences. In the observational fear conditioning protocol, the participant (observer) watches a demonstrator being presented with a conditioned stimulus (CS) paired with an aversive unconditioned stimulus (US). The expression of threat learning is measured as the conditioned response (CR) expressed by the observer in the absence of the demonstrator. CRs are commonly measured as skin conductance responses, but behavioral and neural measures have also been implemented. The experimental procedure is suitable for divergent populations, can be administered by a graduate student and takes ∼40 min. Similar protocols are used in animals, emphasizing its value as a translational tool for studying socioemotional learning.

  1. The Impact of Instructions on Generalization of Conditioned Fear in Humans.

    PubMed

    Ahmed, Ola; Lovibond, Peter F

    2015-09-01

    Generalization of conditioned fear has been implicated in the maintenance and proliferation of fear in anxiety disorders. The role of cognitive processes in generalization of conditioning is an important yet understudied issue. Vervliet et al. (2010) tested generalization of fear to a visual stimulus of a particular color and shape paired with electric shock. Test stimuli shared either the color or shape of the CS+. Prior to conditioning, participants were instructed that either color or shape would be predictive of shock. Generalization was stronger to the stimulus containing the instructed feature, suggesting that instructions impacted generalization of fear. However, the result may also reflect the impact of instructions on attention and learning during the conditioning phase. In the present study, the instructional manipulation was given after the conditioning phase to control for any impact of instructions on learning. A similar result to that reported by Vervliet et al. was observed. On self-reported expectancy of shock, generalization was greater to the test stimulus that included the instructed stimulus feature. The same pattern was observed on skin conductance, although it did not reach statistical significance. The findings indicate that explicitly instructed information affected generalization of conditioned fear independently of any impact on learning, pointing to the role of cognitive processes in human fear generalization. They also support the utility of cognitive therapy approaches, which are employed after fear has already developed, in addressing clinical overgeneralization.

  2. Influence of stress on fear memory processes in an aversive differential conditioning paradigm in humans.

    PubMed

    Bentz, Dorothée; Michael, Tanja; Wilhelm, Frank H; Hartmann, Francina R; Kunz, Sabrina; von Rohr, Isabelle R Rudolf; de Quervain, Dominique J-F

    2013-07-01

    It is widely assumed that learning and memory processes play an important role in the pathogenesis, expression, maintenance and therapy of anxiety disorders, such as phobias or post-traumatic stress disorder (PTSD). Memory retrieval is involved in symptom expression and maintenance of these disorders, while memory extinction is believed to be the underlying mechanism of behavioral exposure therapy of anxiety disorders. There is abundant evidence that stress and stress hormones can reduce memory retrieval of emotional information, whereas they enhance memory consolidation of extinction training. In this study we aimed at investigating if stress affects these memory processes in a fear conditioning paradigm in healthy human subjects. On day 1, fear memory was acquired through a standard differential fear conditioning procedure. On day 2 (24h after fear acquisition), participants either underwent a stressful cold pressor test (CPT) or a control condition, 20 min before memory retrieval testing and extinction training. Possible prolonged effects of the stress manipulation were investigated on day 3 (48 h after fear acquisition), when memory retrieval and extinction were tested again. On day 2, men in the stress group showed a robust cortisol response to stress and showed lower unconditioned stimulus (US) expectancy ratings than men in the control group. This reduction in fear memory retrieval was maintained on day 3. In women, who showed a significantly smaller cortisol response to stress than men, no stress effects on fear memory retrieval were observed. No group differences were observed with respect to extinction. In conclusion, the present study provides evidence that stress can reduce memory retrieval of conditioned fear in men. Our findings may contribute to the understanding of the effects of stress and glucocorticoids on fear symptoms in anxiety disorders and suggest that such effects may be sex-specific.

  3. Functional MRI of human amygdala activity during Pavlovian fear conditioning: stimulus processing versus response expression.

    PubMed

    Cheng, Dominic T; Knight, David C; Smith, Christine N; Stein, Elliot A; Helmstetter, Fred J

    2003-02-01

    Although laboratory animal studies have shown that the amygdala plays multiple roles in conditional fear, less is known about the human amygdala. Human subjects were trained in a Pavlovian fear conditioning paradigm during functional magnetic resonance imaging (fMRI). Brain activity maps correlated with reference waveforms representing the temporal pattern of visual conditional stimuli (CSs) and subject-derived autonomic responses were compared. Subjects receiving paired CS-shock presentations showed greater amygdala activity than subjects receiving unpaired CS-shock presentations when their brain activity was correlated with a waveform generated from their behavioral responses. Stimulus-based waveforms revealed learning differences in the visual cortex, but not in the amygdala. These data support the view that the amygdala is important for the expression of learned behavioral responses during Pavlovian fear conditioning.

  4. From Pavlov to PTSD: The extinction of conditioned fear in rodents, humans, and in anxiety disorders

    PubMed Central

    VanElzakker, Michael B.; Dahlgren, M. Kathryn; Davis, F. Caroline; Dubois, Stacey; Shin, Lisa M.

    2014-01-01

    Nearly 100 years ago, Ivan Pavlov demonstrated that dogs could learn to use a neutral cue to predict a biologically relevant event: after repeated predictive pairings, Pavlov's dogs were conditioned to anticipate food at the sound of a bell, which caused them to salivate. Like sustenance, danger is biologically relevant, and neutral cues can take on great salience when they predict a threat to survival. In anxiety disorders such as posttraumatic stress disorder (PTSD), this type of conditioned fear fails to extinguish, and reminders of traumatic events can cause pathological conditioned fear responses for decades after danger has passed. In this review, we use fear conditioning and extinction studies to draw a direct line from Pavlov to PTSD and other anxiety disorders. We explain how rodent studies have informed neuroimaging studies of healthy humans and humans with PTSD. We describe several genes that have been linked to both PTSD and fear conditioning and extinction and explain how abnormalities in fear conditioning or extinction may reflect a general biomarker of anxiety disorders. Finally, we explore drug and neuromodulation treatments that may enhance therapeutic extinction in anxiety disorders. PMID:24321650

  5. From Pavlov to PTSD: the extinction of conditioned fear in rodents, humans, and anxiety disorders.

    PubMed

    VanElzakker, Michael B; Dahlgren, M Kathryn; Davis, F Caroline; Dubois, Stacey; Shin, Lisa M

    2014-09-01

    Nearly 100 years ago, Ivan Pavlov demonstrated that dogs could learn to use a neutral cue to predict a biologically relevant event: after repeated predictive pairings, Pavlov's dogs were conditioned to anticipate food at the sound of a bell, which caused them to salivate. Like sustenance, danger is biologically relevant, and neutral cues can take on great salience when they predict a threat to survival. In anxiety disorders such as posttraumatic stress disorder (PTSD), this type of conditioned fear fails to extinguish, and reminders of traumatic events can cause pathological conditioned fear responses for decades after danger has passed. In this review, we use fear conditioning and extinction studies to draw a direct line from Pavlov to PTSD and other anxiety disorders. We explain how rodent studies have informed neuroimaging studies of healthy humans and humans with PTSD. We describe several genes that have been linked to both PTSD and fear conditioning and extinction and explain how abnormalities in fear conditioning or extinction may reflect a general biomarker of anxiety disorders. Finally, we explore drug and neuromodulation treatments that may enhance therapeutic extinction in anxiety disorders. Copyright © 2013 Elsevier Inc. All rights reserved.

  6. Effect of Conditioned Stimulus Exposure during Slow Wave Sleep on Fear Memory Extinction in Humans

    PubMed Central

    He, Jia; Sun, Hong-Qiang; Li, Su-Xia; Zhang, Wei-Hua; Shi, Jie; Ai, Si-Zhi; Li, Yun; Li, Xiao-Jun; Tang, Xiang-Dong; Lu, Lin

    2015-01-01

    Study Objectives: Repeated exposure to a neutral conditioned stimulus (CS) in the absence of a noxious unconditioned stimulus (US) elicits fear memory extinction. The aim of the current study was to investigate the effects of mild tone exposure (CS) during slow wave sleep (SWS) on fear memory extinction in humans. Design: The healthy volunteers underwent an auditory fear conditioning paradigm on the experimental night, during which tones served as the CS, and a mild shock served as the US. They were then randomly assigned to four groups. Three groups were exposed to the CS for 3 or 10 min or an irrelevant tone (control stimulus, CtrS) for 10 min during SWS. The fourth group served as controls and was not subjected to any interventions. All of the subjects completed a memory test 4 h after SWS-rich stage to evaluate the effect on fear extinction. Moreover, we conducted similar experiments using an independent group of subjects during the daytime to test whether the memory extinction effect was specific to the sleep condition. Participants: Ninety-six healthy volunteers (44 males) aged 18–28 y. Measurements and Results: Participants exhibited undisturbed sleep during 2 consecutive nights, as assessed by sleep variables (all P > 0.05) from polysomnographic recordings and power spectral analysis. Participants who were re-exposed to the 10 min CS either during SWS and wakefulness exhibited attenuated fear responses (wake-10 min CS, P < 0.05; SWS-10 min CS, P < 0.01). Conclusions: Conditioned stimulus re-exposure during slow wave sleep promoted fear memory extinction without altering sleep profiles. Citation: He J, Sun HQ, Li SX, Zhang WH, Shi J, Ai SZ, Li Y, Li XJ, Tang XD, Lu L. Effect of conditioned stimulus exposure during slow wave sleep on fear memory extinction in humans. SLEEP 2015;38(3):423–431. PMID:25348121

  7. P50 suppression in human discrimination fear conditioning paradigm using danger and safety signals.

    PubMed

    Kurayama, Taichi; Matsuzawa, Daisuke; Komiya, Zen; Nakazawa, Ken; Yoshida, Susumu; Shimizu, Eiji

    2012-04-01

    Auditory P50 suppression, which is assessed using a paired auditory stimuli (S1 and S2) paradigm to record the P50 mid-latency evoked potential, is assumed to reflect sensory gating. Recently, P50 suppression deficits were observed in patients with anxiety disorders, including panic disorder, post-traumatic stress disorder and obsessive-compulsive disorder, as we previously reported. The processes of fear conditioning are thought to play a role in the pathophysiology of anxiety disorders. In addition, we found that the P50 sensory gating mechanism might be physiologically associated with fear conditioning and extinction in a simple human fear-conditioning paradigm that involved a light signal as a conditioned stimulus (CS+). Our objective was to investigate the different patterns of P50 suppression in a discrimination fear-conditioning paradigm with both a CS+ (danger signal) and a CS- (safety signal). Twenty healthy volunteers were recruited. We measured the auditory P50 suppression in the control (baseline) phase, in the fear-acquisition phase, and in the fear-extinction phase using a discrimination fear-conditioning paradigm. Two-way (CSs vs. phase) Analysis of variance with repeated measures demonstrated a significant interaction between the two factors. Post-hoc LSD analysis indicated that the P50 S2/S1 ratio in the CS+ acquisition phase was significantly higher than that in the CS- acquisition phase. These results suggest that the auditory P50 sensory gating might differ according to the cognition of the properties (potentially dangerous or safe) of the perceived signal.

  8. Prefrontal oscillations during recall of conditioned and extinguished fear in humans.

    PubMed

    Mueller, Erik M; Panitz, Christian; Hermann, Christiane; Pizzagalli, Diego A

    2014-05-21

    Human neuroimaging studies indicate that the anterior midcingulate cortex (AMC) and the ventromedial prefrontal cortex (vmPFC) play important roles in the expression and extinction of fear, respectively. Electrophysiological rodent studies further indicate that oscillatory neuronal activity in homolog regions (i.e., prelimbic and infralimbic cortices) changes during fear expression and fear extinction recall. Whether similar processes occur in humans remains largely unexplored. By assessing scalp surface EEG in conjunction with LORETA source estimation of CS-related theta and gamma activity, we tested whether a priori defined ROIs in the human AMC and vmPFC similarly modulate their oscillatory activity during fear expression and extinction recall, respectively. To this end, 42 healthy individuals underwent a differential conditioning/differential extinction protocol with a Recall Test on the next day. In the Recall Test, nonextinguished versus extinguished stimuli evoked an increased differential (CS(+) vs CS(-)) response with regard to skin conductance and AMC-localized theta power. Conversely, extinguished versus nonextinguished stimuli evoked an increased differential response with regard to vmPFC-localized gamma power. Finally, individuals who failed to show a suppressed skin conductance response to the extinguished versus nonextinguished CS(+) also failed to show the otherwise observed alterations in vmPFC gamma power to extinguished CS(+). These results indicate that fear expression is associated with AMC theta activity, whereas successful fear extinction recall relates to changes in vmPFC gamma activity. The present work thereby bridges findings from prior rodent electrophysiological research and human neuroimaging studies and indicates that EEG is a valuable tool for future fear extinction research. Copyright © 2014 the authors 0270-6474/14/347059-08$15.00/0.

  9. Effect of conditioned stimulus exposure during slow wave sleep on fear memory extinction in humans.

    PubMed

    He, Jia; Sun, Hong-Qiang; Li, Su-Xia; Zhang, Wei-Hua; Shi, Jie; Ai, Si-Zhi; Li, Yun; Li, Xiao-Jun; Tang, Xiang-Dong; Lu, Lin

    2015-03-01

    Repeated exposure to a neutral conditioned stimulus (CS) in the absence of a noxious unconditioned stimulus (US) elicits fear memory extinction. The aim of the current study was to investigate the effects of mild tone exposure (CS) during slow wave sleep (SWS) on fear memory extinction in humans. The healthy volunteers underwent an auditory fear conditioning paradigm on the experimental night, during which tones served as the CS, and a mild shock served as the US. They were then randomly assigned to four groups. Three groups were exposed to the CS for 3 or 10 min or an irrelevant tone (control stimulus, CtrS) for 10 min during SWS. The fourth group served as controls and was not subjected to any interventions. All of the subjects completed a memory test 4 h after SWS-rich stage to evaluate the effect on fear extinction. Moreover, we conducted similar experiments using an independent group of subjects during the daytime to test whether the memory extinction effect was specific to the sleep condition. Ninety-six healthy volunteers (44 males) aged 18-28 y. Participants exhibited undisturbed sleep during 2 consecutive nights, as assessed by sleep variables (all P > 0.05) from polysomnographic recordings and power spectral analysis. Participants who were re-exposed to the 10 min CS either during SWS and wakefulness exhibited attenuated fear responses (wake-10 min CS, P < 0.05; SWS-10 min CS, P < 0.01). Conditioned stimulus re-exposure during SWS promoted fear memory extinction without altering sleep profiles. © 2015 Associated Professional Sleep Societies, LLC.

  10. What's wrong with fear conditioning?

    PubMed

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

    2013-01-01

    Fear conditioning is one of the prime paradigms of behavioural neuroscience and a source of tremendous insight in the fundamentals of learning and memory and the psychology and neurobiology of emotion. It is also widely regarded as a model for the pathogenesis of anxiety disorders in a diathesis-stress model of psychopathology. Starting from the apparent paradox between the adaptive nature of fear conditioning and the dysfunctional nature of pathological anxiety, we present a critique of the human fear conditioning paradigm as an experimental model for psychopathology. We discuss the potential benefits of expanding the human fear conditioning paradigm by (1) including action tendencies as an important index of fear and (2) paying more attention to "weak" (i.e., ambiguous) rather than "strong" fear learning situations (Lissek et al., 2006), such as contained in selective learning procedures. We present preliminary data that illustrate these ideas and discuss the importance of response systems divergence in understanding individual differences in vulnerability for the development of pathological anxiety.

  11. Effect of continuous and partial reinforcement on the acquisition and extinction of human conditioned fear.

    PubMed

    Grady, Ashley K; Bowen, Kenton H; Hyde, Andrew T; Totsch, Stacie K; Knight, David C

    2016-02-01

    Extinction of Pavlovian conditioned fear in humans is a popular paradigm often used to study learning and memory processes that mediate anxiety-related disorders. Fear extinction studies often only pair the conditioned stimulus (CS) and unconditioned stimulus (UCS) on a subset of acquisition trials (i.e., partial reinforcement/pairing) to prolong extinction (i.e., partial reinforcement extinction effect; PREE) and provide more time to study the process. However, there is limited evidence that the partial pairing procedures typically used during fear conditioning actually extend the extinction process, while there is strong evidence these procedures weaken conditioned response (CR) acquisition. Therefore, determining conditioning procedures that support strong CR acquisition and that also prolong the extinction process would benefit the field. The present study investigated 4 separate CS-UCS pairing procedures to determine methods that support strong conditioning and that also exhibit a PREE. One group (C-C) of participants received continuous CS-UCS pairings; a second group (C-P) received continuous followed by partial CS-UCS pairings; a third group (P-C) received partial followed by continuous CS-UCS pairings; and a fourth group (P-P) received partial CS-UCS pairings during acquisition. A strong skin conductance CR was expressed by C-C and P-C groups but not by C-P and P-P groups at the end of the acquisition phase. The P-C group maintained the CR during extinction. In contrast, the CR extinguished quickly within the C-C group. These findings suggest that partial followed by continuous CS-UCS pairings elicit strong CRs and prolong the extinction process following human fear conditioning.

  12. Neural signatures of human fear conditioning: an updated and extended meta-analysis of fMRI studies.

    PubMed

    Fullana, M A; Harrison, B J; Soriano-Mas, C; Vervliet, B; Cardoner, N; Àvila-Parcet, A; Radua, J

    2016-04-01

    Classical Pavlovian fear conditioning remains the most widely employed experimental model of fear and anxiety, and continues to inform contemporary pathophysiological accounts of clinical anxiety disorders. Despite its widespread application in human and animal studies, the neurobiological basis of fear conditioning remains only partially understood. Here we provide a comprehensive meta-analysis of human fear-conditioning studies carried out with functional magnetic resonance imaging (fMRI), yielding a pooled sample of 677 participants from 27 independent studies. As a distinguishing feature of this meta-analysis, original statistical brain maps were obtained from the authors of 13 of these studies. Our primary analyses demonstrate that human fear conditioning is associated with a consistent and robust pattern of neural activation across a hypothesized genuine network of brain regions resembling existing anatomical descriptions of the 'central autonomic-interoceptive network'. This finding is discussed with a particular emphasis on the neural substrates of conscious fear processing. Our associated meta-analysis of functional deactivations-a scarcely addressed dynamic in fMRI fear-conditioning studies-also suggests the existence of a coordinated brain response potentially underlying the 'safety signal' (that is, non-threat) processing. We attempt to provide an integrated summary on these findings with the view that they may inform ongoing studies of fear-conditioning processes both in healthy and clinical populations, as investigated with neuroimaging and other experimental approaches.

  13. Impaired acquisition of classically conditioned fear-potentiated startle reflexes in humans with focal bilateral basolateral amygdala damage

    PubMed Central

    Morgan, Barak; Terburg, David; Stein, Dan J.; van Honk, Jack

    2015-01-01

    Based on studies in rodents, the basolateral amygdala (BLA) is considered a key site for experience-dependent neural plasticity underlying the acquisition of conditioned fear responses. In humans, very few studies exist of subjects with selective amygdala lesions and those studies have only implicated the amygdala more broadly leaving the role of amygdala sub-regions underexplored. We tested a rare sample of subjects (N = 4) with unprecedented focal bilateral BLA lesions due to a genetic condition called Urbach–Wiethe disease. In a classical delay fear conditioning experiment, these subjects showed impaired acquisition of conditioned fear relative to a group of matched control subjects (N = 10) as measured by fear-potentiation of the defensive eye-blink startle reflex. After the experiment, the BLA-damaged cases showed normal declarative memory of the conditioned association. Our findings provide new evidence that the human BLA is essential to drive fast classically conditioned defensive reflexes. PMID:25552573

  14. 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…

  15. 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…

  16. 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

  17. Avoiding Negative Outcomes: Tracking the Mechanisms of Avoidance Learning in Humans During Fear Conditioning

    PubMed Central

    Delgado, Mauricio R.; Jou, Rita L.; LeDoux, Joseph E.; Phelps, Elizabeth A.

    2009-01-01

    Previous research across species has shown that the amygdala is critical for learning about aversive outcomes, while the striatum is involved in reward-related processing. Less is known, however, about the role of the amygdala and the striatum in learning how to exert control over emotions and avoid negative outcomes. One potential mechanism for active avoidance of stressful situations is postulated to involve amygdala–striatal interactions. The goal of this study was to investigate the physiological and neural correlates underlying avoidance learning in humans. Specifically, we used a classical conditioning paradigm where three different conditioned stimuli (CS) were presented. One stimulus predicted the delivery of a shock upon stimulus offset (CS+), while another predicted no negative consequences (CS−). A third conditioned cue also predicted delivery of a shock, but participants were instructed that upon seeing this stimulus, they could avoid the shock if they chose the correct action (AV+). After successful learning, participants could then easily terminate the shock during subsequent stimulus presentations (AV−). Physiological responses (as measured by skin conductance responses) confirmed a main effect of conditioning, particularly showing higher arousal responses during pre (AV+) compared to post (AV−) learning of an avoidance response. Consistent with animal models, amygdala–striatal interactions were observed to underlie the acquisition of an avoidance response. These results support a mechanism of active coping with conditioned fear that allows for the control over emotional responses such as fears that can become maladaptive and influence our decision-making. PMID:19847311

  18. Avoiding negative outcomes: tracking the mechanisms of avoidance learning in humans during fear conditioning.

    PubMed

    Delgado, Mauricio R; Jou, Rita L; Ledoux, Joseph E; Phelps, Elizabeth A

    2009-01-01

    Previous research across species has shown that the amygdala is critical for learning about aversive outcomes, while the striatum is involved in reward-related processing. Less is known, however, about the role of the amygdala and the striatum in learning how to exert control over emotions and avoid negative outcomes. One potential mechanism for active avoidance of stressful situations is postulated to involve amygdala-striatal interactions. The goal of this study was to investigate the physiological and neural correlates underlying avoidance learning in humans. Specifically, we used a classical conditioning paradigm where three different conditioned stimuli (CS) were presented. One stimulus predicted the delivery of a shock upon stimulus offset (CS+), while another predicted no negative consequences (CS-). A third conditioned cue also predicted delivery of a shock, but participants were instructed that upon seeing this stimulus, they could avoid the shock if they chose the correct action (AV+). After successful learning, participants could then easily terminate the shock during subsequent stimulus presentations (AV-). Physiological responses (as measured by skin conductance responses) confirmed a main effect of conditioning, particularly showing higher arousal responses during pre (AV+) compared to post (AV-) learning of an avoidance response. Consistent with animal models, amygdala-striatal interactions were observed to underlie the acquisition of an avoidance response. These results support a mechanism of active coping with conditioned fear that allows for the control over emotional responses such as fears that can become maladaptive and influence our decision-making.

  19. Attentional Bias for Uncertain Cues of Shock in Human Fear Conditioning: Evidence for Attentional Learning Theory.

    PubMed

    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.

  20. The effect of intranasal oxytocin treatment on conditioned fear extinction and recall in a healthy human sample

    PubMed Central

    Acheson, Dean T.; Feifel, David; de Wilde, Sofieke; Mckinney, Rebecca; Lohr, James B.; Risbrough, Victoria B.

    2017-01-01

    Rationale To improve outcomes for patients undergoing extinction-based therapies (e.g. exposure therapy) for anxiety disorders such as post-traumatic stress disorder, there has been interest in identifying pharmaceutical compounds which might facilitate fear extinction learning and recall. Oxytocin (OT) is a mammalian neuropeptide that modulates activation of fear extinction-based neural circuits and fear responses. Little is known however about the effects of OT treatment on conditioned fear responding and extinction in humans. Objectives The purpose of the present study was to assess the effects of OT in a fear-potentiated startle task of fear conditioning and extinction. Methods A double-blind, placebo-controlled study of 44 healthy human participants was conducted. Participants underwent a conditioned fear acquisition procedure, after which they were randomized to treatment group and delivered OT (24 IU) or placebo via intranasal spray. Forty-five min after treatment, participants underwent extinction training. Twenty-four hrs later subjects were tested for extinction recall. Results Relative to placebo, the OT group showed increased fear potentiated startle responding during the earliest stage of extinction training relative to placebo, however all treatment groups showed the same level of reduced responding by the end of extinction training. Twenty-four hours later the OT group showed significantly higher recall of extinction relative to placebo. Conclusions The current study provides preliminary evidence that OT may facilitate fear extinction recall in humans. These results support further study of OT as a potential adjunctive treatment for extinction-based therapies in fear-related disorders. PMID:23644911

  1. An overview of translationally informed treatments for PTSD: animal models of Pavlovian fear conditioning to human clinical trials

    PubMed Central

    Bowers, Mallory E.; Ressler, Kerry J.

    2015-01-01

    Posttraumatic stress disorder (PTSD) manifests after exposure to a traumatic event and is characterized by avoidance/numbing, intrusive symptoms and flashbacks, mood and cognitive disruptions, and hyperarousal/reactivity symptoms. These symptoms reflect dysregulation of the fear system likely caused by poor fear inhibition/extinction, increased generalization, and/or enhanced consolidation or acquisition of fear. These phenotypes can be modeled in animal subjects using Pavlovian fear conditioning, allowing investigation of the underlying neurobiology of normative and pathological fear. Pre-clinical studies reveal a number of neurotransmitter systems and circuits critical for aversive learning and memory, which have informed the development of therapies used in human clinical trials. In this review, we discuss the evidence for a number of established and emerging pharmacotherapies and device-based treatments for PTSD that have been developed via a bench to bedside translational model. PMID:26238379

  2. An Overview of Translationally Informed Treatments for Posttraumatic Stress Disorder: Animal Models of Pavlovian Fear Conditioning to Human Clinical Trials.

    PubMed

    Bowers, Mallory E; Ressler, Kerry J

    2015-09-01

    Posttraumatic stress disorder manifests after exposure to a traumatic event and is characterized by avoidance/numbing, intrusive symptoms and flashbacks, mood and cognitive disruptions, and hyperarousal/reactivity symptoms. These symptoms reflect dysregulation of the fear system likely caused by poor fear inhibition/extinction, increased generalization, and/or enhanced consolidation or acquisition of fear. These phenotypes can be modeled in animal subjects using Pavlovian fear conditioning, allowing investigation of the underlying neurobiology of normative and pathological fear. Preclinical studies reveal a number of neurotransmitter systems and circuits critical for aversive learning and memory that have informed the development of therapies used in human clinical trials. In this review, we discuss the evidence for a number of established and emerging pharmacotherapies and device-based treatments for posttraumatic stress disorder that have been developed via a bench to bedside translational model. Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  3. Fear-potentiated startle processing in humans: Parallel fMRI and orbicularis EMG assessment during cue conditioning and extinction.

    PubMed

    Lindner, Katja; Neubert, Jörg; Pfannmöller, Jörg; Lotze, Martin; Hamm, Alfons O; Wendt, Julia

    2015-12-01

    Studying neural networks and behavioral indices such as potentiated startle responses during fear conditioning has a long tradition in both animal and human research. However, most of the studies in humans do not link startle potentiation and neural activity during fear acquisition and extinction. Therefore, we examined startle blink responses measured with electromyography (EMG) and brain activity measured with functional MRI simultaneously during differential conditioning. Furthermore, we combined these behavioral fear indices with brain network activity by analyzing the brain activity evoked by the startle probe stimulus presented during conditioned visual threat and safety cues as well as in the absence of visual stimulation. In line with previous research, we found a fear-induced potentiation of the startle blink responses when elicited during a conditioned threat stimulus and a rapid decline of amygdala activity after an initial differentiation of threat and safety cues in early acquisition trials. Increased activation during processing of threat cues was also found in the anterior insula, the anterior cingulate cortex (ACC), and the periaqueductal gray (PAG). More importantly, our results depict an increase of brain activity to probes presented during threatening in comparison to safety cues indicating an involvement of the anterior insula, the ACC, the thalamus, and the PAG in fear-potentiated startle processing during early extinction trials. Our study underlines that parallel assessment of fear-potentiated startle in fMRI paradigms can provide a helpful method to investigate common and distinct processing pathways in humans and animals and, thus, contributes to translational research.

  4. Serotonin in fear conditioning processes.

    PubMed

    Bauer, Elizabeth P

    2015-01-15

    This review describes the latest developments in our understanding of how the serotonergic system modulates Pavlovian fear conditioning, fear expression and fear extinction. These different phases of classical fear conditioning involve coordinated interactions between the extended amygdala, hippocampus and prefrontal cortices. Here, I first define the different stages of learning involved in cued and context fear conditioning and describe the neural circuits underlying these processes. The serotonergic system can be manipulated by administering serotonin receptor agonists and antagonists, as well as selective serotonin reuptake inhibitors (SSRIs), and these can have significant effects on emotional learning and memory. Moreover, variations in serotonergic genes can influence fear conditioning and extinction processes, and can underlie differential responses to pharmacological manipulations. This research has considerable translational significance as imbalances in the serotonergic system have been linked to anxiety and depression, while abnormalities in the mechanisms of conditioned fear contribute to anxiety disorders.

  5. Thwarting the Renewal (Relapse) of Conditioned Fear with the Explicitly Unpaired Procedure: Possible Interpretations and Implications for Treating Human Fears and Phobias

    ERIC Educational Resources Information Center

    Thomas, Brian L.; Longo, Craig L.; Ayres, John J. B.

    2005-01-01

    In three experiments using the barpress conditioned suppression task with albino rats, we studied the renewal (relapse) of conditioned fear in an ABA fear-renewal paradigm. We found that explicitly unpaired (EU) deliveries of conditioned stimuli (CSs) and unconditioned stimuli (USs) in Context B thwarted fear renewal in Context A. Evidence…

  6. Dynamic competition between large-scale functional networks differentiates fear conditioning and extinction in humans.

    PubMed

    Marstaller, Lars; Burianová, Hana; Reutens, David C

    2016-07-01

    The high evolutionary value of learning when to respond to threats or when to inhibit previously learned associations after changing threat contingencies is reflected in dedicated networks in the animal and human brain. Recent evidence further suggests that adaptive learning may be dependent on the dynamic interaction of meta-stable functional brain networks. However, it is still unclear which functional brain networks compete with each other to facilitate associative learning and how changes in threat contingencies affect this competition. The aim of this study was to assess the dynamic competition between large-scale networks related to associative learning in the human brain by combining a repeated differential conditioning and extinction paradigm with independent component analysis of functional magnetic resonance imaging data. The results (i) identify three task-related networks involved in initial and sustained conditioning as well as extinction, and demonstrate that (ii) the two main networks that underlie sustained conditioning and extinction are anti-correlated with each other and (iii) the dynamic competition between these two networks is modulated in response to changes in associative contingencies. These findings provide novel evidence for the view that dynamic competition between large-scale functional networks differentiates fear conditioning from extinction learning in the healthy brain and suggest that dysfunctional network dynamics might contribute to learning-related neuropsychiatric disorders. Crown Copyright © 2016. Published by Elsevier Inc. All rights reserved.

  7. Dissociable roles for hippocampal and amygdalar volume in human fear conditioning.

    PubMed

    Cacciaglia, Raffaele; Pohlack, Sebastian T; Flor, Herta; Nees, Frauke

    2015-09-01

    Fear conditioning is a basic learning process which involves the association of a formerly neutral conditioned stimulus (CS) with a biologically relevant aversive unconditioned stimulus (US). Previous studies conducted in brain-lesioned patients have shown that while the acquisition of autonomic fear responses requires an intact amygdala, a spared hippocampus is necessary for the development of the CS-US contingency awareness. Although these data have been supported by studies using functional neuroimaging techniques in healthy people, attempts to extend these findings to the morphological aspects of amygdala and hippocampus are missing. Here we tested the hypothesis that amygdalar and hippocampal volumes play dissociable roles in determining autonomic responses and contingency awareness during fear conditioning. Fifty-two healthy individuals (mean age 21.83) underwent high-resolution magnetic resonance imaging. We used a differential delay fear conditioning paradigm while assessing skin conductance responses (SCRs), subjective ratings of CS-US contingency, as well as emotional valence and perceived arousal. Left amygdalar volume significantly predicted the magnitude of differential SCRs during fear acquisition, but had no impact on contingency learning. Conversely, bilateral hippocampal volumes were significantly related to contingency ratings, but not to SCRs. Moreover, left amygdalar volume predicted SCRs to the reinforced CS alone, but not those elicited by the US. Our findings bridge the gap between previous lesion and functional imaging studies, by showing that amygdalar and hippocampal volumes differentially modulate the acquisition of conditioned fear. Further, our results reveal that the morphology of these limbic structures moderate learning and memory already in healthy persons.

  8. Generalization of conditioned fear along a dimension of increasing fear intensity.

    PubMed

    Dunsmoor, Joseph E; Mitroff, Stephen R; LaBar, Kevin S

    2009-07-01

    The present study investigated the extent to which fear generalization in humans is determined by the amount of fear intensity in nonconditioned stimuli relative to a perceptually similar conditioned stimulus. Stimuli consisted of graded emotionally expressive faces of the same identity morphed between neutral and fearful endpoints. Two experimental groups underwent discriminative fear conditioning between a face stimulus of 55% fear intensity (conditioned stimulus, CS+), reinforced with an electric shock, and a second stimulus that was unreinforced (CS-). In Experiment 1 the CS- was a relatively neutral face stimulus, while in Experiment 2 the CS- was the most fear-intense stimulus. Before and following fear conditioning, skin conductance responses (SCR) were recorded to different morph values along the neutral-to-fear dimension. Both experimental groups showed gradients of generalization following fear conditioning that increased with the fear intensity of the stimulus. In Experiment 1 a peak shift in SCRs extended to the most fear-intense stimulus. In contrast, generalization to the most fear-intense stimulus was reduced in Experiment 2, suggesting that discriminative fear learning procedures can attenuate fear generalization. Together, the findings indicate that fear generalization is broadly tuned and sensitive to the amount of fear intensity in nonconditioned stimuli, but that fear generalization can come under stimulus control. These results reveal a novel form of fear generalization in humans that is not merely based on physical similarity to a conditioned exemplar, and may have implications for understanding generalization processes in anxiety disorders characterized by heightened sensitivity to nonthreatening stimuli.

  9. Genetic variation in brain-derived neurotrophic factor and human fear conditioning.

    PubMed

    Hajcak, G; Castille, C; Olvet, D M; Dunning, J P; Roohi, J; Hatchwell, E

    2009-02-01

    Brain-derived neurotrophic factor (BDNF) has been implicated in hippocampal-dependent learning processes, and carriers of the Met allele of the Val66Met BDNF genotype are characterized by reduced hippocampal structure and function. Recent nonhuman animal work suggests that BDNF is also crucial for amygdala-dependent associative learning. The present study sought to examine fear conditioning as a function of the BDNF polymorphism. Fifty-seven participants were genotyped for the BDNF polymorphism and took part in a differential-conditioning paradigm. Participants were shocked following a particular conditioned stimulus (CS+) and were also presented with stimuli that ranged in perceptual similarity to the CS+ (20, 40 or 60% smaller or larger than the CS+). The eye blink component of the startle response was measured to quantify fear conditioning; post-task shock likelihood ratings for each stimulus were also obtained. All participants reported that shock likelihood varied with perceptual similarity to the CS+ and showed potentiated startle in response to CS +/- 20% stimuli. However, only the Val/Val group had potentiated startle responses to the CS+. Met allele carrying individuals were characterized by deficient fear conditioning--evidenced by an attenuated startle response to CS+ stimuli. Variation in the BDNF genotype appears related to abnormal fear conditioning, consistent with nonhuman animal work on the importance of BDNF in amygdala-dependent associative learning. The relation between genetic variation in BDNF and amygdala-dependent associative learning deficits is discussed in terms of potential mechanisms of risk for psychopathology.

  10. Dissociation between implicit and explicit responses in postconditioning UCS revaluation after fear conditioning in humans

    PubMed Central

    Schultz, Douglas H.; Balderston, Nicholas L.; Geiger, Jennifer A.; Helmstetter, Fred J.

    2014-01-01

    The nature of the relationship between explicit and implicit learning is a topic of considerable debate. In order to investigate this relationship we conducted two experiments on postconditioning revaluation of the unconditional stimulus (UCS) in human fear conditioning. In Experiment 1, the intensity of the UCS was decreased following acquisition for one group (devaluation) and held constant for another group (control). A subsequent test revealed that even though both groups exhibited similar levels of UCS expectancy, the devaluation group had significantly smaller conditional skin conductance responses. The devaluation effect was not explained by differences in the explicit estimates of UCS probability or explicit knowledge that the UCS intensity had changed. In Experiment 2, the value of the UCS was increased following acquisition for one group (inflation) and held constant for another group (control). Test performance revealed that UCS inflation did not alter expectancy ratings, but the inflation group exhibited larger learned skin conductance responses than the control group. The inflation effect was not explained by differences in the explicit estimates of UCS probability or explicit knowledge that the UCS intensity had changed. The SCR revaluation effect was not dependent on explicit memory processes in either experiment. In both experiments we found differences on an implicit measure of learning in the absence of changes in explicit measures. Together, the differences observed between expectancy measures and skin conductance support the idea that these responses might reflect different types of memory formed during the same training procedure and be supported by separate neural systems. PMID:23731073

  11. Testing the effects of Δ9-THC and D-cycloserine on extinction of conditioned fear in humans

    PubMed Central

    Klumpers, Floris; Denys, Damiaan; Kenemans, J Leon; Grillon, Christian; van der Aart, Jasper; Baas, Johanna MP

    2012-01-01

    Preclinical evidence implicates several neurotransmitter systems in the extinction of conditioned fear. These results are of great interest, because the reduction of acquired fear associations is critical in therapies for anxiety disorders. We tested whether findings with respect to the N-methyl-D-aspartate (NMDA) and cannabinoid receptor (CB) systems in animals carry over to healthy human subjects. To that end, we administered selected doses of D-cycloserine (partial NMDA receptor agonist, 250 mg), delta-9-tetrahydrocannabinol (THC, CB1 receptor agonist, 10 mg), or placebo prior to the extinction session of a 3-day conditioning protocol. D-cycloserine did not affect within-session extinction, or the retention of extinction in healthy human participants, in contrast with patient data but in line with previous reports in healthy volunteers. During extinction training, Δ9-THC reduced conditioned skin conductance responses, but not fear-potentiated startle. This effect was not retained at the retention test 2 days later, suggesting it was dependent on acute effects of the drug. Our findings implicate that facilitation of the CB1 or NMDA system with the substances used in this study does not affect conditioned fear extinction lastingly in healthy humans. The apparent discrepancy between these findings and the results from (pre-) clinical trials is discussed in terms of room for improvement in these systems in healthy volunteers, and the lack of specificity of THC as a CB1 agonist. PMID:22351380

  12. Genetic variation in brain-derived neurotrophic factor and human fear conditioning

    PubMed Central

    Hajcak, G.; Castille, C.; Olvet, D. M.; Dunning, J. P.; Roohi, J.; Hatchwell, E.

    2015-01-01

    Brain-derived neurotrophic factor (BDNF) has been implicated in hippocampal-dependent learning processes, and carriers of the Met allele of the Val66Met BDNF genotype are characterized by reduced hippocampal structure and function. Recent nonhuman animal work suggests that BDNF is also crucial for amygdala-dependent associative learning. The present study sought to examine fear conditioning as a function of the BDNF polymorphism. Fifty-seven participants were genotyped for the BDNF polymorphism and took part in a differential-conditioning paradigm. Participants were shocked following a particular conditioned stimulus (CS+) and were also presented with stimuli that ranged in perceptual similarity to the CS+ (20, 40 or 60% smaller or larger than the CS+). The eye blink component of the startle response was measured to quantify fear conditioning; post-task shock likelihood ratings for each stimulus were also obtained. All participants reported that shock likelihood varied with perceptual similarity to the CS+ and showed potentiated startle in response to CS ± 20% stimuli. However, only the Val/Val group had potentiated startle responses to the CS+. Met allele carrying individuals were characterized by deficient fear conditioning – evidenced by an attenuated startle response to CS+ stimuli. Variation in the BDNF genotype appears related to abnormal fear conditioning, consistent with nonhuman animal work on the importance of BDNF in amygdala-dependent associative learning. The relation between genetic variation in BDNF and amygdala-dependent associative learning deficits is discussed in terms of potential mechanisms of risk for psychopathology. PMID:19220486

  13. Dissociation between implicit and explicit responses in postconditioning UCS revaluation after fear conditioning in humans.

    PubMed

    Schultz, Douglas H; Balderston, Nicholas L; Geiger, Jennifer A; Helmstetter, Fred J

    2013-06-01

    The nature of the relationship between explicit and implicit learning is a topic of considerable debate. To investigate this relationship we conducted two experiments on postconditioning revaluation of the unconditional stimulus (UCS) in human fear conditioning. In Experiment 1, the intensity of the UCS was decreased after acquisition for one group (devaluation) and held constant for another group (control). A subsequent test revealed that even though both groups exhibited similar levels of UCS expectancy, the devaluation group had significantly smaller conditional skin conductance responses. The devaluation effect was not explained by differences in the explicit estimates of UCS probability or explicit knowledge that the UCS intensity had changed. In Experiment 2, the value of the UCS was increased after acquisition for one group (inflation) and held constant for another group (control). Test performance revealed that UCS inflation did not alter expectancy ratings, but the inflation group exhibited larger learned skin conductance responses than the control group. The inflation effect was not explained by differences in the explicit estimates of UCS probability or explicit knowledge that the UCS intensity had changed. The SCR revaluation effect was not dependent on explicit memory processes in either experiment. In both experiments we found differences on an implicit measure of learning in the absence of changes in explicit measures. Together, the differences observed between expectancy measures and skin conductance support the idea that these responses might reflect different types of memory formed during the same training procedure and be supported by separate neural systems. PsycINFO Database Record (c) 2013 APA, all rights reserved.

  14. 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.

  15. 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

  16. The acquisition of fear of movement-related pain and associative learning: a novel pain-relevant human fear conditioning paradigm.

    PubMed

    Meulders, Ann; Vansteenwegen, Debora; Vlaeyen, Johan W S

    2011-11-01

    Current fear-avoidance models consider fear of pain as a key factor in the development of chronic musculoskeletal pain. Generally, the idea is that by virtue of the formation of associations or acquired propositional knowledge about the relation between neutral movements and pain, these movements may signal pain, and hence start to elicit defensive fear responses (eg, avoidance behavior). This assumption has never been investigated experimentally. Therefore, we developed a pain-relevant fear conditioning paradigm using a movement as a conditioned stimulus (CS) and a painful electrocutaneous stimulus as an unconditioned stimulus (US) to examine the acquisition of fear of movement-related pain in healthy subjects. In a within-subjects design, participants manipulated a joystick to the left/right in the experimental (predictable) condition, and upward/downward in the control (unpredictable) condition or vice versa. In the predictable condition, one movement direction (CS+), and not the other (CS-), was followed by painful stimuli. In the unpredictable condition, painful stimuli were always delivered during the intertrial interval. Both fear of movement-related pain ratings and eyeblink startle measures were more elevated in response to the CS+ than to the CS-, whereas no differences occurred between both unreinforced CSs in the control condition. Participants were slower initiating a CS+ movement than a CS- movement, while response latencies to CSs in the control condition did not differ. These data support the acquisition of fear of movement-related pain by associative learning. Results are discussed in the broader context of the acquisition of pain-related fear in patients with musculoskeletal pain.

  17. Generalization of conditioned fear along a dimension of increasing fear intensity

    PubMed Central

    Dunsmoor, Joseph E.; Mitroff, Stephen R.; LaBar, Kevin S.

    2009-01-01

    The present study investigated the extent to which fear generalization in humans is determined by the amount of fear intensity in nonconditioned stimuli relative to a perceptually similar conditioned stimulus. Stimuli consisted of graded emotionally expressive faces of the same identity morphed between neutral and fearful endpoints. Two experimental groups underwent discriminative fear conditioning between a face stimulus of 55% fear intensity (conditioned stimulus, CS+), reinforced with an electric shock, and a second stimulus that was unreinforced (CS−). In Experiment 1 the CS− was a relatively neutral face stimulus, while in Experiment 2 the CS− was the most fear-intense stimulus. Before and following fear conditioning, skin conductance responses (SCR) were recorded to different morph values along the neutral-to-fear dimension. Both experimental groups showed gradients of generalization following fear conditioning that increased with the fear intensity of the stimulus. In Experiment 1 a peak shift in SCRs extended to the most fear-intense stimulus. In contrast, generalization to the most fear-intense stimulus was reduced in Experiment 2, suggesting that discriminative fear learning procedures can attenuate fear generalization. Together, the findings indicate that fear generalization is broadly tuned and sensitive to the amount of fear intensity in nonconditioned stimuli, but that fear generalization can come under stimulus control. These results reveal a novel form of fear generalization in humans that is not merely based on physical similarity to a conditioned exemplar, and may have implications for understanding generalization processes in anxiety disorders characterized by heightened sensitivity to nonthreatening stimuli. PMID:19553384

  18. Brain activation during fear conditioning in humans depends on genetic variations related to functioning of the hypothalamic–pituitary–adrenal axis: first evidence from two independent subsamples

    PubMed Central

    Ridder, S.; Treutlein, J.; Nees, F.; Lang, S.; Diener, S.; Wessa, M.; Kroll, A.; Pohlack, S.; Cacciaglia, R.; Gass, P.; Schütz, G.; Schumann, G.; Flor, H.

    2012-01-01

    Background Enhanced acquisition and delayed extinction of fear conditioning are viewed as major determinants of anxiety disorders, which are often characterized by a dysfunctional hypothalamic–pituitary–adrenal (HPA) axis. Method In this study we employed cued fear conditioning in two independent samples of healthy subjects (sample 1: n=60, sample 2: n=52). Two graphical shapes served as conditioned stimuli and painful electrical stimulation as the unconditioned stimulus. In addition, guided by findings from published animal studies on HPA axis-related genes in fear conditioning, we examined variants of the glucocorticoid receptor and corticotropin-releasing hormone receptor 1 genes. Results Variation in these genes showed enhanced amygdala activation during the acquisition and reduced prefrontal activation during the extinction of fear as well as altered amygdala–prefrontal connectivity. Conclusions This is the first demonstration of the involvement of genes related to the HPA axis in human fear conditioning. PMID:22410078

  19. Generalization of Conditioned Fear along a Dimension of Increasing Fear Intensity

    ERIC Educational Resources Information Center

    Dunsmoor, Joseph E.; Mitroff, Stephen R.; LaBar, Kevin S.

    2009-01-01

    The present study investigated the extent to which fear generalization in humans is determined by the amount of fear intensity in nonconditioned stimuli relative to a perceptually similar conditioned stimulus. Stimuli consisted of graded emotionally expressive faces of the same identity morphed between neutral and fearful endpoints. Two…

  20. Generalization of Conditioned Fear along a Dimension of Increasing Fear Intensity

    ERIC Educational Resources Information Center

    Dunsmoor, Joseph E.; Mitroff, Stephen R.; LaBar, Kevin S.

    2009-01-01

    The present study investigated the extent to which fear generalization in humans is determined by the amount of fear intensity in nonconditioned stimuli relative to a perceptually similar conditioned stimulus. Stimuli consisted of graded emotionally expressive faces of the same identity morphed between neutral and fearful endpoints. Two…

  1. [Mechanisms for regulation of fear conditioning and memory].

    PubMed

    Kida, Satoshi

    2014-11-01

    Pavlovian fear conditioning is a model of fear learning and memory. The mechanisms regulating fear conditioning and memory have been investigated in humans and rodents. In this paradigm, animals learn and memorize an association between a conditioned stimulus (CS), such as context, and an unconditioned stimulus (US), such as an electrical footshock that induces fear. Fear memory generated though fear conditioning is stabilized via a memory consolidation process. Moreover, recent studies have shown the existence of memory processes that control fear memory following the retrieval of consolidated memory. Indeed, when fear memory is retrieved by re-exposure to the CS, the retrieved memory is re-stabilized via the reconsolidation process. On the other hand, the retrieval of fear memory by prolonged re-exposure to the CS also leads to fear memory extinction, new inhibitory learning against the fear memory, in which animals learn that they do not need to respond to the CS. Importantly, the reinforcement of fear memory after retrieval (i.e., re-experience such as flashbacks or nightmares) has been thought to be associated with the development of emotional disorders such as post-traumatic stress disorder (PTSD). In this review, I summarize recent progress in studies on the mechanism of fear conditioning and memory consolidation, reconsolidation and extinction, and furthermore, introduce our recent establishment of a mouse PTSD model that shows enhancement of fear memory after retrieval.

  2. Fear potentiation and fear inhibition in a human fear-potentiated startle paradigm.

    PubMed

    Jovanovic, Tanja; Keyes, Megan; Fiallos, Ana; Myers, Karyn M; Davis, Michael; Duncan, Erica J

    2005-06-15

    The inability to suppress excessive fear or anxiety is a significant clinical problem. In the laboratory, extinction is a preferred method for the study of fear inhibition; however, in this paradigm the same stimulus causes both elicitation (excitation) and inhibition of fear, making it difficult to know whether an experimental manipulation that affects extinction does so by affecting one or both of these processes. For this reason, we sought to develop a behavioral procedure in humans that would render a stimulus primarily inhibitory. We adapted a conditional discrimination procedure (AX+/BX-), previously validated in animals, to a human fear-potentiated startle paradigm. Forty-one healthy volunteers were presented with one set of colored lights paired with the delivery of aversive airblasts to the throat (AX+) and a different series of lights presented without airblasts (BX-). Participants exhibited fear potentiation to AX+, discrimination between AX+ and BX-, and transfer of fear inhibition to A in an AB compound test but not in an AC compound test. We believe this procedure will advance clinical research on fear disorders, such as posttraumatic stress disorder and phobias, by providing an effective and relatively independent measure of fear potentiation and fear inhibition.

  3. 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.

  4. Stressor controllability modulates fear extinction in humans.

    PubMed

    Hartley, Catherine A; Gorun, Alyson; Reddan, Marianne C; Ramirez, Franchesca; Phelps, Elizabeth A

    2014-09-01

    Traumatic events are proposed to play a role in the development of anxiety disorders, however not all individuals exposed to extreme stress experience a pathological increase in fear. Recent studies in animal models suggest that the degree to which one is able to control an aversive experience is a critical factor determining its behavioral consequences. In this study, we examined whether stressor controllability modulates subsequent conditioned fear expression in humans. Participants were randomly assigned to an escapable stressor condition, a yoked inescapable stressor condition, or a control condition involving no stress exposure. One week later, all participants underwent fear conditioning, fear extinction, and a test of extinction retrieval the following day. Participants exposed to inescapable stress showed impaired fear extinction learning and increased fear expression the following day. In contrast, escapable stress improved fear extinction and prevented the spontaneous recovery of fear. Consistent with the bidirectional controllability effects previously reported in animal models, these results suggest that one's degree of control over aversive experiences may be an important factor influencing the development of psychological resilience or vulnerability in humans.

  5. Stressor controllability modulates fear extinction in humans

    PubMed Central

    Hartley, Catherine A.; Gorun, Alyson; Reddan, Marianne C.; Ramirez, Franchesca; Phelps, Elizabeth A.

    2014-01-01

    Traumatic events are proposed to play a role in the development of anxiety disorders, however not all individuals exposed to extreme stress experience a pathological increase in fear. Recent studies in animal models suggest that the degree to which one is able to control an aversive experience is a critical factor determining its behavioral consequences. In this study, we examined whether stressor controllability modulates subsequent conditioned fear expression in humans. Participants were randomly assigned to an escapable stressor condition, a yoked inescapable stressor condition, or a control condition involving no stress exposure. One week later, all participants underwent fear conditioning, fear extinction, and a test of extinction retrieval the following day. Participants exposed to inescapable stress showed impaired fear extinction learning and increased fear expression the following day. In contrast, escapable stress improved fear extinction and prevented the spontaneous recovery of fear. Consistent with the bidirectional controllability effects previously reported in animal models, these results suggest that one's degree of control over aversive experiences may be an important factor influencing the development of psychological resilience or vulnerability in humans. PMID:24333646

  6. Multi-echo EPI of human fear conditioning reveals improved BOLD detection in ventromedial prefrontal cortex.

    PubMed

    Fernandez, Brice; Leuchs, Laura; Sämann, Philipp G; Czisch, Michael; Spoormaker, Victor I

    2017-08-01

    Standard T2(*) weighted functional magnetic resonance imaging (fMRI) performed with echo-planar imaging (EPI) suffers from signal loss in the ventromedial prefrontal cortex (vmPFC) due to macroscopic field inhomogeneity. However, this region is of special interest to affective neuroscience and psychiatry. The Multi-echo EPI (MEPI) approach has several advantages over EPI but its performance against EPI in the vmPFC has not yet been examined in a study with sufficient statistical power using a task specifically eliciting activity in this region. We used a fear conditioning task with MEPI to compare the performance of MEPI and EPI in vmPFC and control regions in 32 healthy young subjects. We analyzed activity associated with short (12ms), standard (29ms) and long (46ms) echo times, and a voxel-wise combination of these three echo times. Behavioral data revealed successful differentiation of the conditioned versus safety stimulus; activity in the vmPFC was shown by the contrast "safety stimulus > conditioned stimulus" as in previous research and proved significantly stronger with the combined MEPI than standard single-echo EPI. Then, we aimed to demonstrate that the additional cluster extent (ventral extension) detected in the vmPFC with MEPI reflects activation in a relevant cluster (i.e., not just non-neuronal noise). To do this, we used resting state data from the same subjects to show that the time-course of this region was both connected to bilateral amygdala and the default mode network. Overall, we demonstrate that MEPI (by means of the weighted sum combination approach) outperforms standard EPI in vmPFC; MEPI performs always at least as good as the best echo time for a given brain region but provides all necessary echo times for an optimal BOLD sensitivity for the whole brain. This is relevant for affective neuroscience and psychiatry given the critical role of the vmPFC in emotion regulation. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Equal pain-Unequal fear response: enhanced susceptibility of tooth pain to fear conditioning.

    PubMed

    Meier, Michael L; de Matos, Nuno M P; Brügger, Mike; Ettlin, Dominik A; Lukic, Nenad; Cheetham, Marcus; Jäncke, Lutz; Lutz, Kai

    2014-01-01

    Experimental fear conditioning in humans is widely used as a model to investigate the neural basis of fear learning and to unravel the pathogenesis of anxiety disorders. It has been observed that fear conditioning depends on stimulus salience and subject vulnerability to fear. It is further known that the prevalence of dental-related fear and phobia is exceedingly high in the population. Dental phobia is unique as no other body part is associated with a specific phobia. Therefore, we hypothesized that painful dental stimuli exhibit an enhanced susceptibility to fear conditioning when comparing to equal perceived stimuli applied to other body sites. Differential susceptibility to pain-related fear was investigated by analyzing responses to an unconditioned stimulus (UCS) applied to the right maxillary canine (UCS-c) vs. the right tibia (UCS-t). For fear conditioning, UCS-c and USC-t consisted of painful electric stimuli, carefully matched at both application sites for equal intensity and quality perception. UCSs were paired to simple geometrical forms which served as conditioned stimuli (CS+). Unpaired CS+ were presented for eliciting and analyzing conditioned fear responses. Outcome parameter were (1) skin conductance changes and (2) time-dependent brain activity (BOLD responses) in fear-related brain regions such as the amygdala, anterior cingulate cortex, insula, thalamus, orbitofrontal cortex, and medial prefrontal cortex. A preferential susceptibility of dental pain to fear conditioning was observed, reflected by heightened skin conductance responses and enhanced time-dependent brain activity (BOLD responses) in the fear network. For the first time, this study demonstrates fear-related neurobiological mechanisms that point toward a superior conditionability of tooth pain. Beside traumatic dental experiences our results offer novel evidence that might explain the high prevalence of dental-related fears in the population.

  8. Limbic areas are functionally decoupled and visual cortex takes a more central role during fear conditioning in humans

    PubMed Central

    Lithari, Chrysa; Moratti, Stephan; Weisz, Nathan

    2016-01-01

    Going beyond the focus on isolated brain regions (e.g. amygdala), recent neuroimaging studies on fear conditioning point to the relevance of a network of mutually interacting brain regions. In the present MEG study we used Graph Theory to uncover changes in the architecture of the brain functional network shaped by fear conditioning. Firstly, induced power analysis revealed differences in local cortical excitability (lower alpha and beta power) between CS+ and CS− localized to somatosensory cortex and insula. What is more striking however is that the graph theoretical measures unveiled a re-organization of brain functional connections, not evident using conventional power analysis. Subcortical fear-related structures exhibited reduced connectivity with temporal and frontal areas rendering the overall brain functional network more sparse during fear conditioning. At the same time, the calcarine took on a more central role in the network. Interestingly, the more the connectivity of limbic areas is reduced, the more central the role of the occipital cortex becomes. We speculated that both, the reduced coupling in some regions and the emerging centrality of others, contribute to the efficient processing of fear-relevant information during fear learning. PMID:27381479

  9. Limbic areas are functionally decoupled and visual cortex takes a more central role during fear conditioning in humans.

    PubMed

    Lithari, Chrysa; Moratti, Stephan; Weisz, Nathan

    2016-07-06

    Going beyond the focus on isolated brain regions (e.g. amygdala), recent neuroimaging studies on fear conditioning point to the relevance of a network of mutually interacting brain regions. In the present MEG study we used Graph Theory to uncover changes in the architecture of the brain functional network shaped by fear conditioning. Firstly, induced power analysis revealed differences in local cortical excitability (lower alpha and beta power) between CS+ and CS- localized to somatosensory cortex and insula. What is more striking however is that the graph theoretical measures unveiled a re-organization of brain functional connections, not evident using conventional power analysis. Subcortical fear-related structures exhibited reduced connectivity with temporal and frontal areas rendering the overall brain functional network more sparse during fear conditioning. At the same time, the calcarine took on a more central role in the network. Interestingly, the more the connectivity of limbic areas is reduced, the more central the role of the occipital cortex becomes. We speculated that both, the reduced coupling in some regions and the emerging centrality of others, contribute to the efficient processing of fear-relevant information during fear learning.

  10. Quantitative proteomics of auditory fear conditioning.

    PubMed

    Hong, Ingie; Kang, Taewook; Yun, Ki Na; Yoo, YongCheol; Park, Sungmo; Kim, Jihye; An, Bobae; Song, Sukwoon; Lee, Sukwon; Kim, Jeongyeon; Song, Beomjong; Kwon, Kyung-Hoon; Kim, Jin Young; Park, Young Mok; Choi, Sukwoo

    2013-04-26

    Auditory fear conditioning is a well-characterized rodent learning model where a neutral auditory cue is paired with an aversive outcome to induce associative fear memory. The storage of long-term auditory fear memory requires long-term potentiation (LTP) in the lateral amygdala and de novo protein synthesis. Although many studies focused on individual proteins have shown their contribution to LTP and fear conditioning, non-biased genome-wide studies have only recently been possible with microarrays, which nevertheless fall short of measuring changes at the level of proteins. Here we employed quantitative proteomics to examine the expression of hundreds of proteins in the lateral amygdala in response to auditory fear conditioning. We found that various proteins previously implicated in LTP, learning and axon/dendrite growth were regulated by fear conditioning. A substantial number of proteins that were regulated by fear conditioning have not yet been studied specifically in learning or synaptic plasticity.

  11. On the Road to Translation for PTSD Treatment: Theoretical and Practical Considerations of the Use of Human Models of Conditioned Fear for Drug Development.

    PubMed

    Risbrough, Victoria B; Glenn, Daniel E; Baker, Dewleen G

    The use of quantitative, laboratory-based measures of threat in humans for proof-of-concept studies and target development for novel drug discovery has grown tremendously in the last 2 decades. In particular, in the field of posttraumatic stress disorder (PTSD), human models of fear conditioning have been critical in shaping our theoretical understanding of fear processes and importantly, validating findings from animal models of the neural substrates and signaling pathways required for these complex processes. Here, we will review the use of laboratory-based measures of fear processes in humans including cued and contextual conditioning, generalization, extinction, reconsolidation, and reinstatement to develop novel drug treatments for PTSD. We will primarily focus on recent advances in using behavioral and physiological measures of fear, discussing their sensitivity as biobehavioral markers of PTSD symptoms, their response to known and novel PTSD treatments, and in the case of d-cycloserine, how well these findings have translated to outcomes in clinical trials. We will highlight some gaps in the literature and needs for future research, discuss benefits and limitations of these outcome measures in designing proof-of-concept trials, and offer practical guidelines on design and interpretation when using these fear models for drug discovery.

  12. A risk variant for alcoholism in the NMDA receptor affects amygdala activity during fear conditioning in humans.

    PubMed

    Cacciaglia, Raffaele; Nees, Frauke; Pohlack, Sebastian T; Ruttorf, Michaela; Winkelmann, Tobias; Witt, Stephanie H; Nieratschker, Vanessa; Rietschel, Marcella; Flor, Herta

    2013-09-01

    People at high risk for alcoholism show deficits in aversive learning, as indicated by impaired electrodermal responses during fear conditioning, a basic form of associative learning that depends on the amygdala. A positive family history of alcohol dependence has also been related to decreased amygdala responses during emotional processing. In the present study we report reduced amygdala activity during the acquisition of conditioned fear in healthy carriers of a risk variant for alcoholism (rs2072450) in the NR2A subunit-containing N-methyl-d-aspartate (NMDA)-receptor. These results indicate that rs2072450 might confer risk for alcohol dependence through deficient fear acquisition indexed by a diminished amygdala response during aversive learning, and provide a neural basis for a weak behavioral inhibition previously documented in individuals at high risk for alcohol dependence. Carriers of the risk variant additionally exhibit dampened insula activation, a finding that further strengthens our data, given the importance of this brain region in fear conditioning. Copyright © 2013 Elsevier B.V. All rights reserved.

  13. Human trace fear conditioning: right-lateralized cortical activity supports trace-interval processes.

    PubMed

    Haritha, Abhishek T; Wood, Kimberly H; Ver Hoef, Lawrence W; Knight, David C

    2013-06-01

    Pavlovian conditioning requires the convergence and simultaneous activation of neural circuitry that supports conditioned stimulus (CS) and unconditioned stimulus (US) processes. However, in trace conditioning, the CS and US are separated by a period of time called the trace interval, and thus do not overlap. Therefore, determining brain regions that support associative learning by maintaining a CS representation during the trace interval is an important issue for conditioning research. Prior functional magnetic resonance imaging (fMRI) research has identified brain regions that support trace-conditioning processes. However, relatively little is known about whether this activity is specific to the trace CS, the trace interval, or both periods of time. The present study was designed to disentangle the hemodynamic response produced by the trace CS from that associated with the trace interval, in order to identify learning-related activation during these distinct components of a trace-conditioning trial. Trace-conditioned activity was observed within dorsomedial prefrontal cortex (PFC), dorsolateral PFC, insula, inferior parietal lobule (IPL), and posterior cingulate (PCC). Each of these regions showed learning-related activity during the trace CS, while trace-interval activity was only observed within a subset of these areas (i.e., dorsomedial PFC, PCC, right dorsolateral PFC, right IPL, right superior/middle temporal gyrus, and bilateral insula). Trace-interval activity was greater in right than in left dorsolateral PFC, IPL, and superior/middle temporal gyrus. These findings indicate that components of the prefrontal, cingulate, insular, and parietal cortices support trace-interval processes, as well as suggesting that a right-lateralized fronto-parietal circuit may play a unique role in trace conditioning.

  14. Sex differences in fear conditioning in posttraumatic stress disorder

    PubMed Central

    Inslicht, Sabra S.; Metzler, Thomas J.; Garcia, Natalia M.; Pineles, Suzanne L.; Milad, Mohammed R.; Orr, Scott P.; Marmar, Charles R.; Neylan, Thomas C.

    2013-01-01

    Background Women are twice as likely as men to develop Posttraumatic Stress Disorder (PTSD). Abnormal acquisition of conditioned fear has been suggested as a mechanism for the development of PTSD. While some studies of healthy humans suggest that women are either no different or express less conditioned fear responses during conditioning relative to men, differences in the acquisition of conditioned fear between men and women diagnosed with PTSD has not been examined. Methods Thirty-one participants (18 men; 13 women) with full or subsyndromal PTSD completed a fear conditioning task. Participants were shown computer-generated colored circles that were paired (CS+) or unpaired (CS−) with an aversive electrical stimulus and skin conductance levels were assessed throughout the task. Results Repeated measures ANOVA indicated a significant sex by stimulus interaction during acquisition. Women had greater differential conditioned skin conductance responses (CS + trials compared to CS− trials) than did men, suggesting greater acquisition of conditioned fear in women with PTSD. Conclusions In contrast to studies of healthy individuals, we found enhanced acquisition of conditioned fear in women with PTSD. Greater fear conditioning in women may either be a pre-existing vulnerability trait or an acquired phenomenon that emerges in a sex-dependent manner after the development of PTSD. Characterizing the underlying mechanisms of these differences is needed to clarify sex-related differences in the pathophysiology of PTSD. PMID:23107307

  15. Valproic acid but not D-cycloserine facilitates sleep-dependent offline learning of extinction and habituation of conditioned fear in humans.

    PubMed

    Kuriyama, Kenichi; Honma, Motoyasu; Yoshiike, Takuya; Kim, Yoshiharu

    2013-01-01

    The effectiveness of D-cycloserine (DCS), an N-methyl-D-aspartate glutamate receptor partial agonist, and valproic acid (VPA), a histone deacetylase inhibitor, in facilitating the extinction of fear-conditioned memory has been explored in humans and animals. Here, we confirmed whether DCS (100 mg) and VPA (400 mg) act in off-line learning processes during sleep or waking, for further clinical application to anxiety disorders and posttraumatic stress disorder (PTSD). We performed a randomized, blind, placebo-controlled clinical trial in 90 healthy adults. Visual cues and electric shocks were used as the conditioned stimulus (CS) and unconditioned stimulus (US), respectively. The extinction effect was observed not in simple recall after the extinction of coupled CS-US, but was observed in the post-re-exposure phase after unexpected re-exposure to reinstatement CS-US coupling. Newly acquired conditioned fear was also eliminated or habituated by DCS and VPA administration, in line with previous findings. Furthermore, VPA facilitated the off-line learning process of conditioned fear extinction and habituation during sleep, while DCS facilitated this process during waking. These novel findings suggest that DCS and VPA might enhance exposure-based cognitive therapy for anxiety disorders and PTSD by reducing the vulnerability to reinstatement and preventing relapses of fear-conditioned responses, and provide evidence for a peculiarity of the sleep-dependent off-line learning process for conditioned fear extinction. This article is part of a Special Issue entitled 'Cognitive Enhancers'. Copyright © 2012 Elsevier Ltd. All rights reserved.

  16. 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

  17. Reinstatement of extinguished fear by an unextinguished conditional stimulus.

    PubMed

    Halladay, Lindsay R; Zelikowsky, Moriel; Blair, Hugh T; Fanselow, Michael S

    2012-01-01

    Anxiety disorders are often treated using extinction-based exposure therapy, but relapse is common and can occur as a result of reinstatement, whereby an aversive "trigger" can reinstate extinguished fear. Animal models of reinstatement commonly utilize a Pavlovian fear conditioning procedure, in which subjects are first trained to fear a conditional stimulus (CS) by pairing it with an aversive unconditional stimulus (US), and then extinguished by repeated presentations of the CS alone. Reinstatement is typically induced by exposing subjects to an aversive US after extinction, but here we show that exposure to a non-extinguished CS can reinstate conditional fear responding to an extinguished CS, a phenomenon we refer to as "conditional reinstatement" (CRI). Rats were trained to fear two CSs (light and tone) and subsequently underwent extinction training to only one CS (counterbalanced). Presenting the unextinguished CS (but not a novel cue) immediately after extinction reinstated conditional fear responding to the extinguished CS in a test session given 24 h later. These findings indicate that reinstatement of extinguished fear can be triggered by exposure to conditional as well as unconditional aversive stimuli, and this may help to explain why relapse is common following clinical extinction therapy in humans. Further study of CRI using animal models may prove useful for developing refined extinction therapies that are more resistant to reinstatement.

  18. Central amygdala activity during fear conditioning.

    PubMed

    Duvarci, Sevil; Popa, Daniela; Paré, Denis

    2011-01-05

    The central amygdala (Ce), particularly its medial sector (CeM), is the main output station of the amygdala for conditioned fear responses. However, there is uncertainty regarding the nature of CeM control over conditioned fear. The present study aimed to clarify this question using unit recordings in rats. Fear conditioning caused most CeM neurons to increase their conditioned stimulus (CS) responsiveness. The next day, CeM cells responded similarly during the recall test, but these responses disappeared as extinction of conditioned fear progressed. In contrast, the CS elicited no significant average change in central lateral (CeL) firing rates during fear conditioning and a small but significant reduction during the recall test. Yet, cell-by-cell analyses disclosed large but heterogeneous CS-evoked responses in CeL. By the end of fear conditioning, roughly equal proportions of CeL cells exhibited excitatory (CeL(+)) or inhibitory (CeL(-)) CS-evoked responses (∼10%). The next day, the proportion of CeL(-) cells tripled with no change in the incidence of CeL(+) cells, suggesting that conditioning leads to overnight synaptic plasticity in an inhibitory input to CeL(-) cells. As in CeM, extinction training caused the disappearance of CS-evoked activity in CeL. Overall, these findings suggest that conditioned freezing depends on increased CeM responses to the CS. The large increase in the incidence of CeL(-) but not CeL(+) cells from conditioning to recall leads us to propose a model of fear conditioning involving the potentiation of an extrinsic inhibitory input (from the amygdala or elsewhere) to CeL, ultimately leading to disinhibition of CeM neurons.

  19. 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

  20. BDNFval66met affects neural activation pattern during fear conditioning and 24 h delayed fear recall

    PubMed Central

    Golkar, Armita; Lindström, Kara M.; Haaker, Jan; Öhman, Arne; Schalling, Martin; Ingvar, Martin

    2015-01-01

    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. PMID:25103087

  1. Influence of the stress hormone cortisol on fear conditioning in humans: evidence for sex differences in the response of the prefrontal cortex.

    PubMed

    Stark, Rudolf; Wolf, Oliver T; Tabbert, Katharina; Kagerer, Sabine; Zimmermann, Mark; Kirsch, Peter; Schienle, Anne; Vaitl, Dieter

    2006-09-01

    The stress hormone cortisol is known to influence declarative memory and associative learning. In animals, stress has often been reported to have opposing effects on memory and learning in males and females. In humans, the effects of cortisol have mainly been studied at the behavioral level. The aim of the present experiment was to characterize the effects of a single cortisol dose (30 mg) on the hemodynamic correlates of fear conditioning. In a double-blind group comparison study subjects (17 females and 17 males) received 30 mg cortisol or placebo orally before participating in a discriminative fear conditioning paradigm. Results revealed that cortisol impaired electrodermal signs of learning (the first interval response) in males, while no conditioned SCRs emerged for the females independent of treatment. fMRI results showed that cortisol reduced activity for the CS+ > CS- comparison in the anterior cingulate, the lateral orbitofrontal cortex and the medial prefrontal cortex in males. Opposite findings (increase in these regions under cortisol) were detected in females. In addition, cortisol reduced the habituation in the CS+ > CS- contrast in the dorsolateral prefrontal cortex independent of sex. Finally, cortisol also modified the response to the electric shock (the UCS) by enhancing the activity of the anterior as well as the posterior cingulate. In sum, these findings demonstrate that in humans cortisol mostly influences prefrontal brain activation during fear conditioning and that these effects appear to be modulated by sex.

  2. Contextual fear conditioning depresses infralimbic excitability.

    PubMed

    Soler-Cedeño, Omar; Cruz, Emmanuel; Criado-Marrero, Marangelie; Porter, James T

    2016-04-01

    Patients with posttraumatic stress disorder (PTSD) show hypo-active ventromedial prefrontal cortices (vmPFC) that correlate with their impaired ability to discriminate between safe and dangerous contexts and cues. Previously, we found that auditory fear conditioning depresses the excitability of neurons populating the homologous structure in rodents, the infralimbic cortex (IL). However, it is undetermined if IL depression was mediated by the cued or contextual information. The objective of this study was to examine whether contextual information was sufficient to depress IL neuronal excitability. After exposing rats to context-alone, pseudoconditioning, or contextual fear conditioning, we used whole-cell current-clamp recordings to examine the excitability of IL neurons in prefrontal brain slices. We found that contextual fear conditioning reduced IL neuronal firing in response to depolarizing current steps. In addition, neurons from contextual fear conditioned animals showed increased slow afterhyperpolarization potentials (sAHPs). Moreover, the observed changes in IL excitability correlated with contextual fear expression, suggesting that IL depression may contribute to the encoding of contextual fear.

  3. Effects of exercise on Pavlovian fear conditioning.

    PubMed

    Baruch, David E; Swain, Rodney A; Helmstetter, Fred J

    2004-10-01

    Exercise promotes multiple changes in hippocampal morphology and should, as a result, alter behavioral function. The present experiment investigated the effect of exercise on learning using contextual and auditory Pavlovian fear conditioning. Rats remained inactive or voluntarily exercised (VX) for 30 days, after which they received auditory-cued fear conditioning. Twenty-four hours later, rats were tested for learning of the contextual and auditory conditional responses. No differences in freezing behavior to the discrete auditory cue were observed during the training or testing sessions. However, VX rats did freeze significantly more compared to controls when tested in the training context 24 hr after exposure to shock. The enhancement of contextual fear conditioning provides further evidence that exercise alters hippocampal function and learning.

  4. Cerebellar role in fear-conditioning consolidation

    PubMed Central

    Sacchetti, Benedetto; Baldi, Elisabetta; Lorenzini, Carlo Ambrogi; Bucherelli, Corrado

    2002-01-01

    Some cerebellar structures are known to be involved in the memorization of several conditioned responses. The role of the interpositus nucleus (IN) and the vermis (VE) in fear-conditioning consolidation was investigated by means of a combined behavioral and neurophysiological technique. The IN and VE were subjected to fully reversible tetrodotoxin (TTX) inactivation during consolidation in adult male Wistar rats that underwent acoustic conditioned stimulus (CS) and context fear training. TTX was injected in different groups of rats at increasing intervals after the acquisition session. Memory was assessed as conditioned freezing duration measured during retention testing, always performed 72 and 96 h after the stereotaxic TTX administration. This schedule ensures that there is no interference with normal cerebellar function during either the acquisition or the retrieval phase so that any amnesic effect may be due only to consolidation disruption. Our results show that IN functional integrity is necessary for acoustic CS fear response memory formation up to the 96-h after-acquisition delay. VE functional integrity was shown to be necessary for memory formation of both context (up to the 96-h after-acquisition delay) and acoustic CS (up to the 192-h after-acquisition delay) fear responses. The present findings help to elucidate the role of the cerebellum in memory consolidation and better define the neural circuits involved in fear memories. PMID:12034877

  5. Auditory trace fear conditioning requires perirhinal cortex

    PubMed Central

    Kholodar-Smith, D.B.; Boguszewski, P.; Brown, T.H.

    2008-01-01

    The hippocampus is well-known to be critical for trace fear conditioning, but nothing is known about the importance of perirhinal cortex (PR), which has reciprocal connections with hippocampus. PR damage severely impairs delay fear conditioning to ultrasonic vocalizations (USVs) and discontinuous tones (pips), but has no effect on delay conditioning to continuous tones (Kholodar-Smith, Allen, and Brown, in press). Here we demonstrate that trace auditory fear conditioning also critically depends on PR function. The trace interval between the CS offset and the US onset was 16 s. Pre-training neurotoxic lesions were produced through multiple injections of N-methyl-D-aspartate along the full length of PR, which was directly visualized during the injections. Control animals received injections with phosphate-buffered saline. Three-dimensional reconstructions of the lesion volumes demonstrated that the neurotoxic damage was well-localized to PR and included most of its anterior-posterior extent. Automated video analysis quantified freezing behavior, which served as the conditional response. PR-damaged rats were profoundly impaired in trace conditioning to either of three different CSs (a USV, tone pips, and a continuous tone) as well as conditioning to the training context. Within both the lesion and control groups, the type of cue had no effect on the mean CR. The overall PR lesion effect size was 2.7 for cue conditioning and 3.9 for context conditioning. We suggest that the role of PR in trace fear conditioning may be distinct from some of its more perceptual functions. The results further define the essential circuitry underlying trace fear conditioning to auditory cues. PMID:18678265

  6. Enhanced Generalization of Auditory Conditioned Fear in Juvenile Mice

    ERIC Educational Resources Information Center

    Ito, Wataru; Pan, Bing-Xing; Yang, Chao; Thakur, Siddarth; Morozov, Alexei

    2009-01-01

    Increased emotionality is a characteristic of human adolescence, but its animal models are limited. Here we report that generalization of auditory conditioned fear between a conditional stimulus (CS+) and a novel auditory stimulus is stronger in 4-5-wk-old mice (juveniles) than in their 9-10-wk-old counterparts (adults), whereas nonassociative…

  7. Enhanced Generalization of Auditory Conditioned Fear in Juvenile Mice

    ERIC Educational Resources Information Center

    Ito, Wataru; Pan, Bing-Xing; Yang, Chao; Thakur, Siddarth; Morozov, Alexei

    2009-01-01

    Increased emotionality is a characteristic of human adolescence, but its animal models are limited. Here we report that generalization of auditory conditioned fear between a conditional stimulus (CS+) and a novel auditory stimulus is stronger in 4-5-wk-old mice (juveniles) than in their 9-10-wk-old counterparts (adults), whereas nonassociative…

  8. The renewal of extinguished conditioned fear with fear-relevant and fear-irrelevant stimuli by a context change after extinction.

    PubMed

    Neumann, David L; Longbottom, Paula L

    2008-02-01

    The acquisition, extinction, and subsequent recovery of conditioned fear can be influenced by the nature of the conditional stimulus (CS) and the context in which the CS is presented. The combined effects of these factors were examined in a differential fear-conditioning procedure with humans. Fear-relevant or fear-irrelevant CSs were followed by a shock unconditional stimulus (US) during acquisition and presented alone during extinction. The CSs were images presented upon different background contexts. Half the participants received the same context during acquisition and extinction and the remaining received different contexts. All participants received test trials in the same context as acquisition. In Experiment 1 (N=64), a renewal of shock expectancy and skin conductance responses was found during test for fear-relevant and fear-irrelevant CSs when extinction was given in a different context. In Experiment 2 (N=72), renewal for fear-relevant stimuli was enhanced when acquisition and test was given in an indoor office context and extinction in an outdoor bush context. The opposite context configuration produced the strongest renewal for fear-irrelevant stimuli. The return of extinguished conditioned fear can occur to fear-relevant stimuli that are commonly associated with clinical fears and its strength may be enhanced when the stimuli are encountered in certain contexts after extinction.

  9. Contextual Fear Extinction Ameliorates Sleep Disturbances Found Following Fear Conditioning in Rats

    PubMed Central

    Wellman, Laurie L.; Yang, Linghui; Tang, Xiangdong; Sanford, Larry D.

    2008-01-01

    Study Objective: To examine the effects of fear extinction on subsequent sleep in rats and to compare it with the effects seen following contextual reminders of fear. Design: Habituation of the rats to handling and baseline recordings were obtained over 2 consecutive days. Afterward, the rats were subjected to shock training (ST; day 1), context reexposure (CR; either 30 or 60 min; day 2), and fear recall (R; day 3). Percentage time spent in freezing (FT%) was observed during ST, CR, and R exposures. Sleep was recorded for 20 h (8-h light and 12-h dark period) following ST, CR, and R. Setting: NA Subjects: The subjects were outbred Wistar rats randomly assigned to one of two groups: contextual fear (FR; n = 7) or contextual extinction (EXT; n = 7). Interventions: The rats were surgically implanted with electrodes for recording the electroencephalogram and electromyogram for determining arousal state. Measurements and Results: There were no differences between groups on FT% during ST or the first 30 min of CR; however, during R, the FR group had greater FT% than EXT. Sleep did not differ between groups following ST. Following CR, EXT exhibited significantly more total sleep, NREM, and REM than FR. After R, there were no differences between groups. Conclusions: Rats that exhibit extinction of contextual fear show significantly increased sleep compared to rats who continue to exhibit contextual fear. This suggests that sleep disturbances normally experienced in humans following traumatic events or reminders may be ameliorated by therapies that address and eliminate the associated fear. Citation: Wellman LL; Yang L; Tang X; Sanford LD. Contextual fear extinction ameliorates sleep disturbances found following fear conditioning in rats. SLEEP 2008;31(7):1035-1042. PMID:18652099

  10. Early Extinction after Fear Conditioning Yields a Context-Independent and Short-Term Suppression of Conditional Freezing in Rats

    ERIC Educational Resources Information Center

    Chang, Chun-hui; Maren, Stephen

    2009-01-01

    Extinction of Pavlovian fear conditioning in rats is a useful model for therapeutic interventions in humans with anxiety disorders. Recently, we found that delivering extinction trials soon (15 min) after fear conditioning yields a short-term suppression of fear, but little long-term extinction. Here, we explored the possible mechanisms underlying…

  11. Early Extinction after Fear Conditioning Yields a Context-Independent and Short-Term Suppression of Conditional Freezing in Rats

    ERIC Educational Resources Information Center

    Chang, Chun-hui; Maren, Stephen

    2009-01-01

    Extinction of Pavlovian fear conditioning in rats is a useful model for therapeutic interventions in humans with anxiety disorders. Recently, we found that delivering extinction trials soon (15 min) after fear conditioning yields a short-term suppression of fear, but little long-term extinction. Here, we explored the possible mechanisms underlying…

  12. 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

  13. Passive avoidance is linked to impaired fear extinction in humans.

    PubMed

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

    2013-02-20

    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.

  14. Contextual fear conditioning induces differential alternative splicing.

    PubMed

    Poplawski, Shane G; Peixoto, Lucia; Porcari, Giulia S; Wimmer, Mathieu E; McNally, Anna G; Mizuno, Keiko; Giese, K Peter; Chatterjee, Snehajyoti; Koberstein, John N; Risso, Davide; Speed, Terence P; Abel, Ted

    2016-10-01

    The process of memory consolidation requires transcription and translation to form long-term memories. Significant effort has been dedicated to understanding changes in hippocampal gene expression after contextual fear conditioning. However, alternative splicing by differential transcript regulation during this time period has received less attention. Here, we use RNA-seq to determine exon-level changes in expression after contextual fear conditioning and retrieval. Our work reveals that a short variant of Homer1, Ania-3, is regulated by contextual fear conditioning. The ribosome biogenesis regulator Las1l, small nucleolar RNA Snord14e, and the RNA-binding protein Rbm3 also change specific transcript usage after fear conditioning. The changes in Ania-3 and Las1l are specific to either the new context or the context-shock association, while the changes in Rbm3 occur after context or shock only. Our analysis revealed novel transcript regulation of previously undetected changes after learning, revealing the importance of high throughput sequencing approaches in the study of gene expression changes after learning. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. 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

  16. Improvement of memory recall by quercetin in rodent contextual fear conditioning and human early-stage Alzheimer's disease patients.

    PubMed

    Nakagawa, Toshiyuki; Itoh, Masanori; Ohta, Kazunori; Hayashi, Yuichi; Hayakawa, Miki; Yamada, Yasushi; Akanabe, Hiroshi; Chikaishi, Tokio; Nakagawa, Kiyomi; Itoh, Yoshinori; Muro, Takato; Yanagida, Daisuke; Nakabayashi, Ryo; Mori, Tetsuya; Saito, Kazuki; Ohzawa, Kaori; Suzuki, Chihiro; Li, Shimo; Ueda, Masashi; Wang, Miao-Xing; Nishida, Emika; Islam, Saiful; Tana; Kobori, Masuko; Inuzuka, Takashi

    2016-06-15

    Patients with Alzheimer's disease (AD) experience a wide array of cognitive deficits, which typically include the impairment of explicit memory. In previous studies, the authors reported that a flavonoid, quercetin, reduces the expression of ATF4 and delays memory deterioration in an early-stage AD mouse model. In the present study, the effects of long-term quercetin intake on memory recall were assessed using contextual fear conditioning in aged wild-type mice. In addition, the present study examined whether memory recall was affected by the intake of quercetin-rich onion (a new cultivar of hybrid onion 'Quergold') powder in early-stage AD patients. In-vivo analysis indicated that memory recall was enhanced in aged mice fed a quercetin-containing diet. Memory recall in early-stage AD patients, determined using the Revised Hasegawa Dementia Scale, was significantly improved by the intake of quercetin-rich onion (Quergold) powder for 4 weeks compared with the intake of control onion ('Mashiro' white onion) powder. These results indicate that quercetin might influence memory recall.

  17. Young and old Pavlovian fear memories can be modified with extinction training during reconsolidation in humans

    PubMed Central

    Steinfurth, Elisa C.K.; Kanen, Jonathan W.; Raio, Candace M.; Clem, Roger L.; Huganir, Richard L.; Phelps, Elizabeth A.

    2014-01-01

    Extinction training during reconsolidation has been shown to persistently diminish conditioned fear responses across species. We investigated in humans if older fear memories can benefit similarly. Using a Pavlovian fear conditioning paradigm we compared standard extinction and extinction after memory reactivation 1 d or 7 d following acquisition. Participants who underwent extinction during reconsolidation showed no evidence of fear recovery, whereas fear responses returned in participants who underwent standard extinction. We observed this effect in young and old fear memories. Extending the beneficial use of reconsolidation to older fear memories in humans is promising for therapeutic applications. PMID:24934333

  18. Conditioned Fear Acquisition and Generalization in Generalized Anxiety Disorder.

    PubMed

    Tinoco-González, Daniella; Fullana, Miquel Angel; Torrents-Rodas, David; Bonillo, Albert; Vervliet, Bram; Blasco, María Jesús; Farré, Magí; Torrubia, Rafael

    2015-09-01

    Abnormal fear conditioning processes (including fear acquisition and conditioned fear-generalization) have been implicated in the pathogenesis of anxiety disorders. Previous research has shown that individuals with panic disorder present enhanced conditioned fear-generalization in comparison to healthy controls. Enhanced conditioned fear-generalization could also characterize generalized anxiety disorder (GAD), but research so far is inconclusive. An important confounding factor in previous research is comorbidity. The present study examined conditioned fear-acquisition and fear-generalization in 28 patients with GAD and 30 healthy controls using a recently developed fear acquisition and generalization paradigm assessing fear-potentiated startle and online expectancies of the unconditioned stimulus. Analyses focused on GAD patients without comorbidity but included also patients with comorbid anxiety disorders. Patients and controls did not differ as regards fear acquisition. However, contrary to our hypothesis, both groups did not differ either in most indexes of conditioned fear-generalization. Moreover, dimensional measures of GAD symptoms were not correlated with conditioned fear-generalization indexes. Comorbidity did not have a significant impact on the results. Our data suggest that conditioned fear-generalization is not enhanced in GAD. Results are discussed with special attention to the possible effects of comorbidity on fear learning abnormalities.

  19. The genetic covariation between fear conditioning and self-report fears.

    PubMed

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

    2008-03-15

    Fear conditioning is a traditional model for the acquisition of phobias, whereas behavioral therapies use processes underlying extinction to treat phobic and other anxiety disorders. Furthermore, fear conditioning has been proposed as an endophenotype for genetic studies of anxiety disorders. Although prior studies have demonstrated that fear conditioning and self-report fears are heritable, no studies have determined whether they share a common genetic basis. We obtained fear conditioning data from 173 twin pairs from the Swedish Twin Registry who also provided self-report ratings of 16 common fears. With multivariate structural equation modeling, we analyzed factor-derived scores for the subjective fear ratings together with the electrophysiologic skin conductance responses during habituation, acquisition, and extinction to determine the extent of their genetic covariation. Phenotypic correlations between experimental and self-report fear measures were modest and, counter-intuitively, negative (i.e., subjects who reported themselves as more fearful had smaller electrophysiologic responses). Best-fit models estimated a significant (negative) genetic correlation between them, although genetic factors underlying fear conditioning accounted for only 9% of individual differences in self-report fears. Experimentally derived fear conditioning measures share only a small portion of the genetic factors underlying individual differences in subjective fears, cautioning against relying too heavily on the former as an endophenotype for genetic studies of phobic disorders.

  20. The Genetic Covariation between Fear Conditioning and Self-Report Fears

    PubMed Central

    Hettema, John M.; Annas, Peter; Neale, Michael C.; Fredrikson, Mats; Sci, Dr Med; Kendler, Kenneth S.

    2008-01-01

    Background Fear conditioning is a traditional model for the acquisition of phobias, while behavioral therapies utilize processes underlying extinction to treat phobic and other anxiety disorders. Furthermore, fear conditioning has been proposed as an endophenotype for genetic studies of anxiety disorders. While prior studies have demonstrated that fear conditioning and self-report fears are heritable, no studies have determined whether they share a common genetic basis. Methods We obtained fear conditioning data from 173 twin pairs from the Swedish Twin Registry who also provided self-report ratings of 16 common fears. Using multivariate structural equation modeling, we analyzed factor-derived scores for the subjective fear ratings together with the electrophysiologic skin conductance responses during habituation, acquisition, and extinction to determine the extent of their genetic covariation. Results Phenotypic correlations between experimental and self-report fear measures were modest and, and counter-intuitively, negative; that is, subjects who reported themselves as more fearful had smaller electrophysiologic responses. Best-fit models estimated a significant (negative) genetic correlation between them, although genetic factors underlying fear conditioning accounted for only 9% of individual differences in self-report fears. Conclusions Experimentally-derived fear conditioning measures share only a small portion of the genetic factors underlying individual differences in subjective fears, cautioning against relying too heavily on the former as an endophenotype for genetic studies of phobic disorders. PMID:17698042

  1. Extinction during reconsolidation eliminates recovery of fear conditioned to fear-irrelevant and fear-relevant stimuli.

    PubMed

    Thompson, Alina; Lipp, Ottmar V

    2017-05-01

    Extant literature suggests that extinction training delivered during the memory reconsolidation period is superior to traditional extinction training in the reduction of fear recovery, as it targets the original fear memory trace. At present it is debated whether different types of fear memories are differentially sensitive to behavioral manipulations of reconsolidation. Here, we examined post-reconsolidation recovery of fear as a function of conditioned stimulus (CS) fear-relevance, using the unconditioned stimulus (US) to reactivate and destabilize conditioned fear memories. Participants (N = 56; 25 male; M = 24.39 years, SD = 7.71) in the US-reactivation and control group underwent differential fear conditioning to fear-relevant (spiders/snakes) and fear-irrelevant (geometric shapes) CSs on Day 1. On Day 2, participants received either reminded (US-reactivation) or non-reminded extinction training. Tests of fear recovery, conducted 24 h later, revealed recovery of differential electrodermal responding to both classes of CSs in the control group, but not in the US-reactivation group. These findings indicate that the US reactivation-extinction procedure eliminated recovery of extinguished responding not only to fear-irrelevant, but also to fear-relevant CSs. Contrasting previous reports, our findings show that post-reconsolidation recovery of conditioned responding is not a function of CS fear-relevance and that persistent reduction of fear, conditioned to fear-relevant CSs, can be achieved through behavioral manipulations of reconsolidation. Copyright © 2017 Elsevier Ltd. All rights reserved.

  2. Sleep Deprivation Selectively Impairs Memory Consolidation for Contextual Fear Conditioning

    PubMed Central

    Graves, Laurel A.; Heller, Elizabeth A.; Pack, Allan I.; Abel, Ted

    2003-01-01

    Many behavioral and electrophysiological studies in animals and humans have suggested that sleep and circadian rhythms influence memory consolidation. In rodents, hippocampus-dependent memory may be particularly sensitive to sleep deprivation after training, as spatial memory in the Morris water maze is impaired by rapid eye movement sleep deprivation following training. Spatial learning in the Morris water maze, however, requires multiple training trials and performance, as measured by time to reach the hidden platform is influenced by not only spatial learning but also procedural learning. To determine if sleep is important for the consolidation of a single-trial, hippocampus-dependent task, we sleep deprived animals for 0–5 and 5–10 h after training for contextual and cued fear conditioning. We found that sleep deprivation from 0–5 h after training for this task impaired memory consolidation for contextual fear conditioning whereas sleep deprivation from 5–10 h after training had no effect. Sleep deprivation at either time point had no effect on cued fear conditioning, a hippocampus-independent task. Previous studies have determined that memory consolidation for fear conditioning is impaired when protein kinase A and protein synthesis inhibitors are administered at the same time as when sleep deprivation is effective, suggesting that sleep deprivation may act by modifying these molecular mechanisms of memory storage. PMID:12773581

  3. Hippocampal Structural Plasticity Accompanies the Resulting Contextual Fear Memory Following Stress and Fear Conditioning

    ERIC Educational Resources Information Center

    Giachero, Marcelo; Calfa, Gaston D.; Molina, Victor A.

    2013-01-01

    The present research investigated the resulting contextual fear memory and structural plasticity changes in the dorsal hippocampus (DH) following stress and fear conditioning. This combination enhanced fear retention and increased the number of total and mature dendritic spines in DH. Intra-basolateral amygdala (BLA) infusion of midazolam prior to…

  4. Hippocampal Structural Plasticity Accompanies the Resulting Contextual Fear Memory Following Stress and Fear Conditioning

    ERIC Educational Resources Information Center

    Giachero, Marcelo; Calfa, Gaston D.; Molina, Victor A.

    2013-01-01

    The present research investigated the resulting contextual fear memory and structural plasticity changes in the dorsal hippocampus (DH) following stress and fear conditioning. This combination enhanced fear retention and increased the number of total and mature dendritic spines in DH. Intra-basolateral amygdala (BLA) infusion of midazolam prior to…

  5. 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.

  6. Perceiving Threat In the Face of Safety: Excitation and Inhibition of Conditioned Fear in Human Visual Cortex

    PubMed Central

    2013-01-01

    Previous findings have established that cortical sensory systems exhibit experience-dependent biases toward stimuli consistently associated with threat. It remains unclear whether safety cues also facilitate perceptual engagement or how competition between learned threat and safety cues is resolved within visual cortex. Here, we used classical discrimination conditioning with simple luminance modulated visual stimuli that predicted the presence or absence of an aversive sound to examine visuocortical competition between features signaling threat versus safety. We tracked steady-state visual evoked potentials to label distinct visual cortical responses in humans to conditioned and control stimuli. Trial-by-trial expectancy ratings collected online confirmed that participants discriminated between threat and safety cues. Conditioning was associated with heightened activation of the extended visual cortex in response to the threat, but not the safety, stimulus. Cortical facilitation for the threatening stimulus was selective and not decreased by simultaneously presenting safe and associatively novel cues. Our findings shed light on the sensory brain dynamics associated with experience-dependent acquisition of perceptual biases for danger and safety signals. PMID:23283323

  7. The relationship between fear of falling and human postural control.

    PubMed

    Davis, Justin R; Campbell, Adam D; Adkin, Allan L; Carpenter, Mark G

    2009-02-01

    This study was designed to improve the understanding of how standing at elevated surface heights and the associated changes in the visual field affect human balance control. Healthy young adults stood at four different surface heights (ground, 0.8, 1.6 and 3.2 m) under three different visual conditions (eyes open, eyes closed and eyes open with peripheral vision occluded). Mean position, Mean Power Frequency (MPF) and Root Mean Square (RMS) of centre of pressure (COP) displacements were calculated from 60s standing trials, and psychosocial and physiological measures of fear and anxiety were also collected. When standing at a height of 3.2 m, 10 of 36 participants reported an increase in anxiety and a robust fear response while the remaining 26 participants experienced only an increase in anxiety and no fear response. A between subjects analysis of the effect of surface height on postural control revealed that fearful and non-fearful participants adopted different postural control strategies with increased heights. Non-fearful participants demonstrated a postural response characterized by increased MPF and decreased RMS of COP displacements with increasing heights. In contrast, fearful participants demonstrated both increasing MPF and RMS of COP displacements with increasing heights. These findings demonstrate, for the first time, a direct relationship between fear of falling and the strategies used for human postural control.

  8. Magnesium deficiency impairs fear conditioning in mice.

    PubMed

    Bardgett, Mark E; Schultheis, Patrick J; McGill, Diana L; Richmond, Raymond E; Wagge, Jordan R

    2005-03-15

    Magnesium (Mg2+) is one of the most abundant cations found in the body. In the central nervous system, Mg2+ plays an important role in the function of N-methyl-D-aspartate (NMDA)-type glutamate receptors, which are centrally involved in memory processing. Despite the relatively large concentration of Mg2+ in the CNS, little is known about the behavioral consequences of Mg2+ deficiency. The purpose of this study was to address this issue by assessing fear conditioning and related behaviors in mice maintained on normal or Mg(2+)-deficient diets. Young adult male C57Bl/6J mice were placed on a control or Mg(2+)-deficient diet, and testing was conducted between 10 and 21 days later. Magnesium-deficient mice exhibited impairments in contextual and cued fear conditioning. These impairments could not be attributed to changes in locomotor activity, exploration, or pain sensitivity. Furthermore, Mg(2+)-deficient mice were more sensitive to the convulsant effects of a peripheral injection of NMDA (100 mg/kg, IP). The results suggest that magnesium deficiency can lead to specific impairments in emotional memory. Such impairments may be related to hypersensitivity of NMDA-type glutamate receptors in Mg(2+)-deficient mice.

  9. Asymmetrical Stimulus Generalization following Differential Fear Conditioning

    PubMed Central

    Bang, Sun Jung; Allen, Timothy A.; Jones, Lauren K.; Boguszewski, Pawel; Brown, Thomas H.

    2008-01-01

    Rodent ultrasonic vocalizations (USVs) are ethologically critical social signals. Rats emit 22 kHz USVs and 50 kHz USVs, respectively, in conjunction with negative and positive affective states. Little is known about what controls emotional reactivity to these social signals. Using male Sprague-Dawley rats, we examined unconditional and conditional freezing behavior in response to the following auditory stimuli: three 22 kHz USVs, a discontinuous tone whose frequency and on-off pattern matched one of the USVs, a continuous tone with the same or lower frequencies, a 4 kHz discontinuous tone with an on-off pattern matched to one of the USVs, and a 50 kHz USV. There were no differences among these stimuli in terms of the unconditional elicitation of freezing behavior. Thus, the stimuli were equally neutral before conditioning. During differential fear conditioning, one of these stimuli (the CS+) always co-terminated with a footshock unconditional stimulus (US) and another stimulus (the CS−) was explicitly unpaired with the US. There were no significant differences among these cues in CS+-elicited freezing behavior. Thus, the stimuli were equally salient or effective as cues in supporting fear conditioning. When the CS+ was a 22 kHz USV or a similar stimulus, rats discriminated based on the principal frequency and/or the temporal pattern of the stimulus. However, when these same stimuli served as the CS−, discrimination failed due to generalization from the CS+. Thus, the stimuli differed markedly in the specificity of conditioning. This strikingly asymmetrical stimulus generalization is a novel bias in discrimination. PMID:18434217

  10. Asymmetrical stimulus generalization following differential fear conditioning.

    PubMed

    Bang, Sun Jung; Allen, Timothy A; Jones, Lauren K; Boguszewski, Pawel; Brown, Thomas H

    2008-07-01

    Rodent ultrasonic vocalizations (USVs) are ethologically critical social signals. Rats emit 22kHz USVs and 50kHz USVs, respectively, in conjunction with negative and positive affective states. Little is known about what controls emotional reactivity to these social signals. Using male Sprague-Dawley rats, we examined unconditional and conditional freezing behavior in response to the following auditory stimuli: three 22kHz USVs, a discontinuous tone whose frequency and on-off pattern matched one of the USVs, a continuous tone with the same or lower frequencies, a 4kHz discontinuous tone with an on-off pattern matched to one of the USVs, and a 50kHz USV. There were no differences among these stimuli in terms of the unconditional elicitation of freezing behavior. Thus, the stimuli were equally neutral before conditioning. During differential fear conditioning, one of these stimuli (the CS(+)) always co-terminated with a footshock unconditional stimulus (US) and another stimulus (the CS(-)) was explicitly unpaired with the US. There were no significant differences among these cues in CS(+)-elicited freezing behavior. Thus, the stimuli were equally salient or effective as cues in supporting fear conditioning. When the CS(+) was a 22kHz USV or a similar stimulus, rats discriminated based on the principal frequency and/or the temporal pattern of the stimulus. However, when these same stimuli served as the CS(-), discrimination failed due to generalization from the CS(+). Thus, the stimuli differed markedly in the specificity of conditioning. This strikingly asymmetrical stimulus generalization is a novel bias in discrimination.

  11. Renewal of conditioned fear in a novel context is associated with hippocampal activation and connectivity

    PubMed Central

    Stark, R.; Milad, M. R.; Merz, C. J.

    2016-01-01

    Return of fear is a serious problem in exposure-based treatments of anxiety disorders. Renewal of the fear response may occur when re-encountering the conditioned stimulus within a novel context. Findings in rodents underpin the hippocampus’ role in conditioned fear renewal in novel contexts, but it has yet to be investigated in humans. Forty-six healthy men took part in a 2-day, context-dependent, cued fear conditioning paradigm with fear acquisition, extinction learning (day 1) and extinction recall in the acquisition, extinction and a novel context one day later. Conditioned evaluative, skin conductance responses (SCRs) and blood-oxygen-level-dependent responses served as dependent variables. Context-dependent fear renewal was reflected in stronger conditioned SCRs. In the acquisition context, individuals with a higher renewal of conditioned SCRs showed stronger activation of the fear circuit. Hippocampal activation distinguished conditioned responding in the novel compared with the extinction context. Individuals with a stronger renewal of conditioned SCRs in the novel context showed increased effective connectivity of hippocampal activation foci with structures in the fear and extinction network. These results outline the pivotal role of the hippocampus and its connectivity in conditioned fear renewal in a novel context in humans and might have important implications for exposure therapy in anxiety disorders. PMID:27053767

  12. Prior chronic nicotine impairs cued fear extinction but enhances contextual fear conditioning in rats.

    PubMed

    Tian, S; Gao, J; Han, L; Fu, J; Li, C; Li, Z

    2008-06-02

    Clinical observations have shown a link for the high comorbid rate between smoking and psychiatric disorders, including anxiety disorders. However, little is known about the neural mechanism underlying the progression from nicotine dependence to an anxiety disorder. A deficit in fear extinction in general is considered to contribute to anxiety disorders. The aim of the present study is to investigate the effects of chronic nicotine on fear extinction in rats. Rats were administrated s.c. nicotine twice per day for 14 days. Two weeks after the last injection rats received a cued or contextual fear conditioning session. Twenty-four hours and 48 h after conditioning, rats received an extinction training session and an extinction test session, respectively. Percent freezing was assessed during all phases of training. In the cued task, prior chronic nicotine did not affect the acquisition of fear response or the within-session fear extinction, but impaired the between-session fear extinction. In the contextual task, the same nicotine treatment schedule did not affect the acquisition of fear response or the within- and between-session fear extinction, but enhanced the retention of fear conditioning. This prior chronic nicotine-induced deficit in cued fear extinction and/or enhanced fear to context may be one of the critical components that contribute to the progression from nicotine dependence to an anxiety disorder.

  13. Fear conditioning and extinction in anxious and nonanxious youth and adults: examining a novel developmentally appropriate fear-conditioning task.

    PubMed

    Shechner, Tomer; Britton, Jennifer C; Ronkin, Emily G; Jarcho, Johanna M; Mash, Jamie A; Michalska, Kalina J; Leibenluft, Ellen; Pine, Daniel S

    2015-04-01

    Fear conditioning and extinction have been implicated in the pathogenesis of anxiety disorders. However, due to ethical and methodological limitations, few studies have examined these learning processes across development, particularly among anxious individuals. The present study examined differences in fear conditioning and extinction in anxious and nonanxious youth and adults using a novel task designed to be more tolerable for children than existing paradigms. Twenty-two anxious adults, 15 anxious youth, 30 healthy adults, and 17 healthy youth completed two discriminative fear-conditioning tasks. A well-validated task paired a woman's fearful face with a scream as the unconditioned stimulus. The novel task paired a bell with an aversive alarm as the unconditioned stimulus. Self-reported fear, skin conductance response, and fear-potentiated startle eye blink were measured. Both tasks were well tolerated and elicited fear responses with moderate stability. Anxious youth and adults reported overall greater fear than healthy participants during the tasks, although no group differences occurred in discriminative fear conditioning or extinction, as assessed by self-report or physiology. The novel bell-conditioning task is potent in eliciting fear responses but tolerable for pediatric and anxious populations. Our findings are consistent with prior studies that have shown comparable fear learning processes in anxious and nonanxious youth, but dissimilar from studies exhibiting between-group differences in extinction. Given the limited research on fear conditioning in youth, methodological issues and suggestions for future work are discussed. © 2014 Wiley Periodicals, Inc.

  14. Young and Old Pavlovian Fear Memories Can Be Modified with Extinction Training during Reconsolidation in Humans

    ERIC Educational Resources Information Center

    Steinfurth, Elisa C. K.; Kanen, Jonathan W.; Raio, Candace M.; Clem, Roger L.; Huganir, Richard L.; Phelps, Elizabeth A.

    2014-01-01

    Extinction training during reconsolidation has been shown to persistently diminish conditioned fear responses across species. We investigated in humans if older fear memories can benefit similarly. Using a Pavlovian fear conditioning paradigm we compared standard extinction and extinction after memory reactivation 1 d or 7 d following acquisition.…

  15. Young and Old Pavlovian Fear Memories Can Be Modified with Extinction Training during Reconsolidation in Humans

    ERIC Educational Resources Information Center

    Steinfurth, Elisa C. K.; Kanen, Jonathan W.; Raio, Candace M.; Clem, Roger L.; Huganir, Richard L.; Phelps, Elizabeth A.

    2014-01-01

    Extinction training during reconsolidation has been shown to persistently diminish conditioned fear responses across species. We investigated in humans if older fear memories can benefit similarly. Using a Pavlovian fear conditioning paradigm we compared standard extinction and extinction after memory reactivation 1 d or 7 d following acquisition.…

  16. Role of Sleep Deprivation in Fear Conditioning and Extinction: Implications for Treatment of PTSD

    DTIC Science & Technology

    2014-10-01

    Annual 3. DATES COVERED (From - To) 4. TITLE AND SUBTITLE Role of Sleep Deprivation in Fear Conditioning and Extinction: Implications for...the mechanism underlying the most successful treatment for PTSD, Prolonged Exposure. In animal models, sleep deprivation has been shown to impair...acquisition, consolidation, and generalization of extinction memory in humans. 15. SUBJECT TERMS PTSD, sleep deprivation , fear conditioning

  17. Fear memory formation can affect a different memory: fear conditioning affects the extinction, but not retrieval, of conditioned taste aversion (CTA) memory

    PubMed Central

    Joels, Gil; Lamprecht, Raphael

    2014-01-01

    The formation of fear memory to a specific stimulus leads to subsequent fearful response to that stimulus. However, it is not apparent whether the formation of fear memory can affect other memories. We study whether specific fearful experience leading to fear memory affects different memories formation and extinction. We revealed that cued fear conditioning, but not unpaired or naïve training, inhibited the extinction of conditioned taste aversion (CTA) memory that was formed after fear conditioning training in rats. Fear conditioning had no effect on retrieval of CTA memory but specifically impaired its extinction. Extinguished fear memory, after fear extinction training, had no effect on future CTA memory extinction. Fear conditioning had no effect on CTA memory extinction if CTA memory was formed before fear conditioning. Conditioned taste aversion had no effect on fear conditioning memory extinction. We conclude that active cued fear conditioning memory can affect specifically the extinction, but not the formation, of future different memory. PMID:25324744

  18. Assessing fear learning via conditioned respiratory amplitude responses.

    PubMed

    Castegnetti, Giuseppe; Tzovara, Athina; Staib, Matthias; Gerster, Samuel; Bach, Dominik R

    2017-02-01

    Respiratory physiology is influenced by cognitive processes. It has been suggested that some cognitive states may be inferred from respiration amplitude responses (RAR) after external events. Here, we investigate whether RAR allow assessment of fear memory in cued fear conditioning, an experimental model of aversive learning. To this end, we built on a previously developed psychophysiological model (PsPM) of RAR, which regards interpolated RAR time series as the output of a linear time invariant system. We first establish that average RAR after CS+ and CS- are different. We then develop the response function of fear-conditioned RAR, to be used in our PsPM. This PsPM is inverted to yield estimates of cognitive input into the respiratory system. We analyze five validation experiments involving fear acquisition and retention, delay and trace conditioning, short and medium CS-US intervals, and data acquired with bellows and MRI-compatible pressure chest belts. In all experiments, CS+ and CS- are distinguished by their estimated cognitive inputs, and the sensitivity of this distinction is higher for model-based estimates than for peak scoring of RAR. Comparing these data with skin conductance responses (SCR) and heart period responses (HPR), we find that, on average, RAR performs similar to SCR in distinguishing CS+ and CS-, but is less sensitive than HPR. Overall, our work provides a novel and robust tool to investigate fear memory in humans that may allow wide and straightforward application to diverse experimental contexts. © 2016 The Authors. Psychophysiology published by Wiley Periodicals, Inc. on behalf of Society for Psychophysiological Research.

  19. Rapid Remission of Conditioned Fear Expression with Extinction Training Paired with Vagus Nerve Stimulation

    PubMed Central

    Peña, David F.; Engineer, Navzer D.; McIntyre, Christa K.

    2012-01-01

    Background Fearful experiences can produce long-lasting and debilitating memories. Extinction of conditioned fear requires consolidation of new memories that compete with fearful associations. In human subjects, as well as rats, posttraining stimulation of the vagus nerve enhances memory consolidation. Subjects with posttraumatic stress disorder (PTSD) show impaired extinction of conditioned fear. The objective of this study was to determine whether vagus nerve stimulation (VNS) can enhance the consolidation of extinction of conditioned fear. Methods Male Sprague-Dawley rats were trained on an auditory fear conditioning task followed by 1–10 days of extinction training. Treatment with vagus nerve or sham stimulation was administered concurrently with exposure to the fear conditioned stimulus. Another group was given VNS and extinction training but the VNS was not paired with exposure to conditioned cues. Retention of fear conditioning was tested 24 hours after each treatment. Results VNS paired with exposure to conditioned cues enhanced the extinction of conditioned fear. After a single extinction trial, rats given VNS stimulation demonstrated a significantly lower level of freezing, compared to that of sham controls. When extinction trials were extended to 10 days, paired VNS accelerated extinction of the conditioned response. Conclusions Extinction paired with VNS is more rapid than extinction paired with sham stimulation. As it is currently approved by the Federal Food and Drug Administration for depression and seizure prevention, VNS is a readily-available and promising adjunct to exposure therapy for the treatment of severe anxiety disorders. PMID:23245749

  20. 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

  1. 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

    2017-02-15

    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.Neuropsychopharmacology advance online publication, 15 February 2017; doi:10.1038/npp.2017.17.

  2. Predicting aversive events and terminating fear in the mouse anterior cingulate cortex during trace fear conditioning.

    PubMed

    Steenland, Hendrik W; Li, Xiang-Yao; Zhuo, Min

    2012-01-18

    A variety of studies have implicated the anterior cingulate cortex (ACC) in fear, including permanent storage of fear memory. Recent pharmacological and genetic studies indicate that early synaptic plasticity in the ACC may also contribute to certain forms of fear memory at early time points. However, no study has directly examined the possible changes in neuronal activity of ACC neurons in freely behaving mice during early learning. In the present study, we examined the neural responses of the ACC during trace fear conditioning. We found that ACC putative pyramidal and nonpyramidal neurons were involved in the termination of fear behavior ("un-freezing"), and the spike activity of these neurons was reduced during freezing. Some of the neurons were also found to acquire un-freezing locked activity and change their tuning. The results implicate the ACC neurons in fear learning and controlling the abolition of fear behavior. We also show that the ACC is important for making cue-related fear memory associations in the trace fear paradigm as measured with tone-evoked potentials and single-unit activity. Collectively, our findings indicate that the ACC is involved in predicting future aversive events and terminating fear during trace fear.

  3. Fear, Faces, and the Human Amygdala

    PubMed Central

    Adolphs, Ralph

    2008-01-01

    Summary The amygdala’s historical role in processing stimuli related to threat and fear is being modified to suggest a role that is broader and more abstract. Amygdala lesions impair the ability to seek out and make use of the eye region of faces, resulting in impaired fear perception. Other studies in rats and humans revive earlier proposals that the amygdala is important not for fear perception as such, but for detecting saliency and biological relevance. Debates about some features of this processing now suggest that while the amygdala can process fearful facial expressions in the absence of conscious perception, and while there is some degree of pre-attentive processing, this depends on context and is not necessarily more rapid than cortical processing routes. A large current research effort extends the amygdala’s putative role to a number of psychiatric illnesses. PMID:18655833

  4. The Genetic Absence Epilepsy Rats from Strasbourg model of absence epilepsy exhibits alterations in fear conditioning and latent inhibition consistent with psychiatric comorbidities in humans.

    PubMed

    Marks, Wendie N; Cavanagh, Mary E; Greba, Quentin; Cain, Stuart M; Snutch, Terrance P; Howland, John G

    2016-01-01

    Behavioural, neurological, and genetic similarities exist in epilepsies, their psychiatric comorbidities, and various psychiatric illnesses, suggesting common aetiological factors. Rodent models of epilepsy are used to characterize the comorbid symptoms apparent in epilepsy and their neurobiological mechanisms. The present study was designed to assess Pavlovian fear conditioning and latent inhibition in a polygenetic rat model of absence epilepsy, i.e. Genetic Absence Epilepsy Rats from Strasbourg (GAERS) and the non-epileptic control (NEC) strain. Electrophysiological recordings confirmed the presence of spike-wave discharges in young adult GAERS but not NEC rats. A series of behavioural tests designed to assess anxiety-like behaviour (elevated plus maze, open field, acoustic startle response) and cognition (Pavlovian conditioning and latent inhibition) was subsequently conducted on male and female offspring. Results showed that GAERS exhibited significantly higher anxiety-like behaviour, a characteristic reported previously. In addition, using two protocols that differed in shock intensity, we found that both sexes of GAERS displayed exaggerated cued and contextual Pavlovian fear conditioning and impaired fear extinction. Fear reinstatement to the conditioned stimuli following unsignalled footshocks did not differ between the strains. Male GAERS also showed impaired latent inhibition in a paradigm using Pavlovian fear conditioning, suggesting that they may have altered attention, particularly related to previously irrelevant stimuli in the environment. Neither the female GAERS nor NEC rats showed evidence of latent inhibition in our paradigm. Together, the results suggest that GAERS may be a particularly useful model for assessing therapeutics designed to improve the emotional and cognitive disturbances associated with absence epilepsy.

  5. The Acquisition and Extinction of Fear of Painful Touch: a Novel Tactile Fear Conditioning Paradigm.

    PubMed

    Biggs, Emma E; Meulders, Ann; Kaas, Amanda L; Goebel, Rainer; Vlaeyen, Johan W S

    2017-08-22

    Fear of touch, due to allodynia and spontaneous pain, is not well-understood. Experimental methods to advance this topic are lacking, and therefore we propose a novel tactile conditioning paradigm. Seventy-six pain-free participants underwent acquisition in both a predictable and unpredictable pain context. In the predictable context, vibrotactile stimulation was paired with painful electrocutaneous stimulation (simulating allodynia). In the unpredictable context, vibrotactile stimulation was unpaired with pain (simulating spontaneous pain). During an extinction phase, a cue exposure and context exposure group continued in the predictable and unpredictable context, respectively, without pain. A control group received continued acquisition in both contexts. Self-reported fear and skin conductance responses (SCRs), but not startle responses, showed fear of touch was acquired in the predictable context. Context-related startle responses showed contextual fear emerged in the unpredictable context, together with elevated self-reported fear and SCRs evoked by the unpaired vibrotactile stimulations. Cue exposure reduced fear of touch, whilst context exposure reduced contextual fear. Thus, painful touch leads to increased fear, as does touch in the same context as unpredictable pain, and extinction protocols can reduce this fear. We conclude that tactile conditioning is valuable for investigating fear of touch and can advance our understanding of chronic pain. Copyright © 2017. Published by Elsevier Inc.

  6. 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

  7. Brain morphology correlates of interindividual differences in conditioned fear acquisition and extinction learning.

    PubMed

    Winkelmann, Tobias; Grimm, Oliver; Pohlack, Sebastian T; Nees, Frauke; Cacciaglia, Raffaele; Dinu-Biringer, Ramona; Steiger, Frauke; Wicking, Manon; Ruttorf, Michaela; Schad, Lothar R; Flor, Herta

    2016-05-01

    The neural circuits underlying fear learning have been intensively investigated in pavlovian fear conditioning paradigms across species. These studies established a predominant role for the amygdala in fear acquisition, while the ventromedial prefrontal cortex (vmPFC) has been shown to be important in the extinction of conditioned fear. However, studies on morphological correlates of fear learning could not consistently confirm an association with these structures. The objective of the present study was to investigate if interindividual differences in morphology of the amygdala and the vmPFC are related to differences in fear acquisition and extinction learning in humans. We performed structural magnetic resonance imaging in 68 healthy participants who underwent a differential cued fear conditioning paradigm. Volumes of subcortical structures as well as cortical thickness were computed by the semi-automated segmentation software Freesurfer. Stronger acquisition of fear as indexed by skin conductance responses was associated with larger right amygdala volume, while the degree of extinction learning was positively correlated with cortical thickness of the right vmPFC. Both findings could be conceptually replicated in an independent sample of 53 subjects. The data complement our understanding of the role of human brain morphology in the mechanisms of the acquisition and extinction of conditioned fear.

  8. Systemic Blockade of D2-Like Dopamine Receptors Facilitates Extinction of Conditioned Fear in Mice

    ERIC Educational Resources Information Center

    Ponnusamy, Ravikumar; Nissim, Helen A.; Barad, Mark

    2005-01-01

    Extinction of conditioned fear in animals is the explicit model of behavior therapy for human anxiety disorders, including panic disorder, obsessive-compulsive disorder, and post-traumatic stress disorder. Based on previous data indicating that fear extinction in rats is blocked by quinpirole, an agonist of dopamine D2 receptors, we hypothesized…

  9. Systemic Blockade of D2-Like Dopamine Receptors Facilitates Extinction of Conditioned Fear in Mice

    ERIC Educational Resources Information Center

    Ponnusamy, Ravikumar; Nissim, Helen A.; Barad, Mark

    2005-01-01

    Extinction of conditioned fear in animals is the explicit model of behavior therapy for human anxiety disorders, including panic disorder, obsessive-compulsive disorder, and post-traumatic stress disorder. Based on previous data indicating that fear extinction in rats is blocked by quinpirole, an agonist of dopamine D2 receptors, we hypothesized…

  10. Memory consolidation of fear conditioning: Bi-stable amygdala connectivity with dorsal anterior cingulate and medial prefrontal cortex

    PubMed Central

    Feng, Pan; Chen, Zhencai; Lei, Xu

    2014-01-01

    Investigations of fear conditioning in rodents and humans have illuminated the neural mechanisms of fear acquisition and extinction. However, the neural mechanism of memory consolidation of fear conditioning is not well understood. To address this question, we measured brain activity and the changes in functional connectivity following fear acquisition using resting-state functional magnetic resonance imaging. The amygdala–dorsal anterior cingulate cortex (dACC) and hippocampus–insula functional connectivity were enhanced, whereas the amygdala–medial prefrontal cortex (mPFC) functional coupling was decreased during fear memory consolidation. Furthermore, the amygdala–mPFC functional connectivity was negatively correlated with the subjective fear ratings. These findings suggest the amygdala functional connectivity with dACC and mPFC may play an important role in memory consolidation of fear conditioning. The change of amygdala-mPFC functional connectivity could predict the subjective fear. Accordingly, this study provides a new perspective for understanding fear memory consolidation. PMID:24194579

  11. Different genetic factors underlie fear conditioning and episodic memory.

    PubMed

    Fredrikson, Mats; Annas, Peter; Hettema, John M

    2015-08-01

    Fear conditioning seems to account for the acquisition of post-traumatic stress disorder, whereas conscious recall of events in aftermath of trauma reflects episodic memory. Studies show that both fear conditioning and episodic memory are heritable, but no study has evaluated whether they reflect common or separate genetic factors. To this end, we studied episodic memory and fear conditioning in 173 healthy twin pairs using visual stimuli predicting unconditioned electric shocks. Fear conditioning acquisition and extinction was determined using conditioned visual stimuli predicting unconditioned mild electric shocks, whereas electrodermal activity served as the fear learning index. Episodic memory was evaluated using cued recall of pictorial stimuli unrelated to conditioning. We used multivariate structural equation modeling to jointly analyze memory performance and acquisition as well as extinction of fear conditioning. Best-fit twin models estimated moderate genetic loadings for conditioning and memory measures, with no genetic covariation between them. Individual differences in fear conditioning and episodic memory reflect distinct genetically influenced processes, suggesting that the genetic risk for learning-induced anxiety disorders includes at least two memory-related genetic factors. These findings are consistent with the facts that the two separate learning forms are distant in their evolutionary development, involve different brain mechanisms, and support that genetically independent memory systems are pivotal in the development and maintenance of syndromes related to fear learning.

  12. The Role of the Medial Prefrontal Cortex in the Generalization of Conditioned Fear.

    PubMed

    Spalding, Kelsey N

    2017-08-31

    Fear generalization, the generalization of fear to innocuous stimuli, is a characteristic component of pathological anxiety. Neural models of fear generalization suggest the involvement of the medial prefrontal cortex (mPFC). However, conflicting empirical findings complicate our understanding of the role of the mPFC in pathological anxiety. To address important unanswered questions in this area, a detailed review and synthesis of results from human and nonhuman animal investigations of conditioned fear generalization was conducted. Empirical articles were identified through March 2017 and selected if they used fear conditioning, measured fear generalization, and included a measure of activity in the mPFC or manipulation of mPFC functioning. In human cued fear conditioning, the ventral mPFC plays an important role in the inhibition of fear generalization, whereas dorsal mPFC is important for the activation of generalized fear. This pattern remains to be further investigated in nonhuman animal models. Nonhuman animal research suggests an interaction between the neural correlates of contextual fear generalization and timing, such that the mPFC appears to increase fear generalization at remote time points and reduce generalization at recent time points following acquisition. The literature suggests a key role for the mPFC in fear generalization, but empirical details vary depending on specific regions within the mPFC, the animal model used, and the timing of the generalization test. Further research is needed to elucidate the role of the mPFC in fear generalization, which could in turn facilitate more effective pharmacological interventions for pathological anxiety. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

  13. Altered resting-state brain activity at functional MRI during automatic memory consolidation of fear conditioning.

    PubMed

    Feng, Tingyong; Feng, Pan; Chen, Zhencai

    2013-07-26

    Investigations of fear conditioning in rodents and humans have illuminated the neural mechanisms of fear acquisition and extinction. However, the neural mechanism of automatic memory consolidation of fear conditioning is still unclear. To address this question, we measured brain activity following fear acquisition using resting-state functional magnetic resonance imaging (rs-fMRI). In the current study, we used a marker of fMRI, amplitude of low-frequency (0.01-0.08Hz) fluctuation (ALFF) to quantify the spontaneous brain activity. Brain activity correlated to fear memory consolidation was observed in parahippocampus, insula, and thalamus in resting-state. Furthermore, after acquired fear conditioning, compared with control group some brain areas showed ALFF increased in ventromedial prefrontal cortex (vmPFC) and anterior cingulate cortex (ACC) in the experimental group, whereas some brain areas showed decreased ALFF in striatal regions (caudate, putamen). Moreover, the change of ALFF in vmPFC was positively correlated with the subjective fear ratings. These findings suggest that the parahippocampus, insula, and thalamus are the neural substrates of fear memory consolidation. The difference in activity could be attributed to a homeostatic process in which the vmPFC and ACC were involved in the fear recovery process, and change of ALFF in vmPFC predicts subjective fear ratings. Copyright © 2013 Elsevier B.V. All rights reserved.

  14. Generalization of Contextual Fear in Humans.

    PubMed

    Andreatta, Marta; Leombruni, Estelle; Glotzbach-Schoon, Evelyn; Pauli, Paul; Mühlberger, Andreas

    2015-09-01

    Enhanced fear responses to cues, which were not associated with the threat but share perceptual characteristics with the threat signal, indicate generalization of conditioned fear. Here, we investigated for the first time generalization processes in contextual fear conditioning. Thirty-two participants were guided through two virtual offices (acquisition phases). Mildly painful electric shocks (unconditioned stimulus, US) were unpredictably delivered in one office (anxiety context, CTX+), but never in the other office (safety context, CTX-). During the generalization test, participants were guided through CTX+, CTX-, and the generalization context (G-CTX), which contained features of both the CTX+ and the CTX-, but no US was delivered. We found successful contextual fear conditioning (i.e., the CTX+ compared to the CTX- elicited potentiated startle responses and was rated with more negative valence, higher arousal and higher anxiety). Importantly, implicit and explicit responses dissociated in the generalization test. Thus, participants rated the G-CTX as more arousing and anxiogenic than the CTX- indicating anxiety generalization, but they showed enhanced startle responses to the CTX+ only, while the G-CTX and the CTX- did not differ. In summary, healthy participants on an explicit level responded to the generalization context like to the anxiety context, but on an implicit level responded to the generalization context like to the safety context. Possibly, this dissociation suggests distinct and specific generalization processes underlying contextual fear.

  15. Distinct Contributions of Median Raphe Nucleus to Contextual Fear Conditioning and Fear-Potentiated Startle

    PubMed Central

    Silva, R. C. B.; Cruz, A. P. M.; Avanzi, V.; Landeira-Fernandez, J.; Brandão, M. L.

    2002-01-01

    Ascending 5-HT projections from the median raphe nucleus (MRN), probably to the hippocampus, are implicated in the acquisition of contextual fear (background stimuli), as assessed by freezing behavior. Foreground cues like light, used as a conditioned stimulus (CS) in classical fear conditioning, also cause freezing through thalamic transmission to the amygdala. As the MRN projects to the hippocampus and amygdala, the role of this raphe nucleus in fear conditioning to explicit cues remains to be explained. Here we analyzed the behavior of rats with MRN electrolytic lesions in a contextual conditioning situation and in a fear-potentiated startle procedure. The animals received MRN electrolytic lesions either before or on the day after two consecutive training sessions in which they were submitted to 10 conditioning trials, each in an experimental chamber (same context) where they. received foot-shocks (0.6 mA, 1 sec) paired to a 4-sec light CS. Seven to ten days later, the animals were submitted to testing sessions for assessing conditioned fear when they were placed for five shocks, and the duration of contextual freezing was recorded. The animals were then submitted to a fear-potentiated startle in response to a 4-sec light-CS, followed by white noise (100 dB, 50 ms). Control rats (sham) tested in the same context showed more freezing than did rats with pre- or post-training MRN lesions. Startle was clearly potentiated in the presence of light CS in the sham-lesioned animals. Whereas pretraining lesions reduced both freezing and fear-potentiated startle, the post-training lesions reduced only freezing to context, without changing the fear-potentiated startle. In a second experiment, neurotoxic lesions of the MRN with local injections of N-methyl-D-aspartate or the activation of 5-HT1A somatodendritic auto-receptors of the MRN by microinjections of the 5-HT1A receptor agonist 8-hydroxy- 2-(di-n-propylamino)tetralin (8-OH-DPAT) before the training sessions also

  16. Association of poor childhood fear conditioning and adult crime.

    PubMed

    Gao, Yu; Raine, Adrian; Venables, Peter H; Dawson, Michael E; Mednick, Sarnoff A

    2010-01-01

    Amygdala dysfunction is theorized to give rise to poor fear conditioning, which in turn predisposes to crime, but it is not known whether poor conditioning precedes criminal offending. This study prospectively assessed whether poor fear conditioning early in life predisposes to adult crime in a large cohort. Electrodermal fear conditioning was assessed in a cohort of 1,795 children at age 3, and registration for criminal offending was ascertained at age 23. In a case-control design, 137 cohort members with a criminal record were matched on gender, ethnicity, and social adversity with 274 noncriminal comparison members. Statistical analyses compared childhood fear conditioning for the two groups. Criminal offenders showed significantly reduced electrodermal fear conditioning at age 3 compared to matched comparison subjects. Poor fear conditioning at age 3 predisposes to crime at age 23. Poor fear conditioning early in life implicates amygdala and ventral prefrontal cortex dysfunction and a lack of fear of socializing punishments in children who grow up to become criminals. These findings are consistent with a neurodevelopmental contribution to crime causation.

  17. Fear Conditioning Effects on Sensitivity to Drug Reward

    DTIC Science & Technology

    2009-06-01

    basolateral amygdala The second step is to demonstrate efficacy of the GABAB receptor agonist baclofen in blocking the development of fear conditioning...controls. The fourth step assesses the impact of baclofen given during the development of fear conditioning and measures its impact on subsequent

  18. Personality and fear responses during conditioning: Beyond extraversion

    PubMed Central

    Pineles, Suzanne L.; Vogt, Dawne S.; Orr, Scott P.

    2008-01-01

    The personality domain of introversion-extraversion has been theorized to be associated with the strength of fear conditioning, but the literature on this topic has been equivocal. Furthermore, except for extraversion and neuroticism, relationships of the other Big Five personality domains with fear response acquisition have not been explored. In the current study, multi-level modeling was used to examine the relationships of facets of the Big 5 domains to fear response acquisition. Participants were 217 police and firefighter trainees who completed the Revised NEO Personality Inventory (NEO-PI-R; Costa & McCrae, 1992) and a fear conditioning task as part of a larger study. Results indicated that several facets of extraversion have opposing associations with fear response acquisition of an electrodermal response– possibly contributing to the mixed results in the literature. Additionally, facets of other Big Five domains were found to be associated with fear response acquisition. PMID:20046207

  19. 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

  20. Can Transcranial Direct Current Stimulation Augment Extinction of Conditioned Fear?

    PubMed

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

    2016-01-01

    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. 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. 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. 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. 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. Copyright © 2016 Elsevier Inc. All rights reserved.

  1. Oxytocin and Social Support as Synergistic Inhibitors of Aversive Fear Conditioning and Fear-Potentiated Startle in Male Rats

    DTIC Science & Technology

    2009-09-01

    startle amplitude. They then received Pavlovian fear conditioning of five pairings of a 3 s light co-terminating with a 500 ms, 0.6mA footshock. Four...Synergistic Inhibitors of Aversive Fear Conditioning and Fear-Potentiated Startle in Male Rats PRINCIPAL INVESTIGATOR: Jeffrey B. Rosen, Ph.D...NUMBER Oxytocin and Social Support as Synergistic Inhibitors of Aversive Fear Conditioning and Fear-Potentiated Startle in Male Rats 5b. GRANT

  2. Cotinine enhances the extinction of contextual fear memory and reduces anxiety after fear conditioning.

    PubMed

    Zeitlin, Ross; Patel, Sagar; Solomon, Rosalynn; Tran, John; Weeber, Edwin J; Echeverria, Valentina

    2012-03-17

    Posttraumatic stress disorder (PTSD) is an anxiety disorder triggered by traumatic events. Symptoms include anxiety, depression and deficits in fear memory extinction (FE). PTSD patients show a higher prevalence of cigarette smoking than the general population. The present study investigated the effects of cotinine, a tobacco-derived compound, over anxiety and contextual fear memory after fear conditioning (FC) in mice, a model for inducing PTSD-like symptoms. Two-month-old C57BL/6J mice were separated into three experimental groups. These groups were used to investigate the effect of pretreatment with cotinine on contextual fear memory and posttreatment on extinction and stability or retrievability of the fear memory. Also, changes induced by cotinine on the expression of extracellular signal-regulated kinase (ERK)1/2 were assessed after extinction in the hippocampus. An increase in anxiety and corticosterone levels were found after fear conditioning. Cotinine did not affect corticosterone levels but enhanced the extinction of contextual fear, decreased anxiety and the stability and/or retrievability of contextual fear memory. Cotinine-treated mice showed higher levels of the active forms of ERK1/2 than vehicle-treated mice after FC. This evidence suggests that cotinine is a potential new pharmacological treatment to reduce symptoms in individuals with PTSD.

  3. Neural Circuitry Underlying the Regulation of Conditioned Fear and Its Relation to Extinction

    PubMed Central

    Delgado, Mauricio R.; Nearing, Katherine I.; LeDoux, Joseph E.; Phelps, Elizabeth A.

    2011-01-01

    SUMMARY Recent efforts to translate basic research to the treatment of clinical disorders have led to a growing interest in exploring mechanisms for diminishing fear. This research has emphasized two approaches: extinction of conditioned fear, examined across species; and cognitive emotion regulation, unique to humans. Here, we sought to examine the similarities and differences in the neural mechanisms underlying these two paradigms for diminishing fear. Using an emotion regulation strategy, we examine the neural mechanisms of regulating conditioned fear using fMRI and compare the resulting activation pattern with that observed during classic extinction. Our results suggest that the lateral PFC regions engaged by cognitive emotion regulation strategies may influence the amygdala, diminishing fear through similar vmPFC connections that are thought to inhibit the amygdala during extinction. These findings further suggest that humans may have developed complex cognition that can aid in regulating emotional responses while utilizing phylogenetically shared mechanisms of extinction. PMID:18786365

  4. 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

  5. Specific phobia: a disorder of fear conditioning and extinction.

    PubMed

    Stein, Dan J; Matsunaga, Hisato

    2006-04-01

    Specific phobia is the most prevalent of the anxiety disorders. Although there have been relatively few studies of its psychobiology and pharmacotherapy, there is a rich laboratory of literature on fear conditioning and extinction and a clear evolutionary perspective. Advances in the cognitive-affective neuroscience of fear processing may ultimately lead to new approaches to the clinical management of phobias.

  6. Attraction under Aversive Conditions: Misattributions or Fear-Reduction?

    ERIC Educational Resources Information Center

    Miller, Rowland S.

    Interpersonal attraction appears to increase under aversive conditions. Two distinct theories suggest that attraction results from either misattribution or fear reduction. To investigate the effects of misattribution and fear reduction on attraction, 36 male college students were ostensibly exposed to an electromagnetic field while an attractive…

  7. Attraction under Aversive Conditions: Misattributions or Fear-Reduction?

    ERIC Educational Resources Information Center

    Miller, Rowland S.

    Interpersonal attraction appears to increase under aversive conditions. Two distinct theories suggest that attraction results from either misattribution or fear reduction. To investigate the effects of misattribution and fear reduction on attraction, 36 male college students were ostensibly exposed to an electromagnetic field while an attractive…

  8. Fear conditioning is disrupted by damage to the postsubiculum.

    PubMed

    Robinson, Siobhan; Bucci, David J

    2012-06-01

    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 theconditioning 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. Copyright © 2011

  9. Understanding posttraumatic stress disorder through fear conditioning, extinction and reconsolidation.

    PubMed

    Careaga, Mariella Bodemeier Loayza; Girardi, Carlos Eduardo Neves; Suchecki, Deborah

    2016-12-01

    Careaga MBL, Girardi CEN, Suchecki D. Understanding posttraumatic stress disorder through fear conditioning, extinction and reconsolidation. NEUROSCI BIOBEHAV REV -Posttraumatic stress disorder (PTSD) is a psychopathology characterized by exacerbation of fear response. A dysregulated fear response may be explained by dysfunctional learning and memory, a hypothesis that was proposed decades ago. A key component of PTSD is fear conditioning and the study of this phenomenon in laboratory has expanded the understanding of the underlying neurobiological changes in PTSD. Furthermore, traumatic memories are strongly present even years after the trauma and maintenance of this memory is usually related to behavioral and physiological maladaptive responses. Persistence of traumatic memory may be explained by a dysregulation of two memory processes: extinction and reconsolidation. The former may explain the over-expression of fear responses as an imbalance between traumatic and extinction memory. The latter, in turn, explains the maintenance of fear responses as a result of enhancing trauma-related memories. Thus, this review will discuss the importance of fear conditioning for the establishment of PTSD and how failure in extinction or abnormal reconsolidation may contribute to the maintenance of fear response overtime. Copyright © 2016 Elsevier Ltd. All rights reserved.

  10. Sleep Promotes Generalization of Extinction of Conditioned Fear

    PubMed Central

    Pace-Schott, Edward F.; Milad, Mohammed R.; Orr, Scott P.; Rauch, Scott L.; Stickgold, Robert; Pitman, Roger K.

    2009-01-01

    Study Objective: To examine the effects of sleep on fear conditioning, extinction, extinction recall, and generalization of extinction recall in healthy humans. Design: During the Conditioning phase, a mild, 0.5-sec shock followed conditioned stimuli (CS+s), which consisted of 2 differently colored lamps. A third lamp color was interspersed but never reinforced (CS-). Immediately after Conditioning, one CS+ was extinguished (CS+E) by presentation without shocks (Extinction phase). The other CS+ went unextinguished (CS+U). Twelve hours later, following continuous normal daytime waking (Wake group, N = 27) or an equal interval containing a normal night's sleep (Sleep group, N = 26), conditioned responses (CRs) to all CSs were measured (Extinction Recall phase). It was hypothesized that the Sleep versus Wake group would show greater extinction recall and/or generalization of extinction recall from the CS+E to the CS+U. Setting: Academic medical center. Subjects: Paid normal volunteers. Measurements and Results: Square-root transformed skin conductance response (SCR) measured conditioned responding. During Extinction Recall, the Group (Wake or Sleep) × CS+ Type (CS+E or CS+U) interaction was significant (P = 0.04). SCRs to the CS+E did not differ between groups, whereas SCRs to the CS+U were significantly smaller in the Sleep group. Additionally, SCRs were significantly larger to the CS+U than CS+E in the Wake but not the Sleep group. Conclusions: After sleep, extinction memory generalized from an extinguished conditioned stimulus to a similarly conditioned but unextinguished stimulus. Clinically, adequate sleep may promote generalization of extinction memory from specific stimuli treated during exposure therapy to similar stimuli later encountered in vivo. Citation: Pace-Schott EF; Milad MR; Orr SP; Rauch SL; Stickgold R; Pitman RK. Sleep promotes generalization of extinction of conditioned fear. SLEEP 2009;32(1):19-26. PMID:19189775

  11. Enhancement of acoustic prepulse inhibition by contextual fear conditioning in mice is maintained even after contextual fear extinction.

    PubMed

    Ishii, Daisuke; Matsuzawa, Daisuke; Fujita, Yuko; Sutoh, Chihiro; Ohtsuka, Hiroyuki; Matsuda, Shingo; Kanahara, Nobuhisa; Hashimoto, Kenji; Iyo, Masaomi; Shimizu, Eiji

    2010-02-01

    Prepulse inhibition (PPI) of the acoustic startle response is one of the few and major paradigms for investigating sensorimotor gating systems in humans and rodents in a similar fashion. PPI deficits are observed not only in patients with schizophrenia, but also in patients with anxiety disorders. Previous studies have shown that PPI in rats can be enhanced by auditory fear conditioning. In this study, we evaluated the effects of contextual fear conditioning (FC) for six times a day and fear extinction (FE) for seven days on PPI in mice. C57BL/6J mice (male, 8-12 weeks) were divided into three groups; no-FC (control), FC and FC + FE. We measured PPI at the following three time points, (1) baseline before FC, (2) after FC, and (3) after FE. The results showed that PPI was increased after FC. Moreover, the enhanced PPI following FC was observed even after FE with decreased freezing behaviors. These results suggested contextual fear conditioning could enhance acoustic PPI, and that contextual fear extinction could decrease freezing behaviors, but not acoustic PPI.

  12. 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

  13. Skin conductance fear conditioning impairments and aggression: a longitudinal study.

    PubMed

    Gao, Yu; Tuvblad, Catherine; Schell, Anne; Baker, Laura; Raine, Adrian

    2015-02-01

    Autonomic fear conditioning deficits have been linked to child aggression and adult criminal behavior. However, it is unknown if fear conditioning deficits are specific to certain subtypes of aggression, and longitudinal research is rare. In the current study, reactive and proactive aggression were assessed in a sample of males and females when aged 10, 12, 15, and 18 years old. Skin conductance fear conditioning data were collected when they were 18 years old. Individuals who were persistently high on proactive aggression measures had significantly poorer conditioned responses at 18 years old when compared to others. This association was not found for reactive aggression. Consistent with prior literature, findings suggest that persistent antisocial individuals have unique neurobiological characteristics and that poor autonomic fear conditioning is associated with the presence of increased instrumental aggressive behavior.

  14. Skin Conductance Fear Conditioning Impairments and Aggression: A Longitudinal Study

    PubMed Central

    Gao, Yu; Tuvblad, Catherine; Schell, Anne; Baker, Laura; Raine, Adrian

    2014-01-01

    Autonomic fear conditioning deficits have been linked to child aggression and adult criminal behavior. However, it is unknown if fear conditioning deficits are specific to certain subtypes of aggression, and longitudinal research is rare. In the current study, reactive and proactive aggression were assessed in a sample of males and females when aged 10, 12, 15, and 18 years old. Skin conductance fear conditioning data were collected when they were 18 years old. Individuals who were persistently high on proactive aggression measures had significantly poorer conditioned responses at 18 years old when compared to others. This association was not found for reactive aggression. Consistent with prior literature, findings suggest that persistent antisocial individuals have unique neurobiological characteristics and that poor autonomic fear conditioning is associated with the presence of increased instrumental aggressive behavior. PMID:25174802

  15. The Role of the Medial Prefrontal Cortex in the Conditioning and Extinction of Fear

    PubMed Central

    Giustino, Thomas F.; Maren, Stephen

    2015-01-01

    Once acquired, a fearful memory can persist for a lifetime. Although learned fear can be extinguished, extinction memories are fragile. The resilience of fear memories to extinction may contribute to the maintenance of disorders of fear and anxiety, including post-traumatic stress disorder (PTSD). As such, considerable effort has been placed on understanding the neural circuitry underlying the acquisition, expression, and extinction of emotional memories in rodent models as well as in humans. A triad of brain regions, including the prefrontal cortex, hippocampus, and amygdala, form an essential brain circuit involved in fear conditioning and extinction. Within this circuit, the prefrontal cortex is thought to exert top-down control over subcortical structures to regulate appropriate behavioral responses. Importantly, a division of labor has been proposed in which the prelimbic (PL) and infralimbic (IL) subdivisions of the medial prefrontal cortex (mPFC) regulate the expression and suppression of fear in rodents, respectively. Here, we critically review the anatomical and physiological evidence that has led to this proposed dichotomy of function within mPFC. We propose that under some conditions, the PL and IL act in concert, exhibiting similar patterns of neural activity in response to aversive conditioned stimuli and during the expression or inhibition of conditioned fear. This may stem from common synaptic inputs, parallel downstream outputs, or cortico-cortical interactions. Despite this functional covariation, these mPFC subdivisions may still be coding for largely opposing behavioral outcomes, with PL biased towards fear expression and IL towards suppression. PMID:26617500

  16. 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.

  17. 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

  18. Stress differentially affects fear conditioning in men and women.

    PubMed

    Merz, Christian Josef; Wolf, Oliver Tobias; Schweckendiek, Jan; Klucken, Tim; Vaitl, Dieter; Stark, Rudolf

    2013-11-01

    Stress and fear conditioning processes are both important vulnerability factors in the development of psychiatric disorders. In behavioral studies considerable sex differences in fear learning have been observed after increases of the stress hormone cortisol. But neuroimaging experiments, which give insights into the neurobiological correlates of stress × sex interactions in fear conditioning, are lacking so far. In the current functional magnetic resonance imaging (fMRI) study, we tested whether a psychosocial stressor (Trier Social Stress Test) compared to a control condition influenced subsequent fear conditioning in 48 men and 48 women taking oral contraceptives (OCs). One of two pictures of a geometrical figure was always paired (conditioned stimulus, CS+) or never paired (CS-) with an electrical stimulation (unconditioned stimulus). BOLD responses as well as skin conductance responses were assessed. Sex-independently, stress enhanced the CS+/CS- differentiation in the hippocampus in early acquisition but attenuated conditioned responses in the medial frontal cortex in late acquisition. In early acquisition, stress reduced the CS+/CS- differentiation in the nucleus accumbens in men, but enhanced it in OC women. In late acquisition, the same pattern (reduction in men, enhancement in OC women) was found in the amygdala as well as in the anterior cingulate. Thus, psychosocial stress impaired the neuronal correlates of fear learning and expression in men, but facilitated them in OC women. A sex-specific modulation of fear conditioning after stress might contribute to the divergent prevalence of men and women in developing psychiatric disorders.

  19. Human fear extinction and return of fear using reconsolidation update mechanisms: the contribution of on-line expectancy ratings.

    PubMed

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

    2014-09-01

    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.

  20. Adrenal-dependent diurnal modulation of conditioned fear extinction learning

    PubMed Central

    Woodruff, Elizabeth R.; Greenwood, Benjamin N.; Chun, Lauren E.; Fardi, Sara; Hinds, Laura R.; Spencer, Robert L.

    2015-01-01

    Post Traumatic Stress Disorder (PTSD) is associated with altered conditioned fear extinction expression and impaired circadian function including dysregulation of glucocorticoid hormone secretion. We examined in adult male rats the relationship between conditioned fear extinction learning, circadian phase, and endogenous glucocorticoids (CORT). Rats maintained on a 12 hr light:dark cycle were trained and tested across 3 separate daily sessions (conditioned fear acquisition and 2 extinction sessions) that were administered during either the rats’ active or inactive circadian phase. In an initial experiment we found that rats at both circadian phases acquired and extinguished auditory cue conditioned fear to a similar degree in the first extinction session. However, rats trained and tested at zeitgeber time-16 (ZT16) (active phase) showed enhanced extinction memory expression during the second extinction session compared to rats trained and tested at ZT4 (inactive phase). In a follow-up experiment, adrenalectomized (ADX) or sham surgery rats were similarly trained and tested across 3 separate daily sessions at either ZT4 or ZT16. ADX had no effect on conditioned fear acquisition or conditioned fear memory. Sham ADX rats trained and tested at ZT16 exhibited better extinction learning across the two extinction sessions compared to all other groups of rats. These results indicate that conditioned fear extinction learning is modulated by time of day, and this diurnal modulation requires the presence of adrenal hormones. These results support an important role of CORT-dependent circadian processes in regulating conditioned fear extinction learning, which may be capitalized upon to optimize effective treatment of PTSD. PMID:25746455

  1. Adrenal-dependent diurnal modulation of conditioned fear extinction learning.

    PubMed

    Woodruff, Elizabeth R; Greenwood, Benjamin N; Chun, Lauren E; Fardi, Sara; Hinds, Laura R; Spencer, Robert L

    2015-06-01

    Post traumatic stress disorder (PTSD) is associated with altered conditioned fear extinction expression and impaired circadian function including dysregulation of glucocorticoid hormone secretion. We examined in adult male rats the relationship between conditioned fear extinction learning, circadian phase, and endogenous glucocorticoids (CORT). Rats maintained on a 12h light:dark cycle were trained and tested across 3 separate daily sessions (conditioned fear acquisition and 2 extinction sessions) that were administered during either the rats' active or inactive circadian phase. In an initial experiment we found that rats at both circadian phases acquired and extinguished auditory cue conditioned fear to a similar degree in the first extinction session. However, rats trained and tested at zeitgeber time-16 (ZT16) (active phase) showed enhanced extinction memory expression during the second extinction session compared to rats trained and tested at ZT4 (inactive phase). In a follow-up experiment, adrenalectomized (ADX) or sham surgery rats were similarly trained and tested across 3 separate daily sessions at either ZT4 or ZT16. ADX had no effect on conditioned fear acquisition or conditioned fear memory. Sham ADX rats trained and tested at ZT16 exhibited better extinction learning across the two extinction sessions compared to all other groups of rats. These results indicate that conditioned fear extinction learning is modulated by time of day, and this diurnal modulation requires the presence of adrenal hormones. These results support an important role of CORT-dependent circadian processes in regulating conditioned fear extinction learning, which may be capitalized upon to optimize effective treatment of PTSD.

  2. How do social fears in adolescence develop? Fear conditioning shapes attention orienting to social threat cues.

    PubMed

    Haddad, Anneke D M; Lissek, Shmuel; Pine, Daniel S; Lau, Jennifer Y F

    2011-09-01

    Social fears emerging in adolescence can have negative effects on emotional well-being. Yet the mechanisms by which these risks occur are unknown. One possibility is that associative learning results in fears to previously neutral social stimuli. Such conditioned responses may alter subsequent processing of social stimuli. We used a novel conditioning task to examine how associative processes influence social fear and attention orienting in adolescents. Neutral photographs were paired with socially rewarding or aversive stimuli during conditioning; a dot-probe task then assessed biases in attention orienting. The social conditioning task modified subjective ratings of the neutral stimuli. Moreover, for the neutral stimulus that was paired with the aversive stimulus, the strength of conditioning showed a relationship with subsequent attentional vigilance. The findings elucidate mechanisms by which negative peer experiences during adolescence may affect emotional processing.

  3. Psychopaths Show Enhanced Amygdala Activation during Fear Conditioning.

    PubMed

    Schultz, Douglas H; Balderston, Nicholas L; Baskin-Sommers, Arielle R; Larson, Christine L; Helmstetter, Fred J

    2016-01-01

    Psychopathy is a personality disorder characterized by emotional deficits and a failure to inhibit impulsive behavior and is often subdivided into "primary" and "secondary" psychopathic subtypes. The maladaptive behavior related to primary psychopathy is thought to reflect constitutional "fearlessness," while the problematic behavior related to secondary psychopathy is motivated by other factors. The fearlessness observed in psychopathy has often been interpreted as reflecting a fundamental deficit in amygdala function, and previous studies have provided support for a low-fear model of psychopathy. However, many of these studies fail to use appropriate screening procedures, use liberal inclusion criteria, or have used unconventional approaches to assay amygdala function. We measured brain activity with BOLD imaging in primary and secondary psychopaths and non-psychopathic control subjects during Pavlovian fear conditioning. In contrast to the low-fear model, we observed normal fear expression in primary psychopaths. Psychopaths also displayed greater differential BOLD activity in the amygdala relative to matched controls. Inverse patterns of activity were observed in the anterior cingulate cortex (ACC) for primary versus secondary psychopaths. Primary psychopaths exhibited a pattern of activity in the dorsal and ventral ACC consistent with enhanced fear expression, while secondary psychopaths exhibited a pattern of activity in these regions consistent with fear inhibition. These results contradict the low-fear model of psychopathy and suggest that the low fear observed for psychopaths in previous studies may be specific to secondary psychopaths.

  4. Psychopaths Show Enhanced Amygdala Activation during Fear Conditioning

    PubMed Central

    Schultz, Douglas H.; Balderston, Nicholas L.; Baskin-Sommers, Arielle R.; Larson, Christine L.; Helmstetter, Fred J.

    2016-01-01

    Psychopathy is a personality disorder characterized by emotional deficits and a failure to inhibit impulsive behavior and is often subdivided into “primary” and “secondary” psychopathic subtypes. The maladaptive behavior related to primary psychopathy is thought to reflect constitutional “fearlessness,” while the problematic behavior related to secondary psychopathy is motivated by other factors. The fearlessness observed in psychopathy has often been interpreted as reflecting a fundamental deficit in amygdala function, and previous studies have provided support for a low-fear model of psychopathy. However, many of these studies fail to use appropriate screening procedures, use liberal inclusion criteria, or have used unconventional approaches to assay amygdala function. We measured brain activity with BOLD imaging in primary and secondary psychopaths and non-psychopathic control subjects during Pavlovian fear conditioning. In contrast to the low-fear model, we observed normal fear expression in primary psychopaths. Psychopaths also displayed greater differential BOLD activity in the amygdala relative to matched controls. Inverse patterns of activity were observed in the anterior cingulate cortex (ACC) for primary versus secondary psychopaths. Primary psychopaths exhibited a pattern of activity in the dorsal and ventral ACC consistent with enhanced fear expression, while secondary psychopaths exhibited a pattern of activity in these regions consistent with fear inhibition. These results contradict the low-fear model of psychopathy and suggest that the low fear observed for psychopaths in previous studies may be specific to secondary psychopaths. PMID:27014154

  5. Noradrenergic blockade of memory reconsolidation: a failure to reduce conditioned fear responding.

    PubMed

    Bos, Marieke Geerte Nynke; Beckers, Tom; Kindt, Merel

    2014-01-01

    Upon recall, a memory can enter a labile state in which it requires new protein synthesis to restabilize. This two-phased reconsolidation process raises the prospect to directly target excessive fear memory as opposed to the formation of inhibitory memory following extinction training. In our previous studies, we convincingly demonstrated that 40 mg propranolol HCl administration before or after memory reactivation eliminated the emotional expression of fear memory indexed by the fear potentiated startle reflex. To apply this procedure in clinical practice it is important to understand the optimal and boundary conditions of this procedure. As part of a large project aimed at unraveling putative boundary conditions of disrupting reconsolidation of associative fear memory with propranolol HCl, we again tested our memory reconsolidation procedure. Participants (N = 44) underwent a three-day differential fear conditioning procedure. Twenty-four hours after fear acquisition, participants received 40 mg propranolol HCl prior to memory reactivation. The next day, participants were subjected to extinction training and reinstatement testing. In sharp contrast to our previous findings, propranolol HCl before memory reactivation did not attenuate the startle fear response. Remarkably, the startle fear response even persisted during extinction training and did not show the usually observed gradual decline in conditioned physiological responding (startle potentiation and skin conductance) upon repeated unreinforced trials. We discuss these unexpected findings and propose some potential explanations. It remains, however, unclear why we observed a resistance to reduce conditioned fear responding by either disrupting reconsolidation or extinction training. The present results underscore that the success of human fear conditioning research may depend on subtle manipulations and instructions.

  6. Noradrenergic Blockade of Memory Reconsolidation: A Failure to Reduce Conditioned Fear Responding

    PubMed Central

    Bos, Marieke Geerte Nynke; Beckers, Tom; Kindt, Merel

    2014-01-01

    Upon recall, a memory can enter a labile state in which it requires new protein synthesis to restabilize. This two-phased reconsolidation process raises the prospect to directly target excessive fear memory as opposed to the formation of inhibitory memory following extinction training. In our previous studies, we convincingly demonstrated that 40 mg propranolol HCl administration before or after memory reactivation eliminated the emotional expression of fear memory indexed by the fear potentiated startle reflex. To apply this procedure in clinical practice it is important to understand the optimal and boundary conditions of this procedure. As part of a large project aimed at unraveling putative boundary conditions of disrupting reconsolidation of associative fear memory with propranolol HCl, we again tested our memory reconsolidation procedure. Participants (N = 44) underwent a three-day differential fear conditioning procedure. Twenty-four hours after fear acquisition, participants received 40 mg propranolol HCl prior to memory reactivation. The next day, participants were subjected to extinction training and reinstatement testing. In sharp contrast to our previous findings, propranolol HCl before memory reactivation did not attenuate the startle fear response. Remarkably, the startle fear response even persisted during extinction training and did not show the usually observed gradual decline in conditioned physiological responding (startle potentiation and skin conductance) upon repeated unreinforced trials. We discuss these unexpected findings and propose some potential explanations. It remains, however, unclear why we observed a resistance to reduce conditioned fear responding by either disrupting reconsolidation or extinction training. The present results underscore that the success of human fear conditioning research may depend on subtle manipulations and instructions. PMID:25506319

  7. Cannabinoid facilitation of fear extinction memory recall in humans.

    PubMed

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

    2013-01-01

    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 h prior to extinction learning in 29 healthy adult volunteers (THC = 14; PBO = 15) and tested extinction retention 24 h 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 h 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. This article is part of a Special Issue entitled 'Cognitive Enhancers'.

  8. Controlled cortical impact before or after fear conditioning does not affect fear extinction in mice

    PubMed Central

    Sierra-Mercado, Demetrio; McAllister, Lauren M.; Lee, Christopher C.H.; Milad, Mohammed R.; Eskandar, Emad N.; Whalen, Michael J.

    2015-01-01

    Post-traumatic stress disorder (PTSD) is characterized in part by impaired extinction of conditioned fear. Traumatic brain injury (TBI) is thought to be a risk factor for development of PTSD. We tested the hypothesis that controlled cortical impact (CCI) would impair extinction of fear learned by Pavlovian conditioning, in mice. To mimic the scenarios in which TBI occurs prior to or after exposure to an aversive event, severe CCI was delivered to the left parietal cortex at one of two time points: (1) Prior to fear conditioning, or (2) after conditioning. Delay auditory conditioning was achieved by pairing a tone with a foot shock in “context A”. Extinction training involved the presentation of tones in a different context (context B) in the absence of foot shock. Test for extinction memory was achieved by presentation of additional tones alone in context B over the following two days. In pre- or post-injury paradigms, CCI did not influence fear learning and extinction. Furthermore, CCI did not affect locomotor activity or elevated plus maze testing. Our results demonstrate that, within the time frame studied, CCI does not impair the acquisition and expression of conditioned fear or extinction memory. PMID:25721797

  9. Controlled cortical impact before or after fear conditioning does not affect fear extinction in mice.

    PubMed

    Sierra-Mercado, Demetrio; McAllister, Lauren M; Lee, Christopher C H; Milad, Mohammed R; Eskandar, Emad N; Whalen, Michael J

    2015-05-05

    Post-traumatic stress disorder (PTSD) is characterized in part by impaired extinction of conditioned fear. Traumatic brain injury (TBI) is thought to be a risk factor for development of PTSD. We tested the hypothesis that controlled cortical impact (CCI) would impair extinction of fear learned by Pavlovian conditioning, in mice. To mimic the scenarios in which TBI occurs prior to or after exposure to an aversive event, severe CCI was delivered to the left parietal cortex at one of two time points: (1) Prior to fear conditioning, or (2) after conditioning. Delay auditory conditioning was achieved by pairing a tone with a foot shock in "context A". Extinction training involved the presentation of tones in a different context (context B) in the absence of foot shock. Test for extinction memory was achieved by presentation of additional tones alone in context B over the following two days. In pre- or post-injury paradigms, CCI did not influence fear learning and extinction. Furthermore, CCI did not affect locomotor activity or elevated plus maze testing. Our results demonstrate that, within the time frame studied, CCI does not impair the acquisition and expression of conditioned fear or extinction memory.

  10. Social buffering ameliorates conditioned fear responses in female rats.

    PubMed

    Ishii, Akiko; Kiyokawa, Yasushi; Takeuchi, Yukari; Mori, Yuji

    2016-05-01

    The stress experienced by an animal is ameliorated when the animal is exposed to distressing stimuli along with a conspecific animal(s). This is known as social buffering. Previously, we found that the presence of an unfamiliar male rat induced social buffering and ameliorated conditioned fear responses of a male rat subjected to an auditory conditioned stimulus (CS). However, because our knowledge of social buffering is highly biased towards findings in male subjects, analyses using female subjects are crucial for comprehensively understanding the social buffering phenomenon. In the present studies, we assessed social buffering of conditioned fear responses in female rats. We found that the estrus cycle did not affect the intensity of the rats' fear responses to the CS or their degree of vigilance due to the presence of a conspecific animal. Based on these findings, we then assessed whether social buffering ameliorated conditioned fear responses in female rats without taking into account their estrus cycles. When fear conditioned female rats were exposed to the CS without the presence of a conspecific, they exhibited behavioral responses, including freezing, and elevated corticosterone levels. By contrast, the presence of an unfamiliar female rat suppressed these responses. Based on these findings, we conclude that social buffering can ameliorate conditioned fear responses in female rats. Copyright © 2016 Elsevier Inc. All rights reserved.

  11. Delayed effects of cortisol enhance fear memory of trace conditioning.

    PubMed

    Cornelisse, Sandra; van Ast, Vanessa A; Joëls, Marian; Kindt, Merel

    2014-02-01

    Corticosteroids induce rapid non-genomic effects followed by slower genomic effects that are thought to modulate cognitive function in opposite and complementary ways. It is presently unknown how these time-dependent effects of cortisol affect fear memory of delay and trace conditioning. This distinction is of special interest because the neural substrates underlying these types of conditioning may be differently affected by time-dependent cortisol effects. Delay conditioning is predominantly amygdala-dependent, while trace conditioning additionally requires the hippocampus. Here, we manipulated the timing of cortisol action during acquisition of delay and trace fear conditioning, by randomly assigning 63 men to one of three possible groups: (1) receiving 10mg hydrocortisone 240 min (slow cort) or (2) 60 min (rapid cort) before delay and trace acquisition, or (3) placebo at both times, in a double-blind design. The next day, we tested memory for trace and delay conditioning. Fear potentiated startle responses, skin conductance responses and unconditioned stimulus expectancy scores were measured throughout the experiment. The fear potentiated startle data show that cortisol intake 240 min before actual fear acquisition (slow cort) uniquely strengthened subsequent trace conditioned memory. No effects of cortisol delivery 60 min prior to fear acquisition were found on any measure of fear memory. Our findings emphasize that slow, presumably genomic, but not more rapid effects of corticosteroids enhance hippocampal-dependent fear memories. On a broader level, our findings underline that basic experimental research and clinically relevant pharmacological treatments employing corticosteroids should acknowledge the timing of corticosteroid administration relative to the learning phase, or therapeutic intervention.

  12. From fear to safety and back: reversal of fear in the human brain.

    PubMed

    Schiller, Daniela; Levy, Ifat; Niv, Yael; LeDoux, Joseph E; Phelps, Elizabeth A

    2008-11-05

    Fear learning is a rapid and persistent process that promotes defense against threats and reduces the need to relearn about danger. However, it is also important to flexibly readjust fear behavior when circumstances change. Indeed, a failure to adjust to changing conditions may contribute to anxiety disorders. A central, yet neglected aspect of fear modulation is the ability to flexibly shift fear responses from one stimulus to another if a once-threatening stimulus becomes safe or a once-safe stimulus becomes threatening. In these situations, the inhibition of fear and the development of fear reactions co-occur but are directed at different targets, requiring accurate responding under continuous stress. To date, research on fear modulation has focused mainly on the shift from fear to safety by using paradigms such as extinction, resulting in a reduction of fear. The aim of the present study was to track the dynamic shifts from fear to safety and from safety to fear when these transitions occur simultaneously. We used functional neuroimaging in conjunction with a fear-conditioning reversal paradigm. Our results reveal a unique dissociation within the ventromedial prefrontal cortex between a safe stimulus that previously predicted danger and a "naive" safe stimulus. We show that amygdala and striatal responses tracked the fear-predictive stimuli, flexibly flipping their responses from one predictive stimulus to another. Moreover, prediction errors associated with reversal learning correlated with striatal activation. These results elucidate how fear is readjusted to appropriately track environmental changes, and the brain mechanisms underlying the flexible control of fear.

  13. Fear Generalization in Humans: Systematic Review and Implications for Anxiety Disorder Research.

    PubMed

    Dymond, Simon; Dunsmoor, Joseph E; Vervliet, Bram; Roche, Bryan; Hermans, Dirk

    2015-09-01

    Fear generalization, in which conditioned fear responses generalize or spread to related stimuli, is a defining feature of anxiety disorders. The behavioral consequences of maladaptive fear generalization are that aversive experiences with one stimulus or event may lead one to regard other cues or situations as potential threats that should be avoided, despite variations in physical form. Theoretical and empirical interest in the generalization of conditioned learning dates to the earliest research on classical conditioning in nonhumans. Recently, there has been renewed focus on fear generalization in humans due in part to its explanatory power in characterizing disorders of fear and anxiety. Here, we review existing behavioral and neuroimaging empirical research on the perceptual and non-perceptual (conceptual and symbolic) generalization of fear and avoidance in healthy humans and patients with anxiety disorders. The clinical implications of this research for understanding the etiology and treatment of anxiety is considered and directions for future research described.

  14. Fear conditioning to discontinuous auditory cues requires perirhinal cortical function.

    PubMed

    Kholodar-Smith, D B; Allen, T A; Brown, T H

    2008-10-01

    Pretraining lesions of rat perirhinal (PR) cortex impair fear conditioning to ultrasonic vocalizations (USVs) but have no effect on conditioning to continuous tones. This study attempted to deconstruct USVs into simpler stimulus features that cause fear conditioning to be PR-dependent. Rats were conditioned to one of three cues: a multicall 19-kHz USV, a 19-kHz discontinuous tone, and a 19-kHz continuous tone. The discontinuous tone duplicated the on/off pattern of the individual calls in the USV, but it lacked the characteristic frequency modulations. Well-localized neurotoxic PR lesions impaired conditioning to the USV, the discontinuous tone, and the training context. However, PR lesions had no effect on conditioning to the continuous tone. The authors suggest that the lesion effects on fear conditioning to both cues and contexts reflect the essential role of PR in binding stimulus elements together into unitary representations.

  15. Sound tuning of amygdala plasticity in auditory fear conditioning

    PubMed Central

    Park, Sungmo; Lee, Junuk; Park, Kyungjoon; Kim, Jeongyeon; Song, Beomjong; Hong, Ingie; Kim, Jieun; Lee, Sukwon; Choi, Sukwoo

    2016-01-01

    Various auditory tones have been used as conditioned stimuli (CS) for fear conditioning, but researchers have largely neglected the effect that different types of auditory tones may have on fear memory processing. Here, we report that at lateral amygdala (LA) synapses (a storage site for fear memory), conditioning with different types of auditory CSs (2.8 kHz tone, white noise, FM tone) recruits distinct forms of long-term potentiation (LTP) and inserts calcium permeable AMPA receptor (CP-AMPAR) for variable periods. White noise or FM tone conditioning produced brief insertion (<6 hr after conditioning) of CP-AMPARs, whereas 2.8 kHz tone conditioning induced more persistent insertion (≥6 hr). Consistently, conditioned fear to 2.8 kHz tone but not to white noise or FM tones was erased by reconsolidation-update (which depends on the insertion of CP-AMPARs at LA synapses) when it was performed 6 hr after conditioning. Our data suggest that conditioning with different auditory CSs recruits distinct forms of LA synaptic plasticity, resulting in more malleable fear memory to some tones than to others. PMID:27488731

  16. Sound tuning of amygdala plasticity in auditory fear conditioning.

    PubMed

    Park, Sungmo; Lee, Junuk; Park, Kyungjoon; Kim, Jeongyeon; Song, Beomjong; Hong, Ingie; Kim, Jieun; Lee, Sukwon; Choi, Sukwoo

    2016-08-04

    Various auditory tones have been used as conditioned stimuli (CS) for fear conditioning, but researchers have largely neglected the effect that different types of auditory tones may have on fear memory processing. Here, we report that at lateral amygdala (LA) synapses (a storage site for fear memory), conditioning with different types of auditory CSs (2.8 kHz tone, white noise, FM tone) recruits distinct forms of long-term potentiation (LTP) and inserts calcium permeable AMPA receptor (CP-AMPAR) for variable periods. White noise or FM tone conditioning produced brief insertion (<6 hr after conditioning) of CP-AMPARs, whereas 2.8 kHz tone conditioning induced more persistent insertion (≥6 hr). Consistently, conditioned fear to 2.8 kHz tone but not to white noise or FM tones was erased by reconsolidation-update (which depends on the insertion of CP-AMPARs at LA synapses) when it was performed 6 hr after conditioning. Our data suggest that conditioning with different auditory CSs recruits distinct forms of LA synaptic plasticity, resulting in more malleable fear memory to some tones than to others.

  17. The influence of acute stress on the regulation of conditioned fear

    PubMed Central

    Raio, Candace M.; Phelps, Elizabeth A.

    2014-01-01

    Fear learning and regulation is a prominent model for describing the pathogenesis of anxiety disorders and stress-related psychopathology. Fear expression can be modulated using a number of regulatory strategies, including extinction, cognitive emotion regulation, avoidance strategies and reconsolidation. In this review, we examine research investigating the effects of acute stress and stress hormones on these regulatory techniques. We focus on what is known about the impact of stress on the ability to flexibly regulate fear responses that are acquired through Pavlovian fear conditioning. Our primary aim is to explore the impact of stress on fear regulation in humans. Given this, we focus on techniques where stress has been linked to alterations of fear regulation in humans (extinction and emotion regulation), and briefly discuss other techniques (avoidance and reconsolidation) where the impact of stress or stress hormones have been mainly explored in animal models. These investigations reveal that acute stress may impair the persistent inhibition of fear, presumably by altering prefrontal cortex function. Characterizing the effects of stress on fear regulation is critical for understanding the boundaries within which existing regulation strategies are viable in everyday life and can better inform treatment options for those who suffer from anxiety and stress-related psychopathology. PMID:25530986

  18. Cerebellar vermis contributes to the extinction of conditioned fear.

    PubMed

    Utz, A; Thürling, M; Ernst, T M; Hermann, A; Stark, R; Wolf, O T; Timmann, D; Merz, C J

    2015-09-14

    The cerebellum is known to contribute to the acquisition and retention of conditioned motor and emotional responses. Eyeblink conditioning and fear conditioning have been studied in greatest detail. Whereas a considerable number of studies have shown that the cerebellum is also involved in extinction of conditioned eyeblink responses, the likely contribution of the cerebellum to extinction of conditioned fear responses has largely been ignored. In the present study, we analyzed functional brain imaging data (fMRI) of previous work investigating extinction of conditioned fear in 32 young and healthy men, in which event-related fMRI analysis did not include the cerebellum. This dataset was analyzed using a spatial normalization method optimized for the cerebellum. During fear acquisition, an unpleasant electric shock (unconditioned stimulus; US) was paired with one of two pictures of geometrical figures (conditioned stimulus; CS+), while the other picture (CS-) was never paired with the US. During extinction, CS+ and CS- were presented without the US. During the acquisition phase, the fMRI signal related to the CS+ was significantly higher in hemispheric lobule VI in early compared to late acquisition (p<.05, permutation corrected). During the extinction phase, the fMRI signal related to the contrast CS+>CS- was significantly higher within the anterior vermis in early compared to late extinction (p<.05, permutation corrected). The present data show that the cerebellum is not only associated with the acquisition but also with the extinction of conditioned fear.

  19. An Appetitive Conditioned Stimulus Enhances Fear Acquisition and Impairs Fear Extinction

    ERIC Educational Resources Information Center

    Leung, Hiu T.; Holmes, Nathan M.; Westbrook, R. Frederick

    2016-01-01

    Four experiments used between- and within-subject designs to examine appetitive-aversive interactions in rats. Experiments 1 and 2 examined the effect of an excitatory appetitive conditioned stimulus (CS) on acquisition and extinction of conditioned fear. In Experiment 1, a CS shocked in a compound with an appetitive excitor (i.e., a stimulus…

  20. An Appetitive Conditioned Stimulus Enhances Fear Acquisition and Impairs Fear Extinction

    ERIC Educational Resources Information Center

    Leung, Hiu T.; Holmes, Nathan M.; Westbrook, R. Frederick

    2016-01-01

    Four experiments used between- and within-subject designs to examine appetitive-aversive interactions in rats. Experiments 1 and 2 examined the effect of an excitatory appetitive conditioned stimulus (CS) on acquisition and extinction of conditioned fear. In Experiment 1, a CS shocked in a compound with an appetitive excitor (i.e., a stimulus…

  1. Measuring Pavlovian fear with conditioned freezing and conditioned suppression reveals different roles for the basolateral amygdala.

    PubMed

    McDannald, Michael A; Galarce, Ezequiel M

    2011-02-16

    In Pavlovian fear conditioning, pairing a neutral cue with aversive foot shock endows a cue with fear-eliciting properties. Studies of Pavlovian fear conditioning measuring freezing have demonstrated the basolateral amygdala (BLA) to be critical to both fear learning and memory. The nucleus accumbens core (NAc), while not important to freezing, is important to the enhancement of instrumental responding by cues paired with food reward. In the present study we investigated the role of the BLA and the NAc in another property of fear cues, the ability to suppress instrumental responding for food rewards (conditioned suppression). Sham, BLA and NAc-lesioned rats received a fear discrimination procedure in which one visual cue (CS+) predicted foot shock while a second cue (CS-) did not. Conditioning took place over a baseline of instrumental responding, allowing for concurrent measure of freezing and instrumental suppression. NAc lesions left fear conditioning fully intact. BLA lesions impaired acquisition and discrimination of fear when assessed with conditioned freezing. However, BLA lesions only altered fear acquisition and left discrimination completely intact when assessed with conditioned suppression. These findings suggest a critical role for the BLA in fear when assessed with conditioned freezing but a diminished role when assessed with conditioned suppression.

  2. Passive Avoidance Is Linked to Impaired Fear Extinction in Humans

    ERIC Educational Resources Information Center

    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…

  3. Passive Avoidance Is Linked to Impaired Fear Extinction in Humans

    ERIC Educational Resources Information Center

    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…

  4. Updating versus Exposure to Prevent Consolidation of Conditioned Fear

    PubMed Central

    Pile, Victoria; Barnhofer, Thorsten; Wild, Jennifer

    2015-01-01

    Targeting the consolidation of fear memories following trauma may offer a promising method for preventing the development of flashbacks and other unwanted re-experiencing symptoms that characterise Posttraumatic Stress Disorder (PTSD). Research has demonstrated that performing visuo-spatial tasks after analogue trauma can block the consolidation of fear memory and reduce the frequency of flashbacks. However, no research has yet used verbal techniques to alter memories during the consolidation window. This is surprising given that the most effective treatments for PTSD are verbally-based with exposure therapy and trauma-focused cognitive behavioural therapy gaining the most evidence of efficacy. Psychological therapies aim to reduce the conditioned fear response, which is in keeping with the preliminary finding that an increased propensity for fear conditioning may be a vulnerability factor for PTSD. Our research had two aims. We investigated the degree to which individual differences in fear conditioning predict the development of PTSD symptoms. We also compared the preventative effects of two clinically informed psychological techniques administered during the consolidation window: exposure to the trauma memory and updating the meaning of the trauma. 115 healthy participants underwent a fear conditioning paradigm in which traumatic film stimuli (unconditioned stimuli) were paired with neutral stimuli (conditioned stimuli). Participants were randomly allocated to an updating, exposure or control group to compare the effects on the conditioned fear response and on PTSD symptomatology. The results showed that stronger conditioned responses at acquisition significantly predicted the development of PTSD symptoms. The updating group, who verbally devalued the unconditioned stimulus within the consolidation window, experienced significantly lower levels of PTSD symptoms during follow-up than the exposure and control groups. These findings are consistent with clinical

  5. Failure to extinguish fear and genetic variability in the human cannabinoid receptor 1.

    PubMed

    Heitland, I; Klumpers, F; Oosting, R S; Evers, D J J; Leon Kenemans, J; Baas, J M P

    2012-09-25

    Failure to extinguish fear can lead to persevering anxiety and has been postulated as an important mechanism in the pathogenesis of human anxiety disorders. In animals, it is well documented that the endogenous cannabinoid system has a pivotal role in the successful extinction of fear, most importantly through the cannabinoid receptor 1. However, no human studies have reported a translation of this preclinical evidence yet. Healthy medication-free human subjects (N=150) underwent a fear conditioning and extinction procedure in a virtual reality environment. Fear potentiation of the eyeblink startle reflex was measured to assess fear-conditioned responding, and subjective fear ratings were collected. Participants were genotyped for two polymorphisms located within the promoter region (rs2180619) and the coding region (rs1049353) of cannabinoid receptor 1. As predicted from the preclinical literature, acquisition and expression of conditioned fear did not differ between genotypes. Crucially, whereas both homozygote (G/G, N=23) and heterozygote (A/G, N=68) G-allele carriers of rs2180619 displayed robust extinction of fear, extinction of fear-potentiated startle was absent in A/A homozygotes (N=51). Additionally, this resistance to extinguish fear left A/A carriers of rs2180619 with significantly higher levels of fear-potentiated startle at the end of the extinction training. No effects of rs1049353 genotype were observed regarding fear acquisition and extinction. These results suggest for the first time involvement of the human endocannabinoid system in fear extinction. Implications are that genetic variability in this system may underlie individual differences in anxiety, rendering cannabinoid receptor 1 a potential target for novel pharmacological treatments of anxiety disorders.

  6. Fear conditioning and extinction in pediatric obsessive-compulsive disorder.

    PubMed

    Geller, Daniel A; McGuire, Joseph F; Orr, Scott P; Pine, Daniel S; Britton, Jennifer C; Small, Brent J; Murphy, Tanya K; Wilhelm, Sabine; Storch, Eric A

    2017-02-01

    Fear acquisition and extinction are central constructs in the cognitive-behavioral model of obsessive-compulsive disorder (OCD), which underlies exposure-based cognitive-behavioral therapy. Youths with OCD may have impairments in fear acquisition and extinction that carry treatment implications. Eighty youths (39 OCD, 41 healthy controls [HC]) completed clinical interviews, rating scales, and a differential conditioning task that included habituation, acquisition, and extinction phases. Skin conductance response (SCR) served as the primary dependent measure. During habituation, participants with OCD exhibited a stronger orienting SCR to initial stimuli relative to HC participants. During acquisition, differential fear conditioning was observed for both groups as evidenced by larger SCRs to the visual conditioned stimulus paired with an aversive unconditioned stimulus (CS+) compared with a CS-; OCD participants exhibited a larger SCR to the CS+ relative to HC participants. The absolute magnitude of the unconditioned fear response was significantly larger in participants with OCD, compared with HC participants. During extinction, OCD participants continued to exhibit a differential SCR to the CS+ and CS-, whereas HC participants exhibited diminished SCR to both stimuli. Participants with OCD exhibit a different pattern of fear extinction relative to HC participants, suggestive of greater fear acquisition and impaired inhibitory learning.

  7. Unconditioned stimulus revaluation to promote conditioned fear extinction in the memory reconsolidation window.

    PubMed

    Zeng, Xiang-Xing; Du, Juan; Zhuang, Chu-Qun; Zhang, Jun-Hua; Jia, Yan-Lei; Zheng, Xi-Fu

    2014-01-01

    The retrieval-extinction paradigm, which disrupts the reconsolidation of fear memories in humans, is a non-invasive technique that can be used to prevent the return of fear in humans. In the present study, unconditioned stimulus revaluation was applied in the retrieval-extinction paradigm to investigate its promotion of conditioned fear extinction in the memory reconsolidation window after participants acquired conditioned fear. This experiment comprised three stages (acquisition, unconditioned stimulus revaluation, retrieval-extinction) and three methods for indexing fear (unconditioned stimulus expectancy, skin conductance response, conditioned stimulus pleasure rating). After the acquisition phase, we decreased the intensity of the unconditioned stimulus in one group (devaluation) and maintained constant for the other group (control). The results indicated that both groups exhibited similar levels of unconditioned stimulus expectancy, but the devaluation group had significantly smaller skin conductance responses and exhibited a growth in conditioned stimulus + pleasure. Thus, our findings indicate unconditioned stimulus revaluation effectively promoted the extinction of conditioned fear within the memory reconsolidation window.

  8. Expression of conditional fear with and without awareness.

    PubMed

    Knight, David C; Nguyen, Hanh T; Bandettini, Peter A

    2003-12-09

    Conditional responding during simple Pavlovian conditioning is often characterized as a form of implicit memory. The extent to which this type of associative learning is independent of awareness is an issue of continuing debate. Previous studies have demonstrated conditioning in the absence of awareness. However, their results have been questioned based on methodological concerns with postexperimental questionnaires. In the present study, skin conductance response (SCR) and unconditioned stimulus (UCS) expectancy were measured concurrently as participants were exposed to a differential delay fear conditioning procedure in which one tone (CS+) predicted a loud white noise, whereas a second tone (CS-) was presented alone. UCS predictability was varied on a trial-by-trial basis by presenting conditioned stimuli (CSs) at volumes just above or below the perceptual threshold. Differential UCS expectancy (awareness) was observed only on perceived trials, whereas differential SCR developed on both perceived and unperceived trials. Although perceived stimuli elicited larger SCRs, the magnitude of conditioning, indexed by differential conditioned response expression (conditioned SCR to CS+ minus the SCR to CS-), was not influenced by stimulus perception. These data indicate that conditional fear can be expressed when individuals are unaware of fear-eliciting stimuli and suggest that the degree of conditioning is independent of awareness during differential Pavlovian fear conditioning.

  9. The structure of Pavlovian fear conditioning in the amygdala.

    PubMed

    Bergstrom, Hadley C; McDonald, Craig G; Dey, Smita; Tang, Haying; Selwyn, Reed G; Johnson, Luke R

    2013-11-01

    Do different brains forming a specific memory allocate the same groups of neurons to encode it? One way to test this question is to map neurons encoding the same memory and quantitatively compare their locations across individual brains. In a previous study, we used this strategy to uncover a common topography of neurons in the dorsolateral amygdala (LAd) that expressed a learning-induced and plasticity-related kinase (p42/44 mitogen-activated protein kinase; pMAPK), following auditory Pavlovian fear conditioning. In this series of experiments, we extend our initial findings to ask to what extent this functional topography depends upon intrinsic neuronal structure. We first showed that the majority (87 %) of pMAPK expression in the lateral amygdala was restricted to principal-type neurons. Next, we verified a neuroanatomical reference point for amygdala alignment using in vivo magnetic resonance imaging and in vitro morphometrics. We then determined that the topography of neurons encoding auditory fear conditioning was not exclusively governed by principal neuron cytoarchitecture. These data suggest that functional patterning of neurons undergoing plasticity in the amygdala following Pavlovian fear conditioning is specific to memory formation itself. Further, the spatial allocation of activated neurons in the LAd was specific to cued (auditory), but not contextual, fear conditioning. Spatial analyses conducted at another coronal plane revealed another spatial map unique to fear conditioning, providing additional evidence that the functional topography of fear memory storing cells in the LAd is non-random and stable. Overall, these data provide evidence for a spatial organizing principle governing the functional allocation of fear memory in the amygdala.

  10. Appetitive-aversive interactions in Pavlovian fear conditioning.

    PubMed

    Nasser, Helen M; McNally, Gavan P

    2012-06-01

    The existence of value coding and salience coding neurons in the mammalian brain, including in habenula and ventral tegmental area, has sparked considerable interest in the interactions that occur between Pavlovian appetitive and aversive conditioning. Here we studied these appetitive-aversive interactions at the behavioral level by assessing the learning that occurs when a Pavlovian appetitive conditioned stimulus (conditional stimulus, CS) serves as a CS for shock in Pavlovian fear conditioning. A Pavlovian appetitive CS was retarded in the rate at which it could be transformed into a fear CS (counterconditioning), but the presence of the appetitive CS augmented fear learning to a concurrently presented neutral CS (superconditioning). Retardation of fear learning was not alleviated by manipulations designed to restore the associability of the appetitive CS before fear conditioning but was alleviated by manipulations designed to increase the aversive quality of the shock unconditioned stimulus (US). These findings are consistent with opponent interactions between the appetitive and aversive motivational systems and provide a behavioral approach for assessing the neural correlates of these appetitive-aversive interactions.

  11. Cognitive processes during fear acquisition and extinction in animals and humans

    PubMed Central

    Hofmann, Stefan G.

    2007-01-01

    Anxiety disorders are highly prevalent. Fear conditioning and extinction learning in animals often serve as simple models of fear acquisition and exposure therapy of anxiety disorders in humans. This article reviews the empirical and theoretical literature on cognitive processes in fear acquisition, extinction, and exposure therapy. It is concluded that exposure therapy is a form of cognitive intervention that specifically changes the expectancy of harm. Implications for therapy research are discussed. PMID:17532105

  12. Computer-assisted behavioral assessment of Pavlovian fear conditioning in mice.

    PubMed

    Anagnostaras, S G; Josselyn, S A; Frankland, P W; Silva, A J

    2000-01-01

    In Pavlovian fear conditioning, a conditional stimulus (CS, usually a tone) is paired with an aversive unconditional stimulus (US, usually a foot shock) in a novel context. After even a single pairing, the animal comes to exhibit a long-lasting fear to the CS and the conditioning context, which can be measured as freezing, an adaptive defense reaction in mice. Both context and tone conditioning depend on the integrity of the amygdala, and context conditioning further depends on the hippocampus. The reliability and efficiency of the fear conditioning assay makes it an excellent candidate for the screening of learning and memory deficits in mutant mice. One obstacle is that freezing in mice has been accurately quantified only by human observers, using a tedious method that can be subject to bias. In the present study we generated a simple, high-speed, and highly accurate algorithm that scores freezing of four mice simultaneously using NIH Image on an ordinary Macintosh computer. The algorithm yielded a high correlation and excellent linear fit between computer and human scores across a broad range of conditions. This included the ability to score low pretraining baseline scores and accurately mimic the effects of two independent variables (shock intensity and test modality) on fear. Because we used a computer and digital video, we were able to acquire a secondary index of fear, activity suppression, as well as baseline activity scores. Moreover, we measured the unconditional response to shock. These additional measures can enhance the sensitivity of the assay to detect interesting memory phenotypes and control for possible confounds. Thus, this computer-assisted system for measuring behavior during fear conditioning allows for the standardized and carefully controlled assessment of multiple aspects of the fear conditioning experience.

  13. Prediction of "Fear" Acquisition in Healthy Control Participants in a De Novo Fear Conditioning Paradigm

    ERIC Educational Resources Information Center

    Otto, Michael W.; Leyro, Teresa M.; Christian, Kelly; Deveney, Christen M.; Reese, Hannah; Pollack, Mark H.; Orr, Scott P.

    2007-01-01

    Studies using fear-conditioning paradigms have found that anxiety patients are more conditionable than individuals without these disorders, but these effects have been demonstrated inconsistently. It is unclear whether these findings have etiological significance or whether enhanced conditionability is linked only to certain anxiety…

  14. Modeling processes in the acquisition of fears: vicarious electrodermal conditioning to fear-relevant stimuli.

    PubMed

    Hygge, S; Ohman, A

    1978-03-01

    Fear-relevant (snakes, spiders, and rats) and fear-irrelevant (flowers, mushrooms, and berries) pictures were compared as conditioned and instigating stimuli in a vicarious classical conditioning paradigm with skin conductance responses as the dependent variable. A female confederate model and subject watched the pictures side by side. A female stimulus presentations, the experimenter interrupted to investigate alleged overreactions of the model to one of the stimulus classes. The model then vividly described a phobia for this object, which was to serve as a vicarious instigating stimulus. The experiment continued for a few conditioning trials, and then the experimenter announced that the disturbing stimulus would be omitted before the second part of the experiment. There was no effect of stimulus content on vicariously instigated responses, although significant overall instigation was observed. However, the responses to the stimulus that was paired with the model's phobic stimulus, that is, the vicariously conditioned responses, failed to extinguish during the second part of the experiment when it was fear-relevant but extinguished immediately when it was fear-irrelevant.

  15. Adrenergic Transmission Facilitates Extinction of Conditional Fear in Mice

    ERIC Educational Resources Information Center

    Barad, Mark; Cain, Christopher K.; Blouin, Ashley M.

    2004-01-01

    Extinction of classically conditioned fear, like its acquisition, is active learning, but little is known about its molecular mechanisms. We recently reported that temporal massing of conditional stimulus (CS) presentations improves extinction memory acquisition, and suggested that temporal spacing was less effective because individual CS…

  16. Sex Differences in Response to an Observational Fear Conditioning Procedure

    ERIC Educational Resources Information Center

    Kelly, Megan M.; Forsyth, John P.

    2007-01-01

    The present study evaluated sex differences in observational fear conditioning using modeled ''mock'' panic attacks as an unconditioned stimulus (UCS). Fifty-nine carefully prescreened healthy undergraduate participants (30 women) underwent 3 consecutive differential conditioning phases: habituation, acquisition, and extinction. It was expected…

  17. Sex Differences in Response to an Observational Fear Conditioning Procedure

    ERIC Educational Resources Information Center

    Kelly, Megan M.; Forsyth, John P.

    2007-01-01

    The present study evaluated sex differences in observational fear conditioning using modeled ''mock'' panic attacks as an unconditioned stimulus (UCS). Fifty-nine carefully prescreened healthy undergraduate participants (30 women) underwent 3 consecutive differential conditioning phases: habituation, acquisition, and extinction. It was expected…

  18. Adrenergic Transmission Facilitates Extinction of Conditional Fear in Mice

    ERIC Educational Resources Information Center

    Barad, Mark; Cain, Christopher K.; Blouin, Ashley M.

    2004-01-01

    Extinction of classically conditioned fear, like its acquisition, is active learning, but little is known about its molecular mechanisms. We recently reported that temporal massing of conditional stimulus (CS) presentations improves extinction memory acquisition, and suggested that temporal spacing was less effective because individual CS…

  19. Topiramate diminishes fear memory consolidation and extinguishes conditioned fear in rats

    PubMed Central

    do Prado-Lima, Pedro Antônio Schmidt; Perrenoud, Myriam Fortes; Kristensen, Christian Haag; Cammarota, Martin; Izquierdo, Ivan

    2011-01-01

    Background Topiramate has been recognized as a drug that can induce memory and cognitive impairment. Using the one-trial inhibitory avoidance task, we sought to verify the effect of topiramate on consolidation and extinction of aversive memory. Our hypothesis was that topiramate inhibits the consolidation and enhances the extinction of this fear memory. Methods In experiment 1, which occured immediately or 3 hours after training, topiramate was administered to rats, and consolidation of memory was verified 18 days after the conditioning session. In experiment 2, which occured 18–22 days after the training session, rats were submitted to the extinction protocol. Rats received topiramate 14 days before or during the extinction protocol. Results Topiramate blocked fear memory retention (p < 0.01) and enhanced fear memory extinction (p < 0.001) only when administered during the extinction protocol. Limitations This experimental design did not allow us to determine whether topiramate also blocked the reconsolidation of fear memory. Conclusion Topiramate diminishes fear memory consolidation and promotes extinction of inhibitory avoidance memory. PMID:21392483

  20. Fear Conditioning, Synaptic Plasticity, and the Amygdala: Implications for Posttraumatic Stress Disorder

    PubMed Central

    Mahan, Amy L.; Ressler, Kerry J.

    2011-01-01

    Posttraumatic stress disorder (PTSD) is an anxiety disorder that can develop after a traumatic experience such as domestic violence, natural disasters or combat-related trauma. The cost of such disorders on society and the individual can be tremendous. In this article we will review how the neural circuitry implicated in PTSD in humans is related to the neural circuitry of fear. We then discuss how fear conditioning is a suitable model for studying the molecular mechanisms of the fear components which underlie PTSD, and the biology of fear conditioning with a particular focus on the brain derived neurotropic factor (BDNF)-TrkB, GABAergic and glutamatergic ligand-receptor systems. We then summarize how such approaches may help to inform our understanding of PTSD and other stress-related disorders and provide insight to new pharmacological avenues of treatment of PTSD. PMID:21798604

  1. Effects of repeated tickling on conditioned fear and hormonal responses in socially isolated rats.

    PubMed

    Hori, Miyo; Yamada, Kazuo; Ohnishi, Junji; Sakamoto, Shigeko; Takimoto-Ohnishi, Eriko; Miyabe, Shigeki; Murakami, Kazuo; Ichitani, Yukio

    2013-03-01

    Positive emotional states have been reported to modify human resilience to fear and anxiety, but few animal models are available to elucidate underlying mechanisms. In the current study, we examined whether 2 weeks of tickling, which is considered to evoke positive emotions, alters conditioned fear and hormonal reactions in Fischer rats. We conditioned rats to fear an auditory tone which was initially paired with a mild foot-shock (0.2mA), and retention test was conducted 48h and 96h after conditioning. During these tests, we found that prior tickling treatment significantly diminished fear-induced freezing. To examine the effects of tickling on sympatho-adrenal and hypothalamic-pituitary-adrenal responses associated with conditioned fear, we measured plasma catecholamine and corticosterone levels in the retention test 96h after conditioning. The plasma catecholamine concentration of non-tickled rats was higher than basal levels, whereas tickled rats showed significantly reduced concentrations of both plasma adrenaline and noradrenaline. No significant differences in plasma corticosterone levels were observed between tickled and non-tickled rats. These results suggest that repeated exposure to tickling can modulate fear-related behavior and sympatho-adrenal stress responses. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  2. Post-weaning social isolation impairs observational fear conditioning.

    PubMed

    Yusufishaq, Shabana; Rosenkranz, J Amiel

    2013-04-01

    Many mammals can utilize social information to learn by observation of conspecifics (social learning). Social learning of fear is expected to be especially advantageous for survival. However, disruption of social development in early life can impair social cognition and might also be expected to disrupt social learning. Social isolation during a critical period of adolescence disrupts social development. The purpose of this study was to determine whether disruption of social development through post-weaning social isolation leads to impairments of social fear learning. Rats were reared in isolation or pair-housed from immediately post-weaning, for 3 weeks. Social fear learning in rats was acquired by observation of tone-footshock pairings administered to a conspecific. Isolation-reared rats displayed less conditioned freezing than pair-housed rats when tested the next day. This reduction of conditioned freezing was correlated with conspecific-oriented behaviors during conditioning, was measured despite similarities in demonstrator behaviors, and occurred despite a manipulation that equalized freezing during conditioning between the pair-housed and isolation-reared rats. The results could not be explained by abnormal sensitization to a repeated tone or deficits in freezing or direct fear conditioning. These results demonstrate that observational fear conditioning is impaired by social isolation, and provide a model to study impaired social affective learning. Impaired social cognition, manifested as inability to recognize or appropriately interpret social cues, is a symptom of several psychiatric disorders. Better understanding of the mechanisms of impaired social fear learning can lead to novel treatments for social cognition symptoms of psychiatric disorders. Copyright © 2013 Elsevier B.V. All rights reserved.

  3. Post-weaning Social Isolation Impairs Observational Fear Conditioning

    PubMed Central

    Yusufishaq, Shabana; Rosenkranz, J. Amiel

    2013-01-01

    Many mammals can utilize social information to learn by observation of conspecifics (social learning). Social learning of fear is expected to be especially advantageous for survival. However, disruption of social development in early life can impair social cognition and might also be expected to disrupt social learning. Social isolation during a critical period of adolescence disrupts social development. The purpose of this study was to determine whether disruption of social development through post-weaning social isolation leads to impairments of social fear learning. Rats were reared in isolation or pair-housed from immediately post-weaning, for 3 weeks. Social fear learning in rats was acquired by observation of tone-footshock pairings administered to a conspecific. Isolation-reared rats displayed less conditioned freezing than pair-housed rats when tested the next day. This reduction of conditioned freezing was correlated with conspecific-oriented behaviors during conditioning, was measured despite similarities in demonstrator behaviors, and occurred despite a manipulation that equalized freezing during conditioning between the pair-housed and isolation-reared rats. The results could not be explained by abnormal sensitization to a repeated tone or deficits in freezing or direct fear conditioning. These results demonstrate that observational fear conditioning is impaired by social isolation, and provide a model to study impaired social affective learning. Impaired social cognition, manifested as inability to recognize or appropriately interpret social cues, is a symptom of several psychiatric disorders. Better understanding of the mechanisms of impaired social fear learning can lead to novel treatments for social cognition symptoms of psychiatric disorders. PMID:23295398

  4. Early extinction after fear conditioning yields a context-independent and short-term suppression of conditional freezing in rats.

    PubMed

    Chang, Chun-hui; Maren, Stephen

    2009-01-01

    Extinction of Pavlovian fear conditioning in rats is a useful model for therapeutic interventions in humans with anxiety disorders. Recently, we found that delivering extinction trials soon (15 min) after fear conditioning yields a short-term suppression of fear, but little long-term extinction. Here, we explored the possible mechanisms underlying this deficit by assessing the suppression of fear to a CS immediately after extinction training (Experiment 1) and the context specificity of fear after both immediate and delayed extinction training (Experiment 2). We also examined the time course of the immediate extinction deficit (Experiment 3). Our results indicate that immediate extinction produces a short-lived and context-independent suppression of conditional freezing. Deficits in long-term extinction were apparent even when the extinction trials were given up to 6 h after conditioning. Moreover, this deficit was not due to different retention intervals that might have influenced the degree of spontaneous recovery after immediate and delayed extinction (Experiment 4). These results suggest that fear suppression under immediate extinction may be due to a short-term, context-independent habituation process, rather than extinction per se. Long-term extinction memory only develops when extinction training occurs at least six hours after conditioning.

  5. Contextual fear conditioning differs for infant, adolescent, and adult rats

    PubMed Central

    Esmorís-Arranz, Francisco J.; Méndez, Cástor; Spear, Norman E.

    2009-01-01

    Contextual fear conditioning was tested in infant, adolescent, and adult rats in terms of Pavlovian conditioned suppression. When a discrete auditory conditioned stimulus (CS) was paired with footshock (unconditioned stimulus, US) within the largely olfactory context, infants and adolescents conditioned to the context with substantial effectiveness but adult rats did not. When unpaired presentations of the CS and US occurred within the context, contextual fear conditioning was strong for adults, weak for infants, but about as strong for adolescents as when pairings of CS and US occurred in the context. Nonreinforced presentations of either the CS or context markedly reduced contextual fear conditioning in infants, but, in adolescents, CS extinction had no effect on contextual fear conditioning, although context extinction significantly reduced it. Neither CS extinction nor context extinction affected responding to the CS-context compound in infants, suggesting striking discrimination between the compound and its components. Female adolescents showed the same lack of effect of component extinction on response to the compound as infants, but CS extinction reduced responding to the compound in adolescent males, a sex difference seen also in adults. Theoretical implications are discussed for the development of perceptual-cognitive processing and hippocampus role. PMID:18343048

  6. Nicotine enhances both foreground and background contextual fear conditioning

    PubMed Central

    Davis, Jennifer A.; Porter, Jessica; Gould, Thomas J.

    2009-01-01

    The present study examined if nicotine enhances contextual fear conditioning when the training context is either a background stimulus or a foreground stimulus. In the background conditioning experiment, mice were trained using two auditory conditioned stimulus (CS; 30 s, 85 dB white noise)–footshock unconditioned stimulus (US; 2 s, 0.57 mA) pairings and tested 24 h later. In the foreground conditioning experiment, mice were trained with two presentations of a footshock US (2 s, 0.57 mA) and tested 24 h later. Mice received 0.09 mg/kg nicotine before training and testing. For both the foreground and background conditioning experiments, nicotine enhanced contextual conditioning. No enhancement of the auditory CS–US association was seen. These results demonstrate that nicotine enhances contextual fear conditioning regardless of whether the context is a background stimulus or a foreground stimulus during conditioning. PMID:16260086

  7. Social partnering alters sleep in fear-conditioned Wistar rats.

    PubMed

    DaSilva, Jamie K; Husain, Eram; Lei, Yanlin; Mann, Graziella L; Morrison, Adrian R; Tejani-Butt, Shanaz

    2017-01-01

    Social support, when provided following a traumatic experience, is associated with a lower incidence of stress-related psychiatric disorders. Our hypothesis was that providing a social interaction period with a naive conspecific would improve sleep architecture in response to cued fear conditioning in Wistar rats. Rats were randomly assigned to either the socially isolated or socially partnered groups. Rats assigned to the socially isolated group were individually housed following electrode implantation and fear conditioning. Rats assigned to the socially partnered group were initially paired-housed, and then one rat from each pair was randomly chosen for sleep electrode implantation and fear conditioning. Rats from both groups were habituated to a recording chamber, and baseline sleep was recorded over 22 hours. One day later (Training Day), they were fear-conditioned to 10 presentations of a tone (800 Hz, 90 dB, 5 sec) co-terminating with a mild electric foot shock (1.0 mA, 0.5 sec), at 30-sec intervals. While rats in the socially isolated group were left undisturbed in their home cage for 30-min, socially partnered rats interacted for 30 minutes with their non-stressed rat partner immediately after fear conditioning and while the auditory tones were presented on Days 1 and 14. The results indicated that social interaction increased sleep efficiency in partnered rats compared to isolated rats following the fear conditioning procedure. This was due to an increase in the amount of rapid eye movement sleep (REMS) during the light phase. Evaluation of REMS microarchitecture revealed that the increase in REMS was due to an increase in the number of single REMS episodes (siREMS), which represented a more consolidated REMS pattern. A surprising finding was that partnered rats had a greater number of sequential REMS episodes (seqREMS) at Baseline, on the Training Day and on Day 1 when compared to isolated rats. The greater number of seqREMS episodes in partnered rats may

  8. Neural Substrates of Overgeneralized Conditioned Fear in PTSD.

    PubMed

    Kaczkurkin, Antonia N; Burton, Philip C; Chazin, Shai M; Manbeck, Adrienne B; Espensen-Sturges, Tori; Cooper, Samuel E; Sponheim, Scott R; Lissek, Shmuel

    2017-02-01

    Heightened generalization of fear from an aversively reinforced conditioned stimulus (CS+, a conditioned danger cue) to resembling stimuli is widely accepted as a pathogenic marker of posttraumatic stress disorder (PTSD). Indeed, a distress response to benign stimuli that "resemble" aspects of the trauma is a central feature of the disorder. To date, the link between overgeneralization of conditioned fear and PTSD derives largely from clinical observations, with limited empirical work on the subject. This represents the first effort to examine behavioral and brain indices of generalized conditioned fear in PTSD using systematic methods developed in animals known as generalization gradients: the gradual decline in conditioned responding as the presented stimulus gradually differentiates from CS+. Gradients of conditioned fear generalization were assessed using functional MRI and behavioral measures in U.S. combat veterans who served in Iraq or Afghanistan and had PTSD (N=26), subthreshold PTSD (N=19), or no PTSD (referred to as trauma control subjects) (N=17). Presented stimuli included rings of graded size, with extreme sizes serving as CS+ (paired with shock) and as a nonreinforced conditioned stimulus (CS-, a conditioned safety cue), and with intermediate sizes forming a continuum of similarity between CS+ and CS-. Generalization gradients were assessed as response slopes from CS+, through intermediate ring sizes, to CS-, with less steep slopes indicative of stronger generalization. Relative to trauma control subjects, PTSD patients showed stronger conditioned generalization, as evidenced by less steep generalization gradients in both behavioral risk ratings and brain responses in the left and right anterior insula, left ventral hippocampus, dorsolateral and dorsomedial prefrontal cortex, and caudate nucleus. Severity of PTSD symptoms across the three study groups was positively correlated with levels of generalization at two such loci: the right anterior insula

  9. Fear Conditioning Induced by Interpersonal Conflicts in Healthy Individuals

    PubMed Central

    Tada, Mitsuhiro; Uchida, Hiroyuki; Maeda, Takaki; Konishi, Mika; Umeda, Satoshi; Terasawa, Yuri; Nakajima, Shinichiro; Mimura, Masaru; Miyazaki, Tomoyuki; Takahashi, Takuya

    2015-01-01

    Psychophysiological markers have been focused to investigate the psychopathology of psychiatric disorders and personality subtypes. In order to understand neurobiological mechanisms underlying these conditions, fear-conditioning model has been widely used. However, simple aversive stimuli are too simplistic to understand mechanisms because most patients with psychiatric disorders are affected by social stressors. The objective of this study was to test the feasibility of a newly-designed conditioning experiment using a stimulus to cause interpersonal conflicts and examine associations between personality traits and response to that stimulus. Twenty-nine healthy individuals underwent the fear conditioning and extinction experiments in response to three types of stimuli: a simple aversive sound, disgusting pictures, and pictures of an actors’ face with unpleasant verbal messages that were designed to cause interpersonal conflicts. Conditioned response was quantified by the skin conductance response (SCR). Correlations between the SCR changes, and personality traits measured by the Zanarini Rating Scale for Borderline Personality Disorder (ZAN-BPD) and Revised NEO Personality Inventory were explored. The interpersonal conflict stimulus resulted in successful conditioning, which was subsequently extinguished, in a similar manner as the other two stimuli. Moreover, a greater degree of conditioned response to the interpersonal conflict stimulus correlated with a higher ZAN-BPD total score. Fear conditioning and extinction can be successfully achieved, using interpersonal conflicts as a stimulus. Given that conditioned fear caused by the interpersonal conflicts is likely associated with borderline personality traits, this paradigm could contribute to further understanding of underlying mechanisms of interpersonal fear implicated in borderline personality disorder. PMID:25978817

  10. Generalisation of conditioned fear and its behavioural expression in mice.

    PubMed

    Laxmi, T Rao; Stork, Oliver; Pape, Hans-Christian

    2003-10-17

    Mice are favourite subjects in molecular and genetic memory research and frequently studied with classical fear conditioning paradigms that use an auditory cue (conditioned stimulus, CS(+)) to predict an aversive, unconditioned stimulus (US). Yet the conditions that control fear memory specificity and generalisation and their behavioural expression in such conditioned mice have not been analysed systematically. In the current study we addressed these issues in the most widely used mouse strain of behavioural genetics, C57Bl/6. In keeping with findings in other species we demonstrate the dependence of fear memory generalisation on training intensity (i.e. both US intensity and the number of CS(+) and US applied) after both excitatory (explicitly paired presentation of CS(+) and US) and inhibitory training (explicitly unpaired presentation of CS(+) and US). Furthermore, inhibitory overtraining was associated with changes of uncued anxiety-like behaviour in a light/dark exploration test, indicative of an emotional sensitisation reaction as consequence of a lack of US predictability. Together our results describe the qualitatively and quantitatively different increases of defensive behaviour in response to conditioned stimuli of different salience and identify training conditions that lead to fear memory generalisation and emotional sensitisation in C57Bl/6 inbred mice.

  11. The accurate measurement of fear memory in Pavlovian conditioning: Resolving the baseline issue.

    PubMed

    Jacobs, Nathan S; Cushman, Jesse D; Fanselow, Michael S

    2010-07-15

    Fear conditioning has become an indispensable behavioral task in an increasingly vast array of research disciplines. Yet one unresolved issue is how conditional fear to an explicit cue interacts with and is potentially confounded by fear prior to tone presentation, referred to as baseline fear. After tone-shock pairings, we experimentally manipulated baseline fear by presenting unpaired shocks in the testing chamber and then analyzed the accuracy of common methods for reporting tone fear. Our findings indicate that baseline fear and tone fear tend to interact, where freezing to the tone increases as baseline fear increases. However, the form of interaction is not linear across all conditions and none of the commonly used reporting methods were consistently able to eliminate the confounding effects of baseline fear. We propose a methodological solution in which baseline fear is reduced to very low levels by first extinguishing fear to the training context and then pre-exposing to the testing context.

  12. Hyperresponsiveness of the Neural Fear Network During Fear Conditioning and Extinction Learning in Male Cocaine Users.

    PubMed

    Kaag, Anne Marije; Levar, Nina; Woutersen, Karlijn; Homberg, Judith; van den Brink, Wim; Reneman, Liesbeth; van Wingen, Guido

    2016-10-01

    The authors investigated whether cocaine use disorder is associated with abnormalities in the neural underpinnings of aversive conditioning and extinction learning, as these processes may play an important role in the development and persistence of drug abuse. Forty male regular cocaine users and 51 male control subjects underwent a fear conditioning and extinction protocol during functional MRI. Skin conductance response was measured throughout the experiment as an index of conditioned responses. Cocaine users showed hyperresponsiveness of the amygdala and insula during fear conditioning, as well as hyporesponsiveness of the dorsomedial prefrontal cortex during extinction learning. In cocaine users, but not in control subjects, skin conductance responses were positively correlated with responsiveness of the insula, amygdala, and dorsomedial prefrontal cortex during fear conditioning but negatively correlated with responsiveness of the ventromedial prefrontal cortex during extinction learning. Increased sensitivity to aversive conditioned cues in cocaine users might be a risk factor for stress-relief craving in cocaine use disorder. These results support the postulated role of altered aversive conditioning in cocaine use disorder and may be an important step in understanding the role of aversive learning in the pathology of cocaine use disorder.

  13. Teens that fear screams: A comparison of fear conditioning, extinction, and reinstatement in adolescents and adults.

    PubMed

    Den, Miriam Liora; Graham, Bronwyn M; Newall, Carol; Richardson, Rick

    2015-11-01

    This study investigated differences between adolescents and adults on fear conditioning, extinction, and reinstatement (i.e., the recovery of conditioned fear following re-exposure to the unconditioned stimulus [US] post-extinction). Participants underwent differential conditioning (i.e., the Screaming Lady) where one neutral face (CS+) was followed by the same face expressing fear and a loud scream (US) while another neutral face (CS-) remained neutral. Extinction involved non-reinforced presentations of both CSs, after which participants were reinstated (2xUSs) or not. On two self-report measures, both ages showed conditioning, good extinction learning and retention, and reinstatement-induced relapse. However, only adolescents showed conditioning, extinction, and reinstatement on the eye tracking measure; relapse on this measure could not be assessed in adults given they did not show initial conditioning. Lastly, higher levels of depression predicted stronger conditioning and weaker extinction in adolescents only. These findings are discussed in terms of their implications for adolescent anxiety disorders.

  14. A differential neural response in the human amygdala to fearful and happy facial expressions.

    PubMed

    Morris, J S; Frith, C D; Perrett, D I; Rowland, D; Young, A W; Calder, A J; Dolan, R J

    1996-10-31

    The amygdala is thought to play a crucial role in emotional and social behaviour. Animal studies implicate the amygdala in both fear conditioning and face perception. In humans, lesions of the amygdala can lead to selective deficits in the recognition of fearful facial expressions and impaired fear conditioning, and direct electrical stimulation evokes fearful emotional responses. Here we report direct in vivo evidence of a differential neural response in the human amygdala to facial expressions of fear and happiness. Positron-emission tomography (PET) measures of neural activity were acquired while subjects viewed photographs of fearful or happy faces, varying systematically in emotional intensity. The neuronal response in the left amygdala was significantly greater to fearful as opposed to happy expressions. Furthermore, this response showed a significant interaction with the intensity of emotion (increasing with increasing fearfulness, decreasing with increasing happiness). The findings provide direct evidence that the human amygdala is engaged in processing the emotional salience of faces, with a specificity of response to fearful facial expressions.

  15. The relative effectiveness of extinction and counter-conditioning in diminishing children's fear.

    PubMed

    Newall, Carol; Watson, Tiffany; Grant, Kerry-Ann; Richardson, Rick

    2017-08-01

    Two behavioural strategies for reducing learned fear are extinction and counter-conditioning, and in this study we compared the relative effectiveness of the two procedures at diminishing fear in children. Seventy-three children aged 7-12 years old (M = 9.30, SD = 1.62) were exposed to pictures of two novel animals on a computer screen during the fear acquisition phase. One of these animals was paired with a picture of a scared human face (CS+) while the other was not (CS-). The children were then randomly assigned to one of three conditions: counter-conditioning (animal paired with a happy face), extinction (animal without scared face), or control (no fear reduction procedure). Changes in fear beliefs and behavioural avoidance of the animal were measured. Counter-conditioning was more effective at reducing fear to the CS + than extinction. The findings are discussed in terms of implications for behavioural treatments of childhood anxiety disorders. Crown Copyright © 2017. Published by Elsevier Ltd. All rights reserved.

  16. 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.

  17. Eye Movements Index Implicit Memory Expression in Fear Conditioning.

    PubMed

    Hopkins, Lauren S; Schultz, Douglas H; Hannula, Deborah E; Helmstetter, Fred J

    2015-01-01

    The role of contingency awareness in simple associative learning experiments with human participants is currently debated. Since prior work suggests that eye movements can index mnemonic processes that occur without awareness, we used eye tracking to better understand the role of awareness in learning aversive Pavlovian conditioning. A complex real-world scene containing four embedded household items was presented to participants while skin conductance, eye movements, and pupil size were recorded. One item embedded in the scene served as the conditional stimulus (CS). One exemplar of that item (e.g. a white pot) was paired with shock 100 percent of the time (CS+) while a second exemplar (e.g. a gray pot) was never paired with shock (CS-). The remaining items were paired with shock on half of the trials. Participants rated their expectation of receiving a shock during each trial, and these expectancy ratings were used to identify when (i.e. on what trial) each participant became aware of the programmed contingencies. Disproportionate viewing of the CS was found both before and after explicit contingency awareness, and patterns of viewing distinguished the CS+ from the CS-. These observations are consistent with "dual process" models of fear conditioning, as they indicate that learning can be expressed in patterns of viewing prior to explicit contingency awareness.

  18. Eye Movements Index Implicit Memory Expression in Fear Conditioning

    PubMed Central

    Hopkins, Lauren S.; Schultz, Douglas H.; Hannula, Deborah E.; Helmstetter, Fred J.

    2015-01-01

    The role of contingency awareness in simple associative learning experiments with human participants is currently debated. Since prior work suggests that eye movements can index mnemonic processes that occur without awareness, we used eye tracking to better understand the role of awareness in learning aversive Pavlovian conditioning. A complex real-world scene containing four embedded household items was presented to participants while skin conductance, eye movements, and pupil size were recorded. One item embedded in the scene served as the conditional stimulus (CS). One exemplar of that item (e.g. a white pot) was paired with shock 100 percent of the time (CS+) while a second exemplar (e.g. a gray pot) was never paired with shock (CS-). The remaining items were paired with shock on half of the trials. Participants rated their expectation of receiving a shock during each trial, and these expectancy ratings were used to identify when (i.e. on what trial) each participant became aware of the programmed contingencies. Disproportionate viewing of the CS was found both before and after explicit contingency awareness, and patterns of viewing distinguished the CS+ from the CS-. These observations are consistent with “dual process” models of fear conditioning, as they indicate that learning can be expressed in patterns of viewing prior to explicit contingency awareness. PMID:26562298

  19. Delayed extinction fails to reduce skin conductance reactivity to fear-conditioned stimuli.

    PubMed

    Fricchione, Jon; Greenberg, Mark S; Spring, Justin; Wood, Nellie; Mueller-Pfeiffer, Christoph; Milad, Mohammed R; Pitman, Roger K; Orr, Scott P

    2016-09-01

    A brief 10-min time delay between an initial and subsequent exposure to extinction trials has been found to impair memory reconsolidation in fear-conditioned rodents and humans, providing a potential means to reduce fearfulness in anxiety disorders and posttraumatic stress disorder (PTSD). The present study used videos of biologically prepared, conditioned stimuli (tarantulas) to test the efficacy of delayed extinction in blocking reconsolidation of conditioned fear in healthy young adults. Strong differential conditioning, measured by skin conductance, was observed among a screened subset of participants during acquisition. However, the delayed-extinction intervention failed to reduce reactivity to the conditioned stimulus paired with the extinction delay. These results are partially consistent with other recent, mixed findings and point to a need for testing other candidate interventions designed to interfere with the reconsolidation process. © 2016 Society for Psychophysiological Research.

  20. Prereactivation propranolol fails to reduce skin conductance reactivity to prepared fear-conditioned stimuli.

    PubMed

    Spring, Justin D; Wood, Nellie E; Mueller-Pfeiffer, Christoph; Milad, Mohammed R; Pitman, Roger K; Orr, Scott P

    2015-03-01

    Pharmacologic blockade of memory reconsolidation has been demonstrated in fear-conditioned rodents and humans and may provide a means to reduce fearfulness in anxiety disorders and posttraumatic stress disorder. Studying the efficacy of potential interventions in clinical populations is challenging, creating a need for paradigms within which candidate reconsolidation-blocking interventions can be readily tested. We used videos of biologically prepared conditioned stimuli (tarantulas) to test the efficacy of propranolol in blocking reconsolidation of conditioned fear in healthy young adults. Strong differential conditioning, measured by skin conductance, was observed among a screened subset of participants during acquisition. However, subsequent propranolol failed to reduce reactivity to the reactivated conditioned stimulus. These results are consistent with other recent findings and point to a need for testing other candidate drugs. © 2014 Society for Psychophysiological Research.

  1. Yale University's Institute of Human Relations and the Spanish Civil War: Dollard and Miller's study of fear and courage under battle conditions.

    PubMed

    Gondra, José María; Sánchez de Miguel, Manuel

    2009-11-01

    In the late 1930s, the Institute of Human Relations of Yale University developed a research program on conflict and anxiety as an outcome of Clark Hull's informal seminar on the integration of Freud's and Pavlov's theories. The program was launched at the 1937 Annual Meeting of the APA in a session chaired by Clark L. Hull, and the experiments continued through 1941, when the United States entered the Second World War. In an effort to apply the findings from animal experiments to the war situation, John Dollard and Neal E. Miller decided to study soldiers' fear reactions in combat. As a first step, they arranged interviews with a few veterans of the Abraham Lincoln Brigade. Taking these interviews as a point of departure, Dollard devised a questionnaire to which 300 former Lincoln brigaders responded. The present paper analyzes the main outcomes of the questionnaire, together with the war experiences reported in the interview transcripts. Our purpose was to evaluate a project which was initially investigated by the FBI because of the communists among the Lincoln ranks, but eventually supported by the American Army, and which exerted great influence on the military psychology of the time.

  2. Secondary extinction in Pavlovian fear conditioning.

    PubMed

    Vurbic, Drina; Bouton, Mark E

    2011-09-01

    Pavlov (1927/1960) reported that following the conditioning of several stimuli, extinction of one conditioned stimulus (CS) attenuated responding to others that had not undergone direct extinction. However, this secondary extinction effect has not been widely replicated in the contemporary literature. In three conditioned suppression experiments with rats, we further explored the phenomenon. In Experiment 1, we asked whether secondary extinction is more likely to occur with target CSs that have themselves undergone some prior extinction. A robust secondary extinction effect was obtained with a nonextinguished target CS. Experiment 2 showed that extinction of one CS was sufficient to reduce renewal of a second CS when it was tested in a neutral (nonextinction) context. In Experiment 3, secondary extinction was observed in groups that initially received intermixed conditioning trials with the target and nontarget CSs, but not in groups that received conditioning of the two CSs in separate sessions. The results are consistent with the hypothesis that CSs must be associated with a common temporal context during conditioning for secondary extinction to occur.

  3. Blockade of CB1 receptors prevents retention of extinction but does not increase low pre-incubated conditioned fear in the fear incubation procedure

    PubMed Central

    Pickens, Charles L.; Theberge, Florence R.

    2015-01-01

    We recently developed a procedure to study fear incubation in which rats given 100 tone-shock pairings over 10 days show low fear 2 days after conditioned fear training and high fear after 30 days. Notably, fear 2 days after 10 sessions of fear conditioning is lower than fear seen 2 days after a single session of fear conditioning, suggesting that fear is suppressed. Here, we investigate the potential role of CB1 receptor activation by endocannabinoids in this fear suppression. We gave rats 10 days of fear conditioning and then gave systemic injections of the CB1 receptor antagonist SR141716 before a conditioned fear test conducted 2 days later under extinction conditions. A second test was conducted without any injections on the following day (3 days post-training) to examine fear extinction retention. SR141716 injections did not increase fear expression 2 days after extended fear conditioning or affect within-session extinction, but impaired retention of between-session fear extinction in the day 3 test. These data suggest that CB1 receptor activation is not suppressing fear soon after extended fear conditioning in the fear incubation task. The data also add to an existing literature on the effects of CB1 receptors in extinction of conditioned fear. PMID:24346290

  4. Hippocampal encoding of interoceptive context during fear conditioning.

    PubMed

    Yoo, S-W; Bae, M; Tovar-Y-Romo, L B; Haughey, N J

    2017-01-03

    Rodent models of auditory fear conditioning are often used to understand the molecular mechanisms regulating fear- and anxiety-related behaviors. Conditioning and extinction memories are influenced by contextual cues, and the reinstatement of conditioned fear occurs when the conditioning stimulus is presented in a context different from the extinction context. Although it has been proposed that internal state is a feature of context that could influence extinction, contributions of interoception to conditioning have not been experimentally addressed. Here we use ethanol (EtOH) to show that interoceptive cues are encoded through the hippocampus by mechanisms that involve increased phosphorylation of GluR1 on serine 845, and biophysical alterations in neuronal membranes that facilitate stabilization of surface-located calcium-permeable n-2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl) propanoic acid (AMPA) receptor (AMPAR) into membrane microdomains. Conflicting interoceptive cues during extinction and fear relapse testing resulted in a failure to consolidate extinction that was reversed by the administration of AMPAR antagonists immediately following the retrieval cue.

  5. Ethnic Differences in Physiological Responses to Fear Conditioned Stimuli

    PubMed Central

    Martínez, Karen G.; Franco-Chaves, José A.; Milad, Mohammed R.; Quirk, Gregory J.

    2014-01-01

    The idea that emotional expression varies with ethnicity is based largely on questionnaires and behavioral observations rather than physiological measures. We therefore compared the skin conductance responses (SCR) of Hispanic (Puerto Rican) and White non-Hispanic subjects in a fear conditioning and fear extinction task. Subjects were recruited from two sites: San Juan, Puerto Rico (PR), and Boston, Massachusetts (MA), using identical methods. A total of 78 healthy subjects (39 from PR, 39 from MA) were divided by sex and matched for age and educational level. Females from the two sites did not differ in their SCRs during any experimental phase of fear conditioning (habituation, conditioning, or extinction). In contrast, PR males responded significantly to the conditioned stimulus than MA males or PR females. Subtracting ethnic differences observed during the habituation phase (prior to conditioning) eliminated differences from subsequent phases, suggesting that PR males are elevated in their response to novelty rather than fear learning. Our findings suggest that, in addition to sex differences, there are ethnic differences in physiological responses to novel stimuli at least in males, which could be relevant for the assessment and treatment of anxiety disorders. PMID:25501365

  6. Auditory-evoked spike firing in the lateral amygdala and Pavlovian fear conditioning: mnemonic code or fear bias?

    PubMed

    Goosens, Ki A; Hobin, Jennifer A; Maren, Stephen

    2003-12-04

    Amygdala neuroplasticity has emerged as a candidate substrate for Pavlovian fear memory. By this view, conditional stimulus (CS)-evoked activity represents a mnemonic code that initiates the expression of fear behaviors. However, a fear state may nonassociatively enhance sensory processing, biasing CS-evoked activity in amygdala neurons. Here we describe experiments that dissociate auditory CS-evoked spike firing in the lateral amygdala (LA) and both conditional fear behavior and LA excitability in rats. We found that the expression of conditional freezing and increased LA excitability was neither necessary nor sufficient for the expression of conditional increases in CS-evoked spike firing. Rather, conditioning-related changes in CS-evoked spike firing were solely determined by the associative history of the CS. Thus, our data support a model in which associative activity in the LA encodes fear memory and contributes to the expression of learned fear behaviors.

  7. 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.

  8. Learning to fear suffocation: a new paradigm for interoceptive fear conditioning.

    PubMed

    Pappens, Meike; Smets, Elyn; Vansteenwegen, Debora; Van Den Bergh, Omer; Van Diest, Ilse

    2012-06-01

    The present study aimed to establish a new interoceptive fear conditioning paradigm. The conditioned stimulus (CS) was a flow resistor that slightly obstructs breathing; the unconditional stimulus (US) was a breathing occlusion. The paired group (N = 21) received 6 acquisition trials with paired CS-US presentations. The unpaired group (N = 19) received 6 trials of unpaired CS-US presentations. In the extinction phase, both groups were administered 6 CS-only trials. Measurements included startle eyeblink response, electrodermal responses, and self-reported US expectancy. In the paired group, startle blink responses were larger during CS compared to intertrial interval during acquisition and extinction. Electrodermal and US expectancies were larger for the paired than for the unpaired group during acquisition, but not during extinction. The present paradigm successfully established interoceptive fear conditioning with panic-relevant stimuli. Copyright © 2012 Society for Psychophysiological Research.

  9. The human amygdala and the induction and experience of fear.

    PubMed

    Feinstein, Justin S; Adolphs, Ralph; Damasio, Antonio; Tranel, Daniel

    2011-01-11

    Although clinical observations suggest that humans with amygdala damage have abnormal fear reactions and a reduced experience of fear, these impressions have not been systematically investigated. To address this gap, we conducted a new study in a rare human patient, SM, who has focal bilateral amygdala lesions. To provoke fear in SM, we exposed her to live snakes and spiders, took her on a tour of a haunted house, and showed her emotionally evocative films. On no occasion did SM exhibit fear, and she never endorsed feeling more than minimal levels of fear. Likewise, across a large battery of self-report questionnaires, 3 months of real-life experience sampling, and a life history replete with traumatic events, SM repeatedly demonstrated an absence of overt fear manifestations and an overall impoverished experience of fear. Despite her lack of fear, SM is able to exhibit other basic emotions and experience the respective feelings. The findings support the conclusion that the human amygdala plays a pivotal role in triggering a state of fear and that the absence of such a state precludes the experience of fear itself.

  10. The human amygdala and the induction and experience of fear

    PubMed Central

    Feinstein, Justin S.; Adolphs, Ralph; Damasio, Antonio R.; Tranel, Daniel

    2010-01-01

    Summary Although clinical observations suggest that humans with amygdala damage have abnormal fear reactions and a reduced experience of fear [1–3], these impressions have not been systematically investigated. To address this gap, we conducted a new study in a rare human patient, SM, who has focal bilateral amygdala lesions [4]. To provoke fear in SM, we exposed her to live snakes and spiders, took her on a tour of a haunted house, and showed her emotionally evocative films. On no occasion did SM exhibit fear and she never endorsed feeling more than minimal levels of fear. Likewise, across a large battery of self-report questionnaires, three months of real-life experience sampling, and a life history replete with traumatic events, SM repeatedly demonstrated an absence of overt fear manifestations and an overall impoverished experience of fear. Despite her lack of fear, SM is able to exhibit other basic emotions and experience the respective feelings. The findings support the conclusion that the human amygdala plays a pivotal role in triggering a state of fear, and that the absence of such a state precludes the experience of fear itself. PMID:21167712

  11. Disrupting Reconsolidation of Fear Memory in Humans by a Noradrenergic β-Blocker

    PubMed Central

    Kindt, Merel; Soeter, Marieke; Sevenster, Dieuwke

    2014-01-01

    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. PMID:25549103

  12. NPY controls fear conditioning and fear extinction by combined action on Y1 and Y2 receptors

    PubMed Central

    Verma, D; Tasan, RO; Herzog, H; Sperk, G

    2012-01-01

    BACKGROUND AND PURPOSE 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. EXPERIMENTAL APPROACH Here we performed Pavlovian fear conditioning and extinction in NPY knockout (KO) and in NPY receptor KO mice. KEY RESULTS 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. CONCLUSIONS AND IMPLICATIONS 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. PMID:22289084

  13. Glucocorticoids reduce phobic fear in humans.

    PubMed

    Soravia, Leila M; Heinrichs, Markus; Aerni, Amanda; Maroni, Caroline; Schelling, Gustav; Ehlert, Ulrike; Roozendaal, Benno; de Quervain, Dominique J-F

    2006-04-04

    Phobias are characterized by excessive fear, cued by the presence or anticipation of a fearful situation. Whereas it is well established that glucocorticoids are released in fearful situations, it is not known whether these hormones, in turn, modulate perceived fear. As extensive evidence indicates that elevated glucocorticoid levels impair the retrieval of emotionally arousing information, they might also inhibit retrieval of fear memory associated with phobia and, thereby, reduce phobic fear. Here, we investigated whether acutely administrated glucocorticoids reduced phobic fear in two double-blind, placebo-controlled studies in 40 subjects with social phobia and 20 subjects with spider phobia. In the social phobia study, cortisone (25 mg) administered orally 1 h before a socio-evaluative stressor significantly reduced self-reported fear during the anticipation, exposure, and recovery phase of the stressor. Moreover, the stress-induced release of cortisol in placebo-treated subjects correlated negatively with fear ratings, suggesting that endogenously released cortisol in the context of a phobic situation buffers fear symptoms. In the spider phobia study, repeated oral administration of cortisol (10 mg), but not placebo, 1 h before exposure to a spider photograph induced a progressive reduction of stimulus-induced fear. This effect was maintained when subjects were exposed to the stimulus again 2 days after the last cortisol administration, suggesting that cortisol may also have facilitated the extinction of phobic fear. Cortisol treatment did not reduce general, phobia-unrelated anxiety. In conclusion, the present findings in two distinct types of phobias indicate that glucocorticoid administration reduces phobic fear.

  14. Glucocorticoids reduce phobic fear in humans

    PubMed Central

    Soravia, Leila M.; Heinrichs, Markus; Aerni, Amanda; Maroni, Caroline; Schelling, Gustav; Ehlert, Ulrike; Roozendaal, Benno; de Quervain, Dominique J.-F.

    2006-01-01

    Phobias are characterized by excessive fear, cued by the presence or anticipation of a fearful situation. Whereas it is well established that glucocorticoids are released in fearful situations, it is not known whether these hormones, in turn, modulate perceived fear. As extensive evidence indicates that elevated glucocorticoid levels impair the retrieval of emotionally arousing information, they might also inhibit retrieval of fear memory associated with phobia and, thereby, reduce phobic fear. Here, we investigated whether acutely administrated glucocorticoids reduced phobic fear in two double-blind, placebo-controlled studies in 40 subjects with social phobia and 20 subjects with spider phobia. In the social phobia study, cortisone (25 mg) administered orally 1 h before a socio-evaluative stressor significantly reduced self-reported fear during the anticipation, exposure, and recovery phase of the stressor. Moreover, the stress-induced release of cortisol in placebo-treated subjects correlated negatively with fear ratings, suggesting that endogenously released cortisol in the context of a phobic situation buffers fear symptoms. In the spider phobia study, repeated oral administration of cortisol (10 mg), but not placebo, 1 h before exposure to a spider photograph induced a progressive reduction of stimulus-induced fear. This effect was maintained when subjects were exposed to the stimulus again 2 days after the last cortisol administration, suggesting that cortisol may also have facilitated the extinction of phobic fear. Cortisol treatment did not reduce general, phobia-unrelated anxiety. In conclusion, the present findings in two distinct types of phobias indicate that glucocorticoid administration reduces phobic fear. PMID:16567641

  15. Ventromedial prefrontal cortex activity and rapid eye movement sleep are associated with subsequent fear expression in human subjects.

    PubMed

    Spoormaker, V I; Gvozdanovic, G A; Sämann, P G; Czisch, M

    2014-05-01

    In humans, activity patterns in the ventromedial prefrontal cortex (vmPFC) have been found to be predictive of subsequent fear memory consolidation. Pioneering work in rodents has further shown that vmPFC-amygdala theta synchronization is correlated with fear memory consolidation. We aimed to evaluate whether vmPFC activity during fear conditioning is (1) correlated with fear expression the subsequent day and whether (2) this relationship is mediated by rapid eye movement (REM) sleep. We analyzed data from 17 young healthy subjects undergoing a fear conditioning task, followed by a fear extinction task 24 h later, both recorded with simultaneous skin conductance response (SCR) and functional magnetic resonance imaging measurements, with a polysomnographically recorded night sleep in between. Our results showed a correlation between vmPFC activity during fear conditioning and subsequent REM sleep amount, as well as between REM sleep amount and SCR to the conditioned stimulus 24 h later. Moreover, we observed a significant correlation between vmPFC activity during fear conditioning and SCR responses during extinction, which was no longer significant after controlling for REM sleep amount. vmPFC activity during fear conditioning was further correlated with sleep latency. Interestingly, hippocampus activity during fear conditioning was correlated with stage 2 and stage 4 sleep amount. Our results provide preliminary evidence that the relationship between REM sleep and fear conditioning and extinction observed in rodents can be modeled in healthy human subjects, highlighting an interrelated set of potentially relevant trait markers.

  16. Dual Functions of Perirhinal Cortex in Fear Conditioning

    PubMed Central

    Kent, Brianne A.; Brown, Thomas H.

    2012-01-01

    The present review examines the role of perirhinal cortex (PRC) in Pavlovian fear conditioning. The focus is on rats, partly because so much is known, behaviorally and neurobiologically, about fear conditioning in these animals. In addition, the neuroanatomy and neurophysiology of rat PRC have been described in considerable detail at the cellular and systems levels. The evidence suggests that PRC can serve at least two types of mnemonic functions in Pavlovian fear conditioning. The first function, termed "stimulus unitization," refers to the ability to treat two or more separate items or stimulus elements as a single entity. Supporting evidence for this perceptual function comes from studies of context conditioning as well as delay conditioning to discontinuous auditory cues. In a delay paradigm, the conditional stimulus (CS) and unconditional stimulus (US) overlap temporally and co-terminate. The second PRC function entails a type of "transient memory." Supporting evidence comes from studies of trace cue conditioning, where there is a temporal gap or trace interval between the CS offset and the US onset. For learning to occur, there must be a transient CS representation during the trace interval. We advance a novel neurophysiological mechanism for this transient representation. These two hypothesized functions of PRC are consistent with inferences based on non-aversive forms of learning. PMID:22903623

  17. Dual functions of perirhinal cortex in fear conditioning.

    PubMed

    Kent, Brianne A; Brown, Thomas H

    2012-10-01

    The present review examines the role of perirhinal cortex (PRC) in Pavlovian fear conditioning. The focus is on rats, partly because so much is known, behaviorally and neurobiologically, about fear conditioning in these animals. In addition, the neuroanatomy and neurophysiology of rat PRC have been described in considerable detail at the cellular and systems levels. The evidence suggests that PRC can serve at least two types of mnemonic functions in Pavlovian fear conditioning. The first function, termed "stimulus unitization," refers to the ability to treat two or more separate items or stimulus elements as a single entity. Supporting evidence for this perceptual function comes from studies of context conditioning as well as delay conditioning to discontinuous auditory cues. In a delay paradigm, the conditional stimulus (CS) and unconditional stimulus (US) overlap temporally and co-terminate. The second PRC function entails a type of "transient memory." Supporting evidence comes from studies of trace cue conditioning, where there is a temporal gap or trace interval between the CS offset and the US onset. For learning to occur, there must be a transient CS representation during the trace interval. We advance a novel neurophysiological mechanism for this transient representation. These two hypothesized functions of PRC are consistent with inferences based on non-aversive forms of learning.

  18. Methods for developmental studies of fear conditioning circuitry.

    PubMed

    Pine, D S; Fyer, A; Grun, J; Phelps, E A; Szeszko, P R; Koda, V; Li, W; Ardekani, B; Maguire, E A; Burgess, N; Bilder, R M

    2001-08-01

    Psychophysiologic studies use air puff as an aversive stimulus to document abnormal fear conditioning in children of parents with anxiety disorders. This study used functional magnetic resonance imaging (fMRI) to examine changes in amygdala activity during air-puff conditioning among adults. Blood oxygen level-dependent (BOLD) signal was monitored in seven adults during 16 alternating presentations of two different colored lights (CS+ vs. CS-), one of which was consistently paired with an aversive air puff. A region-of-interest analysis demonstrated differential change in BOLD signal in the right but not left amygdala across CS+ versus CS- viewing. The amygdala is engaged by pairing of a light with an air puff. Given that prior studies relate air-puff conditioning to risk for anxiety in children, these methods may provide an avenue for directly studying the developmental neurobiology of fear conditioning.

  19. Neurobehavioral mechanisms of human fear generalization

    PubMed Central

    Dunsmoor, Joseph E.; Prince, Steven E.; Murty, Vishnu P.; Kragel, Philip A.; LaBar, Kevin S.

    2011-01-01

    While much research has elucidated the neurobiology of fear learning, the neural systems supporting the generalization of learned fear are unknown. Using functional magnetic resonance imaging (fMRI), we show that regions involved in the acquisition of fear support the generalization of fear to stimuli that are similar to a learned threat, but vary in fear intensity value. Behaviorally, subjects retrospectively misidentified a learned threat as a more intense stimulus and expressed greater skin conductance responses (SCR) to generalized stimuli of high intensity. Brain activity related to intensity-based fear generalization was observed in the striatum, insula, thalamus/periacqueductal gray, and subgenual cingulate cortex. The psychophysiological expression of generalized fear correlated with amygdala activity, and connectivity between the amygdala and extrastriate visual cortex was correlated with individual differences in trait anxiety. These findings reveal the brain regions and functional networks involved in flexibly responding to stimuli that resemble a learned threat. These regions may comprise an intensity-based fear generalization circuit that underlies retrospective biases in threat value estimation and overgeneralization of fear in anxiety disorders. PMID:21256233

  20. Coantagonism of Glutamate Receptors and Nicotinic Acetylcholinergic Receptors Disrupts Fear Conditioning and Latent Inhibition of Fear Conditioning

    ERIC Educational Resources Information Center

    Gould, Thomas J.; Lewis, Michael C.

    2005-01-01

    The present study investigated the hypothesis that both nicotinic acetylcholinergic receptors (nAChRs) and glutamate receptors ([alpha]-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptors (AMPARs) and N-methyl-D-aspartate glutamate receptors (NMDARs)) are involved in fear conditioning, and may modulate similar processes. The effects of the…

  1. Coantagonism of Glutamate Receptors and Nicotinic Acetylcholinergic Receptors Disrupts Fear Conditioning and Latent Inhibition of Fear Conditioning

    ERIC Educational Resources Information Center

    Gould, Thomas J.; Lewis, Michael C.

    2005-01-01

    The present study investigated the hypothesis that both nicotinic acetylcholinergic receptors (nAChRs) and glutamate receptors ([alpha]-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptors (AMPARs) and N-methyl-D-aspartate glutamate receptors (NMDARs)) are involved in fear conditioning, and may modulate similar processes. The effects of the…

  2. Adolescent traumatic stress experience results in less robust conditioned fear and post-extinction fear cue responses in adult rats.

    PubMed

    Moore, Nicole L T; Gauchan, Sangeeta; Genovese, Raymond F

    2014-05-01

    Early exposure to a traumatic event may produce lasting effects throughout the lifespan. Traumatic stress during adolescence may deliver a distinct developmental insult compared with more-often studied neonatal or juvenile traumatic stress paradigms. The present study describes the lasting effects of adolescent traumatic stress upon adulthood fear conditioning. Adolescent rats were exposed to a traumatic stressor (underwater trauma, UWT), then underwent fear conditioning during adulthood. Fear extinction was tested over five conditioned suppression extinction sessions three weeks later. The efficacies of two potential extinction-enhancing compounds, endocannabinoid reuptake inhibitor AM404 (10mg/kg) and M1 muscarinic positive allosteric modulator BQCA (10mg/kg), were also assessed. Finally, post-extinction fear responses were examined using a fear cue (light) as a prepulse stimulus. Rats traumatically stressed during adolescence showed blunted conditioned suppression on day 1 of extinction training, and AM404 reversed this effect. Post-extinction startle testing showed that fear conditioning eliminates prepulse inhibition to the light cue. Startle potentiation was observed only in rats without adolescent UWT exposure. AM404 and BQCA both ameliorated this startle potentiation, while BQCA increased startle in the UWT group. These results suggest that exposure to a traumatic stressor during adolescence alters developmental outcomes related to stress response and fear extinction compared to rats without adolescent traumatic stress exposure, blunting the adulthood fear response and reducing residual post-extinction fear expression. Efficacy of pharmacological interventions may also vary as a factor of developmental traumatic stress exposure.

  3. Genetic correlation between alcohol preference and conditioned fear: Exploring a functional relationship.

    PubMed

    Chester, Julia A; Weera, Marcus M

    2017-02-01

    Post-traumatic stress disorder (PTSD) and alcohol-use disorders have a high rate of co-occurrence, possibly because they are regulated by common genes. In support of this idea, mice selectively bred for high (HAP) alcohol preference show greater fear potentiated startle (FPS), a model for fear-related disorders such as PTSD, compared to mice selectively bred for low (LAP) alcohol preference. This positive genetic correlation between alcohol preference and FPS behavior suggests that the two traits may be functionally related. This study examined the effects of fear conditioning on alcohol consumption and the effects of alcohol consumption on the expression of FPS in male and female HAP2 and LAP2 mice. In experiment 1, alcohol consumption (g/kg) under continuous-access conditions was monitored daily for 4 weeks following a single fear-conditioning or control treatment (foot shock and no shock). FPS was assessed three times (once at the end of the 4-week alcohol access period, once at 24 h after removal of alcohol, and once at 6-8 days after removal of alcohol), followed by two more weeks of alcohol access. Results showed no change in alcohol consumption, but alcohol-consuming, fear-conditioned, HAP2 males showed increased FPS at 24 h during the alcohol abstinence period compared to control groups. In experiment 2, alcohol consumption under limited-access conditions was monitored daily for 4 weeks. Fear-conditioning or control treatments occurred four times during the first 12 days and FPS testing occurred four times during the second 12 days of the 4-week alcohol consumption period. Results showed that fear conditioning increased alcohol intake in both HAP2 and LAP2 mice immediately following the first conditioning session. Fear-conditioned HAP2 but not LAP2 mice showed greater alcohol intake compared to control groups on drinking days that occurred between fear conditioning and FPS test sessions. FPS did not change as a function of alcohol consumption in either

  4. Human handling and presentation of a novel object evoke independent dimensions of fear in Japanese quail.

    PubMed

    Richard, S; Land, N; Saint-Dizier, H; Leterrier, C; Faure, J M

    2010-09-01

    Fear is a concept comprising several dimensions, but the nature of these dimensions and the relationships between them remain elusive. To investigate these dimensions in birds, we have used two genetic lines of quail divergently selected on tonic immobility duration, a behavioural index of fear. These two lines differ in their behavioural response to some, but not all, fear-inducing situations. In the present study, we investigated the contribution of human intervention in the differentiation between the two lines. To do this, fear responses towards a novel object were compared between lines in three conditions: (1) in the home cage without any human intervention, (2) in the home cage after human handling and (3) after placement in a novel environment by human handling. Fear behaviour differed between lines after human handling, with or without placement in a novel environment, but presentation of a novel object in the home cage without any human intervention induced similar fear responses in the two lines of quail. These results lead us to suggest that in quail, human intervention evokes a dimension of fear that differs from that evoked by sudden presentation of a novel object, in that these two dimensions may be selected independently. Copyright 2010 Elsevier B.V. All rights reserved.

  5. VOLUNTARY WHEEL RUNNING ENHANCES CONTEXTUAL BUT NOT TRACE FEAR CONDITIONING

    PubMed Central

    Kohman, Rachel A.; Clark, Peter J.; DeYoung, Erin K.; Bhattacharya, Tushar K.; Venghaus, Christine E.; Rhodes, Justin S.

    2011-01-01

    Exercise improves performance on a number of hippocampus involved cognitive tasks including contextual fear conditioning, but whether exercise enhances contextual fear when the retention interval is longer than 1 day is not known. Also unknown is whether exercise improves trace conditioning, a task that requires the hippocampus to bridge the time interval between stimuli. Hence, 4-month-old male C57BL/6J mice were housed with or without running wheels. To assess whether hippocampal neurogenesis was associated with behavioral outcomes, during the initial ten days, mice received Bromodeoxyuridine to label dividing cells. After 30 days, one group of mice was trained in a contextual fear conditioning task. Freezing to context was assessed 1, 7, or 21 days post-training. A separate group was trained on a trace procedure, in which a tone and footshock were separated by a 15, 30, or 45 sec interval. Freezing to the tone was measured 24 hrs later in a novel environment, and freezing to training context was measured 48 hrs later. Running enhanced freezing to context when the retention interval was 1, but not 7 or 21 days. Running had no effect on trace conditioning even though runners displayed enhanced freezing to the training context 48 hrs later. Wheel running increased survival of new neurons in the hippocampus. Collectively, findings indicate that wheel running enhances cognitive performance on some tasks but not others and that enhanced neurogenesis is not always associated with improved performance on hippocampus tasks, one example of which is trace conditioning. PMID:21896289

  6. Novelty and fear conditioning induced gene expression in high and low states of anxiety.

    PubMed

    Donley, Melanie P; Rosen, Jeffrey B

    2017-09-01

    Emotional states influence how stimuli are interpreted. High anxiety states in humans lead to more negative, threatening interpretations of novel information, typically accompanied by activation of the amygdala. We developed a handling protocol that induces long-lasting high and low anxiety-like states in rats to explore the role of state anxiety on brain activation during exposure to a novel environment and fear conditioning. In situ hybridization of the inducible transcription factor Egr-1 found increased gene expression in the lateral nucleus of the amygdala (LA) following exposure to a novel environment and contextual fear conditioning in high anxiety-like rats. In contrast, low state anxiety-like rats did not generate Egr-1 increases in LA when placed in a novel chamber. Egr-1 expression was also examined in the dorsal hippocampus and prefrontal cortex. In CA1 of the hippocampus and medial prefrontal cortex (mPFC), Egr-1 expression increased in response to novel context exposure and fear conditioning, independent of state anxiety level. Furthermore, in mPFC, Egr-1 in low anxiety-like rats was increased more with fear conditioning than novel exposure. The current series of experiments show that brain areas involved in fear and anxiety-like states do not respond uniformly to novelty during high and low states of anxiety. © 2017 Donley and Rosen; Published by Cold Spring Harbor Laboratory Press.

  7. The amygdala is critical for trace, delay, and contextual fear conditioning

    PubMed Central

    Kochli, Daniel E.; Thompson, Elaine C.; Fricke, Elizabeth A.; Postle, Abagail F.

    2015-01-01

    Numerous investigations have definitively shown amygdalar involvement in delay and contextual fear conditioning. However, much less is known about amygdala contributions to trace fear conditioning, and what little evidence exists is conflicting as noted in previous studies. This discrepancy may result from selective targeting of individual nuclei within the amygdala. The present experiments further examine the contributions of amygdalar subnuclei to trace, delay, and contextual fear conditioning. Rats were trained using a 10-trial trace, delay, or unpaired fear conditioning procedure. Pretraining lesions targeting the entire basolateral amygdala (BLA) resulted in a deficit in trace, delay, and contextual fear conditioning. Immediate post-training infusions of the protein synthesis inhibitor, cycloheximide, targeting the basal nucleus of the amygdala (BA) attenuated trace and contextual fear memory expression, but had no effect on delay fear conditioning. However, infusions targeting the lateral nucleus of the amygdala (LA) immediately following conditioning attenuated contextual fear memory expression, but had no effect on delay or trace fear conditioning. In follow-up experiments, rats were trained using a three-trial delay conditioning procedure. Immediate post-training infusions targeting the LA produced deficits in both delay tone and context fear, while infusions targeting the BA produced deficits in context but not delay tone fear. These data fully support a role for the BLA in trace, delay, and contextual fear memories. Specifically, these data suggest that the BA may be more critical for trace fear conditioning, whereas the LA may be more critical for delay fear memories. PMID:25593295

  8. The amygdala is critical for trace, delay, and contextual fear conditioning.

    PubMed

    Kochli, Daniel E; Thompson, Elaine C; Fricke, Elizabeth A; Postle, Abagail F; Quinn, Jennifer J

    2015-02-01

    Numerous investigations have definitively shown amygdalar involvement in delay and contextual fear conditioning. However, much less is known about amygdala contributions to trace fear conditioning, and what little evidence exists is conflicting as noted in previous studies. This discrepancy may result from selective targeting of individual nuclei within the amygdala. The present experiments further examine the contributions of amygdalar subnuclei to trace, delay, and contextual fear conditioning. Rats were trained using a 10-trial trace, delay, or unpaired fear conditioning procedure. Pretraining lesions targeting the entire basolateral amygdala (BLA) resulted in a deficit in trace, delay, and contextual fear conditioning. Immediate post-training infusions of the protein synthesis inhibitor, cycloheximide, targeting the basal nucleus of the amygdala (BA) attenuated trace and contextual fear memory expression, but had no effect on delay fear conditioning. However, infusions targeting the lateral nucleus of the amygdala (LA) immediately following conditioning attenuated contextual fear memory expression, but had no effect on delay or trace fear conditioning. In follow-up experiments, rats were trained using a three-trial delay conditioning procedure. Immediate post-training infusions targeting the LA produced deficits in both delay tone and context fear, while infusions targeting the BA produced deficits in context but not delay tone fear. These data fully support a role for the BLA in trace, delay, and contextual fear memories. Specifically, these data suggest that the BA may be more critical for trace fear conditioning, whereas the LA may be more critical for delay fear memories.

  9. Fear potentiated startle at short intervals following conditioned stimulus onset during delay but not trace conditioning.

    PubMed

    Asli, Ole; Kulvedrøsten, Silje; Solbakken, Line E; Flaten, Magne Arve

    2009-07-01

    The latency of conditioned fear after delay and trace conditioning was investigated. Some argue that delay conditioning is not dependent on awareness. In contrast, trace conditioning, where there is a gap between the conditioned stimulus (CS) and the unconditioned stimulus (US), is assumed to be dependent on awareness. In the present study, a tone CS signaled a noise US presented 1000 ms after CS onset in the delay conditioning group. In the trace conditioning group, a 200-ms tone CS was followed by an 800-ms gap prior to US presentation. Fear-potentiated startle should be seen at shorter intervals after delay conditioning compared to trace conditioning. Analyses showed increased startle at 30, 50, 100, and 150 ms after CS onset following delay conditioning compared to trace conditioning. This implies that fear-relevant stimuli elicit physiological reactions before extended processing of the stimuli occur, following delay, but not trace conditioning.

  10. Fear conditioning in frontotemporal lobar degeneration and Alzheimer's disease

    PubMed Central

    Hoefer, M.; Allison, S. C.; Schauer, G. F.; Neuhaus, J. M.; Hall, J.; Dang, J. N.; Weiner, M. W.; Miller, B. L.; Rosen, H. J.

    2008-01-01

    Emotional blunting and abnormal processing of rewards and punishments represent early features of frontotemporal lobar degeneration (FTLD). Better understanding of the physiological underpinnings of these emotional changes can be facilitated by the use of classical psychology approaches. Fear conditioning (FC) is an extensively used paradigm for studying emotional processing that has rarely been applied to the study of dementia.We studied FC in controls (n = 25), Alzheimer's disease (n =25) and FTLD (n = 25). A neutral stimulus (coloured square on a computer screen) was repeatedly paired with a 1s burst of 100 db white noise. Change in skin conductance response to the neutral stimulus was used to measure conditioning. Physiological–anatomical correlations were examined using voxel-based morphometry (VBM). Both patient groups showed impaired acquisition of conditioned responses. However, the basis for this deficit appeared to differ between groups. In Alzheimer's disease, impaired FC occurred despite normal electrodermal responses to the aversive stimulus. In contrast, FTLD patients showed reduced skin conductance responses to the aversive stimulus, which contributed significantly to their FC deficit.VBM identified correlations with physiological reactivity in the amygdala, anterior cingulate cortex, orbitofrontal cortex and insula. These data indicate that Alzheimer's disease and FTLD both show abnormalities in emotional learning, but they suggest that in FTLD this is associated with a deficit in basic electrodermal response to aversive stimuli, consistent with the emotional blunting described with this disorder. Deficits in responses to aversive stimuli could contribute to both the behavioural and cognitive features of FTLD and Alzheimer's disease. Further study of FC in humans and animal models of dementia could provide a valuable window into these symptoms. PMID:18492729

  11. Fear conditioning in frontotemporal lobar degeneration and Alzheimer's disease.

    PubMed

    Hoefer, M; Allison, S C; Schauer, G F; Neuhaus, J M; Hall, J; Dang, J N; Weiner, M W; Miller, B L; Rosen, H J

    2008-06-01

    Emotional blunting and abnormal processing of rewards and punishments represent early features of frontotemporal lobar degeneration (FTLD). Better understanding of the physiological underpinnings of these emotional changes can be facilitated by the use of classical psychology approaches. Fear conditioning (FC) is an extensively used paradigm for studying emotional processing that has rarely been applied to the study of dementia. We studied FC in controls (n = 25), Alzheimer's disease (n = 25) and FTLD (n = 25). A neutral stimulus (coloured square on a computer screen) was repeatedly paired with a 1 s burst of 100 db white noise. Change in skin conductance response to the neutral stimulus was used to measure conditioning. Physiological-anatomical correlations were examined using voxel-based morphometry (VBM). Both patient groups showed impaired acquisition of conditioned responses. However, the basis for this deficit appeared to differ between groups. In Alzheimer's disease, impaired FC occurred despite normal electrodermal responses to the aversive stimulus. In contrast, FTLD patients showed reduced skin conductance responses to the aversive stimulus, which contributed significantly to their FC deficit. VBM identified correlations with physiological reactivity in the amygdala, anterior cingulate cortex, orbitofrontal cortex and insula. These data indicate that Alzheimer's disease and FTLD both show abnormalities in emotional learning, but they suggest that in FTLD this is associated with a deficit in basic electrodermal response to aversive stimuli, consistent with the emotional blunting described with this disorder. Deficits in responses to aversive stimuli could contribute to both the behavioural and cognitive features of FTLD and Alzheimer's disease. Further study of FC in humans and animal models of dementia could provide a valuable window into these symptoms.

  12. Electrolytic lesion of the nucleus incertus retards extinction of auditory conditioned fear.

    PubMed

    Pereira, C W; Santos, F N; Sánchez-Pérez, A M; Otero-García, M; Marchioro, M; Ma, S; Gundlach, A L; Olucha-Bordonau, F E

    2013-06-15

    Fear memory circuits in the brain function to allow animals and humans to recognize putative sources of danger and adopt an appropriate behavioral response; and research on animal models of fear have helped reveal the anatomical and neurochemical nature of these circuits. The nucleus (n.) incertus in the dorsal pontine tegmentum provides a strong GABAergic projection to forebrain 'fear centers' and is strongly activated by neurogenic stressors. In this study in adult male rats, we examined the effect of electrolytic lesions of n. incertus on different stages of the fear conditioning-extinction process and correlated the outcomes with anatomical data on the distribution of n. incertus-derived nerve fibers in areas implicated in fear circuits. In a contextual auditory fear conditioning paradigm, we compared freezing behavior in control (naïve) rats (n=23) and rats with sham- or electrolytic lesions of n. incertus (n=13/group). The effectiveness and extent of the lesions was assessed post-mortem using immunohistochemical markers for n. incertus neurons-calretinin and relaxin-3. There were no differences between the three experimental groups in the habituation, acquisition, or context conditioning phases; but n. incertus lesioned rats displayed a markedly slower, 'delayed' extinction of conditioned freezing responses compared to sham-lesion and control rats, but no differences in retrieval of extinguished fear. These and earlier findings suggest that n. incertus-related circuits normally promote extinction through inhibitory projections to the amygdala, which is involved in acquisition of extinction memories. Copyright © 2013 Elsevier B.V. All rights reserved.

  13. CONTROLLABLE VERSUS UNCONTROLLABLE STRESSORS BI-DIRECTIONALLY MODULATE CONDITIONED BUT NOT INNATE FEAR

    PubMed Central

    Baratta, M. V.; Christianson, J. P.; Gomez, D. M.; Zarza, C. M.; Amat, J.; Masini, C.V.; Watkins, L. R.; Maier, S. F.

    2007-01-01

    Fear conditioning and fear extinction play key roles in the development and treatment of anxiety-related disorders, yet there is little information concerning experiential variables that modulate these processes. Here we examined the impact of exposure to a stressor in a different environment on subsequent fear conditioning and extinction, and whether the degree of behavioral control that the subject has over the stressor is of importance. Rats received a session of either escapable (controllable) tailshock (ES), yoked inescapable (uncontrollable) tailshock (IS), or control treatment (HC) 7 days before fear conditioning in which a tone and footshock were paired. Conditioning was measured 24 h later. In a second experiment rats received ES, IS or HC 24 h after contextual fear conditioning. Extinction then occurred every day beginning 7 days later until a criterion was reached. Spontaneous recovery of fear was assessed 14 days after extinction. IS potentiated fear conditioning when given before fear conditioning, and potentiated fear responding during extinction when given after conditioning. Importantly, ES potently interfered with later fear conditioning, decreased fear responding during fear extinction, and prevented spontaneous recovery of fear. Additionally, we examined if the activation of the ventral medial prefrontal cortex (mPFCv) by ES is critical for the protective effects of ES on later fear conditioning. Inactivation of the mPFCv with muscimol at the time of the initial experience with control prevented ES-induced reductions in later contextual and auditory fear conditioning. Finally, we explored if the protective effects of ES extended to an unconditioned fear stimulus, ferret odor. Unlike conditioned fear, prior ES increased the fear response to ferret odor to the same degree as did IS. PMID:17478046

  14. Nociception and Conditioned Fear in Rats: Strains Matter

    PubMed Central

    Schaap, Manon W. H.; van Oostrom, Hugo; Doornenbal, Arie; van 't Klooster, José; Baars, Annemarie M.; Arndt, Saskia S.; Hellebrekers, Ludo J.

    2013-01-01

    When using rats in pain research, strain-related differences in outcomes of tests for pain and nociception are acknowledged. However, very little is known about the specific characteristics of these strain differences. In this study four phylogenetically distant inbred rat strains, i.e. Wistar Kyoto (WKY), Fawn Hooded (FH), Brown Norway (BN) and Lewis (LE), were investigated in different tests related to pain and nociception. During Pavlovian fear conditioning, the LE and WKY showed a significantly longer duration of freezing behaviour than the FH and BN. Additionally, differences in c-Fos expression in subregions of the prefrontal cortex and amygdala between rat strains during retrieval and expression of conditioned fear were found. For example, the BN did not show recruitment of the basolateral amygdala, whereas the WKY, FH and LE did. During the hot plate test, the WKY and LE showed a lower thermal threshold compared to the BN and FH. In a follow-up experiment, the two most contrasting strains regarding behaviour during the hot plate test and Pavlovian fear conditioning (i.e. FH and WKY) were selected and the hot plate test, Von Frey test and somatosensory-evoked potential (SEP) were investigated. During the Von Frey test, the WKY showed a lower mechanical threshold compared to the FH. When measuring the SEP, the FH appeared to be less reactive to increasing stimulus intensities when considering both peak amplitudes and latencies. Altogether, the combined results indicate various differences between rat strains in Pavlovian fear conditioning, nociception related behaviours and nociceptive processing. These findings demonstrate the necessity of using multiple rat strains when using tests including noxious stimuli and suggest that the choice of rat strains should be considered. When selecting a strain for a particular study it should be considered how this strain behaves during the tests used in that study. PMID:24376690

  15. Angiotensin type 1a receptors on corticotropin-releasing factor neurons contribute to the expression of conditioned fear.

    PubMed

    Hurt, R C; Garrett, J C; Keifer, O P; Linares, A; Couling, L; Speth, R C; Ressler, K J; Marvar, P J

    2015-09-01

    Although generally associated with cardiovascular regulation, angiotensin II receptor type 1a (AT1a R) blockade in mouse models and humans has also been associated with enhanced fear extinction and decreased post-traumatic stress disorder (PTSD) symptom severity, respectively. The mechanisms mediating these effects remain unknown, but may involve alterations in the activities of corticotropin-releasing factor (CRF)-expressing cells, which are known to be involved in fear regulation. To test the hypothesis that AT1a R signaling in CRFergic neurons is involved in conditioned fear expression, we generated and characterized a conditional knockout mouse strain with a deletion of the AT1a R gene from its CRF-releasing cells (CRF-AT1a R((-/-)) ). These mice exhibit normal baseline heart rate, blood pressure, anxiety and locomotion, and freeze at normal levels during acquisition of auditory fear conditioning. However, CRF-AT1a R((-/-)) mice exhibit less freezing than wild-type mice during tests of conditioned fear expression-an effect that may be caused by a decrease in the consolidation of fear memory. These results suggest that central AT1a R activity in CRF-expressing cells plays a role in the expression of conditioned fear, and identify CRFergic cells as a population on which AT1 R antagonists may act to modulate fear extinction. © 2015 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

  16. Angiotensin Type 1a Receptors on Corticotropin-Releasing Factor Neurons Contribute to the Expression of Conditioned Fear

    PubMed Central

    Hurt, Robert C.; Garrett, Jacob C.; Keifer, Orion P.; Linares, Andrea; Couling, Leena; Speth, Robert C.; Ressler, Kerry J.; Marvar, Paul J.

    2015-01-01

    Although generally associated with cardiovascular regulation, angiotensin II receptor type 1 (AT1aR) blockade in mouse models and humans has also been associated with enhanced fear extinction and decreased post-traumatic stress disorder (PTSD) symptom severity, respectively. The mechanisms mediating these effects remain unknown, but may involve alterations in the activities of corticotropin-releasing factor (CRF)-expressing cells, which are known to be involved in fear regulation. To test the hypothesis that AT1aR signaling in CRFergic neurons is involved in conditioned fear expression, we generated and characterized a conditional knockout mouse strain with a deletion of the AT1aR gene from its CRF-releasing cells (CRF-AT1aR(−/−)). These mice exhibit normal baseline heart rate, blood pressure, anxiety, and locomotion, and freeze at normal levels during acquisition of auditory fear conditioning. However, CRF-AT1aR(−/−) mice exhibit less freezing than wild type mice during tests of conditioned fear expression—an effect that may be caused by a decrease in the consolidation of fear memory. These results suggest that central AT1R activity in CRF-expressing cells plays a role in the expression of conditioned fear, and identify CRFergic cells as a population on which AT1R antagonists may act to modulate fear extinction. PMID:26257395

  17. Blocking human fear memory with the matrix metalloproteinase inhibitor doxycycline.

    PubMed

    Bach, D R; Tzovara, A; Vunder, J

    2017-04-04

    Learning to predict threat is a fundamental ability of many biological organisms, and a laboratory model for anxiety disorders. Interfering with such memories in humans would be of high clinical relevance. On the basis of studies in cell cultures and slice preparations, it is hypothesised that synaptic remodelling required for threat learning involves the extracellular enzyme matrix metalloproteinase (MMP) 9. However, in vivo evidence for this proposal is lacking. Here we investigate human Pavlovian fear conditioning under the blood-brain barrier crossing MMP inhibitor doxycyline in a pre-registered, randomised, double-blind, placebo-controlled trial. We find that recall of threat memory, measured with fear-potentiated startle 7 days after acquisition, is attenuated by ~60% in individuals who were under doxycycline during acquisition. This threat memory impairment is also reflected in increased behavioural surprise signals to the conditioned stimulus during subsequent re-learning, and already late during initial acquisition. Our findings support an emerging view that extracellular signalling pathways are crucially required for threat memory formation. Furthermore, they suggest novel pharmacological methods for primary prevention and treatment of posttraumatic stress disorder.Molecular Psychiatry advance online publication, 4 April 2017; doi:10.1038/mp.2017.65.

  18. A role for midline and intralaminar thalamus in the associative blocking of Pavlovian fear conditioning

    PubMed Central

    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. PMID:24822042

  19. Delay and trace fear conditioning in a complex virtual learning environment—neural substrates of extinction

    PubMed Central

    Ewald, Heike; Glotzbach-Schoon, Evelyn; Gerdes, Antje B. M.; Andreatta, Marta; Müller, Mathias; Mühlberger, Andreas; Pauli, Paul

    2014-01-01

    Extinction is an important mechanism to inhibit initially acquired fear responses. There is growing evidence that the ventromedial prefrontal cortex (vmPFC) inhibits the amygdala and therefore plays an important role in the extinction of delay fear conditioning. To our knowledge, there is no evidence on the role of the prefrontal cortex in the extinction of trace conditioning up to now. Thus, we compared brain structures involved in the extinction of human delay and trace fear conditioning in a between-subjects-design in an fMRI study. Participants were passively guided through a virtual environment during learning and extinction of conditioned fear. Two different lights served as conditioned stimuli (CS); as unconditioned stimulus (US) a mildly painful electric stimulus was delivered. In the delay conditioning group (DCG) the US was administered with offset of one light (CS+), whereas in the trace conditioning group (TCG) the US was presented 4 s after CS+ offset. Both groups showed insular and striatal activation during early extinction, but differed in their prefrontal activation. The vmPFC was mainly activated in the DCG, whereas the TCG showed activation of the dorsolateral prefrontal cortex (dlPFC) during extinction. These results point to different extinction processes in delay and trace conditioning. VmPFC activation during extinction of delay conditioning might reflect the inhibition of the fear response. In contrast, dlPFC activation during extinction of trace conditioning may reflect modulation of working memory processes which are involved in bridging the trace interval and hold information in short term memory. PMID:24904363

  20. COCAINE AND PAVLOVIAN FEAR CONDITIONING: DOSE-EFFECT ANALYSIS

    PubMed Central

    Wood, Suzanne C.; Fay, Jonathon; Sage, Jennifer R.; Anagnostaras, Stephan G.

    2007-01-01

    Emerging evidence suggests that cocaine and other drugs of abuse can interfere with many aspects of cognitive functioning. The authors examined the effects of 0.1 – 15 mg/kg of cocaine on Pavlovian contextual and cued fear conditioning in mice. As expected, pre-training cocaine dose-dependently produced hyperactivity and disrupted freezing. Surprisingly, when the mice were tested off-drug later, the group pre-treated with a moderate dose of cocaine (15 mg/kg) displayed significantly less contextual and cued memory, compared to saline control animals. Conversely, mice pre-treated with a very low dose of cocaine (0.1 mg/kg) showed significantly enhanced fear memory for both context and tone, compared to controls. These results were not due to cocaine’s anesthetic effects, as shock reactivity was unaffected by cocaine. The data suggest that despite cocaine’s reputation as a performance-enhancing and anxiogenic drug, this effect is seen only at very low doses, whereas a moderate dose disrupts hippocampus and amygdala-dependent fear conditioning. PMID:17098299

  1. Opioid receptors regulate the extinction of Pavlovian fear conditioning.

    PubMed

    McNally, Gavan P; Westbrook, R Frederick

    2003-12-01

    Rats received a single pairing of an auditory conditioned stimulus (CS) with a footshock unconditioned stimulus (US). The fear (freezing) that had accrued to the CS was then extinguished. Injection of naloxone prior to this extinction significantly impaired the development of extinction. This impairment was mediated by opioid receptors in the brain and was not observed when naloxone was injected after extinction training. Finally, an injection of naloxone on test failed to reinstate extinguished responding that had already accrued to the CS. These experiments show that opioid receptors regulate the development, but not the expression, of fear extinction and are discussed with reference to the roles of opioid receptors in US processing, memory, and appetitive motivation.

  2. Fear conditioned potentiation of the acoustic blink reflex in patients with cerebellar lesions

    PubMed Central

    Maschke, M.; Drepper, J.; Kindsvater, K.; Kolb, F.; Diener, H.; Timmann, D.

    2000-01-01

    OBJECTIVE—To investigate whether the human cerebellum takes part in fear conditioned potentiation of the acoustic blink reflex.
METHODS—A group of 10 cerebellar patients (eight patients with lesions involving the medial cerebellum, two patients with circumscribed lesions of the cerebellar hemispheres) was compared with a group of 16 age and sex matched healthy control subjects. The fear conditioned potentiation paradigm consisted of three phases. During the first, habituation phase subjects received 20 successive acoustic blink stimuli. In the subsequent fear conditioning phase, subjects passed through 20 paired presentations of the unconditioned fear stimulus (US; an electric shock) and the conditioned stimulus (CS; a light). Thereafter, subjects underwent the potentiation phase, which consisted of a pseudorandom order of 12 trials of the acoustic blink stimulus alone, 12 acoustic blink stimuli paired with the conditioned stimulus, and six conditioned stimuli paired with the unconditioned stimulus. The EMG of the acoustic blink reflex was recorded at the orbicularis oculi muscles. The potentiation effect was determined as the difference in normalised peak amplitude of the blink reflex evoked by pairs of CS and acoustic blink stimuli and evoked by the acoustic stimulus alone.
RESULTS—In the habituation phase, short term habituation of the acoustic blink reflex was preserved in all cerebellar patients. However, in the potentiation phase, the potentiation effect of the blink reflex was significantly reduced in patients with medial cerebellar lesions compared with the controls (mean (SD) potentiation effect (%), patients: −6.4 (15.3), controls: 21.6 (35.6)), but was within normal limits in the two patients with lateral lesions.
CONCLUSIONS—The present findings suggest that the human medial cerebellum is involved in associative learning of non-specific aversive reactions—that is, the fear conditioned potentiation of the acoustic blink reflex

  3. Muscarinic receptors in amygdala control trace fear conditioning.

    PubMed

    Baysinger, Amber N; Kent, Brianne A; Brown, Thomas H

    2012-01-01

    Intelligent behavior requires transient memory, which entails the ability to retain information over short time periods. A newly-emerging hypothesis posits that endogenous persistent firing (EPF) is the neurophysiological foundation for aspects or types of transient memory. EPF is enabled by the activation of muscarinic acetylcholine receptors (mAChRs) and is triggered by suprathreshold stimulation. EPF occurs in several brain regions, including the lateral amygdala (LA). The present study examined the role of amygdalar mAChRs in trace fear conditioning, a paradigm that requires transient memory. If mAChR-dependent EPF selectively supports transient memory, then blocking amygdalar mAChRs should impair trace conditioning, while sparing delay and context conditioning, which presumably do not rely upon transient memory. To test the EPF hypothesis, LA was bilaterally infused, prior to trace or delay conditioning, with either a mAChR antagonist (scopolamine) or saline. Computerized video analysis quantified the amount of freezing elicited by the cue and by the training context. Scopolamine infusion profoundly reduced freezing in the trace conditioning group but had no significant effect on delay or context conditioning. This pattern of results was uniquely anticipated by the EPF hypothesis. The present findings are discussed in terms of a systems-level theory of how EPF in LA and several other brain regions might help support trace fear conditioning.

  4. Muscarinic Receptors in Amygdala Control Trace Fear Conditioning

    PubMed Central

    Baysinger, Amber N.; Kent, Brianne A.; Brown, Thomas H.

    2012-01-01

    Intelligent behavior requires transient memory, which entails the ability to retain information over short time periods. A newly-emerging hypothesis posits that endogenous persistent firing (EPF) is the neurophysiological foundation for aspects or types of transient memory. EPF is enabled by the activation of muscarinic acetylcholine receptors (mAChRs) and is triggered by suprathreshold stimulation. EPF occurs in several brain regions, including the lateral amygdala (LA). The present study examined the role of amygdalar mAChRs in trace fear conditioning, a paradigm that requires transient memory. If mAChR-dependent EPF selectively supports transient memory, then blocking amygdalar mAChRs should impair trace conditioning, while sparing delay and context conditioning, which presumably do not rely upon transient memory. To test the EPF hypothesis, LA was bilaterally infused, prior to trace or delay conditioning, with either a mAChR antagonist (scopolamine) or saline. Computerized video analysis quantified the amount of freezing elicited by the cue and by the training context. Scopolamine infusion profoundly reduced freezing in the trace conditioning group but had no significant effect on delay or context conditioning. This pattern of results was uniquely anticipated by the EPF hypothesis. The present findings are discussed in terms of a systems-level theory of how EPF in LA and several other brain regions might help support trace fear conditioning. PMID:23029199

  5. Distinct neuronal populations in the basolateral and central amygdala are activated with acute pain, conditioned fear, and fear-conditioned analgesia.

    PubMed

    Butler, Ryan K; Ehling, Sarah; Barbar, Megan; Thomas, Jess; Hughes, Mary A; Smith, Charles E; Pogorelov, Vladimir M; Aryal, Dipendra K; Wetsel, William C; Lascelles, B Duncan X

    2017-09-12

    Fear-conditioned analgesia (FCA) is modulated by brain areas involved in the descending inhibitory pain pathway such as the basolateral (BLA) and central amygdala (CEA). The BLA contains Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and parvalbumin (PV) neurons. CEA neurons are primarily inhibitory (GABAergic) that comprise enkephalin (ENK) interneurons and corticotropin-releasing factor (CRF) - neurons that project to the periaqueductal grey. The purpose of our experiment was to determine the pattern of activation of CaMKII/PV and ENK/CRF neurons following the expression of acute pain, conditioned fear, and FCA. A significant reduction was observed in nociceptive behaviors in mice re-exposed to a contextually-aversive environment. Using NeuN and cFos as markers for activated neurons, CaMKII, PV, ENK, or CRF were used to identify neuronal subtypes. We find that mice expressing conditioned fear displayed an increase in c-Fos/CaMKII co-localization in the lateral amygdala and BLA compared to controls. Additionally a significant increase in cFos/CRF co-localization was observed in mice expressing FCA. These results show that amygdala processing of conditioned contextual aversive, nociceptive, and FCA behaviors involve different neuronal phenotypes and neural circuits between, within, and from various amygdala nuclei. This information will be important in developing novel therapies for treating pain and emotive disorders in humans. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. No Effect of Cathodal Transcranial Direct Current Stimulation on Fear Memory in Healthy Human Subjects

    PubMed Central

    Mungee, Aditya; Burger, Max; Bajbouj, Malek

    2016-01-01

    Background: Studies have demonstrated that fear memories can be modified using non-invasive methods. Recently, we demonstrated that anodal transcranial direct current stimulation (tDCS) of the right dorsolateral prefrontal cortex is capable of enhancing fear memories. Here, we examined the effects of cathodal tDCS of the right dorsolateral prefrontal cortex during fear reconsolidation in humans. Methods: Seventeen young, healthy subjects were randomly assigned to two groups, which underwent fear conditioning with mild electric stimuli paired with a visual stimulus. Twenty-four hours later, both groups were shown a reminder of the conditioned fearful stimulus. Shortly thereafter, they received either tDCS (right prefrontal—cathodal, left supraorbital—anodal) for 20 min at 1 mA, or sham stimulation. A day later, fear responses of both groups were compared. Results: On Day 3, during fear response assessment, there were no significant differences between the tDCS and sham group (p > 0.05). Conclusion: We conclude that cathodal tDCS of the right dorsolateral prefrontal cortex (right prefrontal—cathodal, left supraorbital—anodal) did not influence fear memories. PMID:27827903

  7. Prior cocaine exposure disrupts extinction of fear conditioning

    PubMed Central

    Burke, Kathryn A.; Franz, Theresa M.; Gugsa, Nishan; Schoenbaum, Geoffrey

    2008-01-01

    Psychostimulant exposure has been shown to cause molecular and cellular changes in prefrontal cortex. It has been hypothesized that these drug-induced changes might affect the operation of prefrontal-limbic circuits, disrupting their normal role in controlling behavior and thereby leading to compulsive drug-seeking. To test this hypothesis, we tested cocaine-treated rats in a fear conditioning, inflation, and extinction task, known to depend on medial prefrontal cortex and amygdala. Cocaine-treated rats conditioned and inflated similar to saline controls but displayed slower extinction learning. These results support the hypothesis that control processes in the medial prefrontal cortex are impaired by cocaine exposure. PMID:16847305

  8. Voluntary wheel running enhances contextual but not trace fear conditioning.

    PubMed

    Kohman, Rachel A; Clark, Peter J; Deyoung, Erin K; Bhattacharya, Tushar K; Venghaus, Christine E; Rhodes, Justin S

    2012-01-01

    Exercise improves performance on a number of hippocampus involved cognitive tasks including contextual fear conditioning, but whether exercise enhances contextual fear when the retention interval is longer than 1 day is not known. Also unknown is whether exercise improves trace conditioning, a task that requires the hippocampus to bridge the time interval between stimuli. Hence, 4-month-old male C57BL/6J mice were housed with or without running wheels. To assess whether hippocampal neurogenesis was associated with behavioral outcomes, during the initial 10 days, mice received Bromodeoxyuridine to label dividing cells. After 30 days, one group of mice was trained in a contextual fear conditioning task. Freezing to context was assessed 1, 7, or 21 days post-training. A separate group was trained on a trace procedure, in which a tone and footshock were separated by a 15, 30, or 45s interval. Freezing to the tone was measured 24h later in a novel environment, and freezing to the training context was measured 48h later. Running enhanced freezing to context when the retention interval was 1, but not 7 or 21 days. Running had no effect on trace conditioning even though runners displayed enhanced freezing to the training context 48h later. Wheel running increased survival of new neurons in the hippocampus. Collectively, findings indicate that wheel running enhances cognitive performance on some tasks but not others and that enhanced neurogenesis is not always associated with improved performance on hippocampus tasks, one example of which is trace conditioning. Published by Elsevier B.V.

  9. Hypervigilance for fear after basolateral amygdala damage in humans

    PubMed Central

    Terburg, D; Morgan, B E; Montoya, E R; Hooge, I T; Thornton, H B; Hariri, A R; Panksepp, J; Stein, D J; van Honk, J

    2012-01-01

    Recent rodent research has shown that the basolateral amygdala (BLA) inhibits unconditioned, or innate, fear. It is, however, unknown whether the BLA acts in similar ways in humans. In a group of five subjects with a rare genetic syndrome, that is, Urbach–Wiethe disease (UWD), we used a combination of structural and functional neuroimaging, and established focal, bilateral BLA damage, while other amygdala sub-regions are functionally intact. We tested the translational hypothesis that these BLA-damaged UWD-subjects are hypervigilant to facial expressions of fear, which are prototypical innate threat cues in humans. Our data indeed repeatedly confirm fear hypervigilance in these UWD subjects. They show hypervigilant responses to unconsciously presented fearful faces in a modified Stroop task. They attend longer to the eyes of dynamically displayed fearful faces in an eye-tracked emotion recognition task, and in that task recognize facial fear significantly better than control subjects. These findings provide the first direct evidence in humans in support of an inhibitory function of the BLA on the brain's threat vigilance system, which has important implications for the understanding of the amygdala's role in the disorders of fear and anxiety. PMID:22832959

  10. Sexually divergent expression of active and passive conditioned fear responses in rats.

    PubMed

    Gruene, Tina M; Flick, Katelyn; Stefano, Alexis; Shea, Stephen D; Shansky, Rebecca M

    2015-11-14

    Traditional rodent models of Pavlovian fear conditioning assess the strength of learning by quantifying freezing responses. However, sole reliance on this measure includes the de facto assumption that any locomotor activity reflects an absence of fear. Consequently, alternative expressions of associative learning are rarely considered. Here we identify a novel, active fear response ('darting') that occurs primarily in female rats. In females, darting exhibits the characteristics of a learned fear behavior, appearing during the CS period as conditioning proceeds and disappearing from the CS period during extinction. This finding motivates a reinterpretation of rodent fear conditioning studies, particularly in females, and it suggests that conditioned fear behavior is more diverse than previously appreciated. Moreover, rats that darted during initial fear conditioning exhibited lower freezing during the second day of extinction testing, suggesting that females employ distinct and adaptive fear response strategies that improve long-term outcomes.

  11. 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…

  12. Human brain responsivity to different intensities of masked fearful eye whites: an ERP study.

    PubMed

    Feng, Wenfeng; Luo, Wenbo; Liao, Yu; Wang, Naiyi; Gan, Tian; Luo, Yue-Jia

    2009-08-25

    Previous studies have shown differential event-related potentials (ERPs) to intensities of fearful facial expressions. There are indications that the eyes may be particularly relevant for the recognition of fearful expressions, even the amount of white sclera exposed above and on sides of the dark pupil could activate the amygdala response. To investigate whether the ERP differences between intensities of fearful expressions are driven by the differential salience of the eyes in the fearful faces, ERPs were measured within a backward masking paradigm, where observers were asked to do a gender-decision task with male and female neutral faces. The emotional stimuli used were low-intensity (50%), prototypical (100%), and caricatured (150%) fearful eye whites that were derived from corresponding intensities of fearful faces respectively. Three groups of white squares that have the same pixels as the eye whites were created as control conditions. Analysis of the ERP data showed a linear increase in amplitudes of the parietal-occipital P120 by three intensities of fearful eye whites. These ERP effects were proved sensitive to intensities of negative emotions but not to the simple physical features as the same patterns of differences were not observed on white squares. Larger parietal-occipital P250 amplitudes were observed for caricatured 150% than low-intensity 50% fearful eye whites. It might reflect the subcortical pathway of emotion-specific, fearful processing. The results demonstrate that the human brain is sensitive to intensities of fear, even if just shown intensities of fearful eye white in the absence of awareness.

  13. Use of the ABA Fear Renewal Paradigm to Assess the Effects of Extinction with Co-Present Fear Inhibitors or Excitors: Implications for Theories of Extinction and for Treating Human Fears and Phobias

    ERIC Educational Resources Information Center

    Thomas, Brian L.; Ayres, John J. B.

    2004-01-01

    In four experiments using albino rats in an ABA fear renewal paradigm, we studied conditioned fear in the A test context following extinction in Context B. Conditioned suppression of operant responding was the index of fear. In Experiments 1-3, we found that extinguishing a feared cue in compound with a putative conditioned inhibitor of fear led…

  14. Does pre-exposure inhibit fear context conditioning? A Virtual Reality Study.

    PubMed

    Tröger, Christian; Ewald, Heike; Glotzbach, Evelyn; Pauli, Paul; Mühlberger, Andreas

    2012-06-01

    Several studies in animals and humans have indicated that familiarity toward cues reduces cue-conditioning effects. The influence of familiarity of a context on context conditioning has been confirmed in animal studies only. Thus, this study examined contextual fear conditioning in humans depending on pre-exposure to the to-be-conditioned context. To accomplish this, a virtual reality paradigm presented via a head mounted display was realized. During conditioning, participants were exposed to one of two office rooms (contexts), of which one became associated with aversive electric stimuli (UCS). 1 day before conditioning, participants were randomly exposed to either the later to-be-conditioned context (n = 20) or to an unrelated virtual environment (n = 20). Startle reflex, skin conductance response, heart rate, and ratings of valence, arousal, and anxiety were measured to assess context conditioning. Successful context conditioning was demonstrated for both ratings and physiological indicators. Pre-exposure did not prevent successful context conditioning. We conclude that in humans, contextual fear conditioning is not easily modified by pre-exposure to the context.

  15. Fear but not fright: re-evaluating traumatic experience attenuates anxiety-like behaviors after fear conditioning.

    PubMed

    Costanzi, Marco; Saraulli, Daniele; Cannas, Sara; D'Alessandro, Francesca; Florenzano, Fulvio; Rossi-Arnaud, Clelia; Cestari, Vincenzo

    2014-01-01

    Fear allows organisms to cope with dangerous situations and remembering these situations has an adaptive role preserving individuals from injury and death. However, recalling traumatic memories can induce re-experiencing the trauma, thus resulting in a maladaptive fear. A failure to properly regulate fear responses has been associated with anxiety disorders, like Posttraumatic Stress Disorder (PTSD). Thus, re-establishing the capability to regulate fear has an important role for its adaptive and clinical relevance. Strategies aimed at erasing fear memories have been proposed, although there are limits about their efficiency in treating anxiety disorders. To re-establish fear regulation, here we propose a new approach, based on the re-evaluation of the aversive value of traumatic experience. Mice were submitted to a contextual-fear-conditioning paradigm in which a neutral context was paired with an intense electric footshock. Three weeks after acquisition, conditioned mice were treated with a less intense footshock (pain threshold). The effectiveness of this procedure in reducing fear expression was assessed in terms of behavioral outcomes related to PTSD (e.g., hyper-reactivity to a neutral tone, anxiety levels in a plus maze task, social avoidance, and learning deficits in a spatial water maze) and of amygdala activity by evaluating c-fos expression. Furthermore, a possible role of lateral orbitofrontal cortex (lOFC) in mediating the behavioral effects induced by the re-evaluation procedure was investigated. We observed that this treatment: (i) significantly mitigates the abnormal behavioral outcomes induced by trauma; (ii) persistently attenuates fear expression without erasing contextual memory; (iii) prevents fear reinstatement; (iv) reduces amygdala activity; and (v) requires an intact lOFC to be effective. These results suggest that an effective strategy to treat pathological anxiety should address cognitive re-evaluation of the traumatic experience mediated

  16. Fear but not fright: re-evaluating traumatic experience attenuates anxiety-like behaviors after fear conditioning

    PubMed Central

    Costanzi, Marco; Saraulli, Daniele; Cannas, Sara; D’Alessandro, Francesca; Florenzano, Fulvio; Rossi-Arnaud, Clelia; Cestari, Vincenzo

    2014-01-01

    Fear allows organisms to cope with dangerous situations and remembering these situations has an adaptive role preserving individuals from injury and death. However, recalling traumatic memories can induce re-experiencing the trauma, thus resulting in a maladaptive fear. A failure to properly regulate fear responses has been associated with anxiety disorders, like Posttraumatic Stress Disorder (PTSD). Thus, re-establishing the capability to regulate fear has an important role for its adaptive and clinical relevance. Strategies aimed at erasing fear memories have been proposed, although there are limits about their efficiency in treating anxiety disorders. To re-establish fear regulation, here we propose a new approach, based on the re-evaluation of the aversive value of traumatic experience. Mice were submitted to a contextual-fear-conditioning paradigm in which a neutral context was paired with an intense electric footshock. Three weeks after acquisition, conditioned mice were treated with a less intense footshock (pain threshold). The effectiveness of this procedure in reducing fear expression was assessed in terms of behavioral outcomes related to PTSD (e.g., hyper-reactivity to a neutral tone, anxiety levels in a plus maze task, social avoidance, and learning deficits in a spatial water maze) and of amygdala activity by evaluating c-fos expression. Furthermore, a possible role of lateral orbitofrontal cortex (lOFC) in mediating the behavioral effects induced by the re-evaluation procedure was investigated. We observed that this treatment: (i) significantly mitigates the abnormal behavioral outcomes induced by trauma; (ii) persistently attenuates fear expression without erasing contextual memory; (iii) prevents fear reinstatement; (iv) reduces amygdala activity; and (v) requires an intact lOFC to be effective. These results suggest that an effective strategy to treat pathological anxiety should address cognitive re-evaluation of the traumatic experience mediated

  17. Aripiprazole Facilitates Extinction of Conditioned Fear in Adolescent Rats.

    PubMed

    Ganella, Despina E; Lee-Kardashyan, Liubov; Luikinga, Sophia J; Nguyen, Danny L D; Madsen, Heather B; Zbukvic, Isabel C; Coulthard, Russell; Lawrence, Andrew J; Kim, Jee Hyun

    2017-01-01

    Anxiety disorders are the most common type of mental disorder during adolescence, which is at least partly due to the resistance to extinction exhibited at this age. The dopaminergic system is known to be dysregulated during adolescence; therefore, we aimed to facilitate extinction in adolescent rats using the dopamine receptor 2 partial agonist aripiprazole (Abilify™), and examine the behavioral and neural outcomes. Adolescent rats were conditioned to fear a tone. The next day, rats received extinction 30 min after a systemic injection of either 5 mg/kg aripiprazole or vehicle, and then were tested the following day. For the immunohistochemistry experiment, naïve and "no extinction" conditions were added and rats were perfused either on the extinction day or test day. To assess the activation of neurons receiving dopaminergic input, c-Fos, and dopamine- and cAMP-regulated neuronal phosphoprotein (DARPP-32) labeled neurons were quantified in the amygdala and the medial prefrontal cortex (mPFC). Systemic treatment with aripiprazole at the time of extinction significantly reduced freezing at test the next day. This effect was not observed in rats that were fear conditioned but did not receive any extinction. Aripiprazole's facilitation of extinction was accompanied by increased activation of neurons in the mPFC. Taken together, aripiprazole represents a novel pharmacological adjunct to exposure therapy worthy of further examination. The effect of aripiprazole is related to enhanced activation of mPFC neurons receiving dopaminergic innervation.

  18. Individual differences in the expression of conditioned fear are associated with endogenous fibroblast growth factor 2

    PubMed Central

    Richardson, Rick

    2016-01-01

    These experiments examined the relationship between the neurotrophic factor fibroblast growth factor 2 (FGF2) and individual differences in the expression of conditioned fear. Experiments 1 and 2 demonstrated that rats naturally expressing low levels of contextual or cued fear have higher levels of hippocampal FGF2 relative to rats that express high levels of conditioned fear and nonconditioned rats. Experiment 3 demonstrated that hippocampal FGF2 is not increased in rats that exhibit pharmacological-induced amnesia of conditioned fear. Together, these experiments provide evidence that FGF2 may be an endogenous regulator of fear responses to conditioned stimuli. PMID:26670186

  19. Retrieval per se is not sufficient to trigger reconsolidation of human fear memory.

    PubMed

    Sevenster, Dieuwke; Beckers, Tom; Kindt, Merel

    2012-03-01

    Ample evidence suggests that consolidated memories, upon their retrieval, enter a labile state, in which they might be susceptible to change. It has been proposed that memory labilization allows for the integration of relevant information in the established memory trace (memory updating). Memory labilization and reconsolidation do not necessarily occur when a memory is being reactivated, but only when there is something to be learned during memory retrieval (prediction error). Thus, updating of a fear memory trace should not occur under retrieval conditions in which the outcome is fully predictable (no prediction error). Here, we addressed this issue, using a human differential fear conditioning procedure, by eliminating the very possibility of reinforcement of the reminder cue. A previously established fear memory (picture-shock pairings) was reactivated with shock-electrodes attached (Propranolol group, n=18) or unattached (Propranolol No-Shock Expectation group, n=19). We additionally tested a placebo-control group with the shock-electrodes attached (Placebo group, n=18). Reconsolidation was not triggered when nothing could be learned during the reminder trial, as noradrenergic blockade did not affect expression of the fear memory 24h later in the Propranolol No-Shock Expectation group. Only when the outcome of the retrieval cue was not fully predictable, propranolol, contrary to placebo, reduced the startle fear response and prevented the return of fear (reinstatement) the following day. In line with previous studies, skin conductance response and shock expectancies were not affected by propranolol. Remarkably, a double dissociation emerged between the emotional (startle response) and more cognitive expression (expectancies, SCR) of the fear memory. Our findings have important implications for reconsolidation blockade as treatment strategy for emotional disorders. First, fear reducing procedures that target the emotional component of fear memory do not

  20. Fear Conditioning in Adolescents With Anxiety Disorders: Results From a Novel Experimental Paradigm

    PubMed Central

    LAU, JENNIFER Y.F.; LISSEK, SHMUEL; NELSON, ERIC E.; LEE, YOON; ROBERSON-NAY, ROXANN; POETH, KAITLIN; JENNESS, JESSICA; ERNST, MONIQUE; GRILLON, CHRISTIAN; PINE, DANIEL S.

    2009-01-01

    Objective Considerable research examines fear conditioning in adult anxiety disorders but few studies examine youths. Adult data suggest that anxiety disorders involve elevated fear but intact differential conditioning. We used a novel paradigm to assess fear conditioning in pediatric anxiety patients. Method Sixteen individuals with anxiety disorders and 38 healthy comparisons viewed two photographs of actresses displaying neutral expressions. One picture served as the conditioned stimulus (CS), paired with a fearful expression and a shrieking scream (CS+), whereas the other picture served as a CS unpaired with the aversive outcome (CS−). Conditioning was indexed by self-reported fear. Subjects participated in two visits involving conditioning and extinction trials. Results Both groups developed greater fear of the CS+ relative to CS−. Higher fear levels collapsed across each CS characterized anxious relative to healthy subjects, but no significant interaction between group and stimulus type emerged. Fear levels at visit 1 predicted avoidance of visit 2. Fear levels to both CS types showed stability even after extinction. Conclusions Consistent with adult data, pediatric anxiety involves higher fear levels following conditioning but not greater differential conditioning. Extending these methods to neuroimaging studies may elucidate neural correlates of fear conditioning. Implications for exposure therapies are discussed. PMID:18174830

  1. Spontaneous brain activity following fear reminder of fear conditioning by using resting-state functional MRI

    PubMed Central

    Feng, Pan; Zheng, Yong; Feng, Tingyong

    2015-01-01

    Although disrupting reconsolidation may be a promising approach to attenuate or erase the expression of fear memory, it is not clear how the neural state following fear reminder contribute to the following fear extinction. To address this question, we used resting-state functional magnetic resonance imaging (rs-fMRI) to measure spontaneous neuronal activity and functional connectivity (RSFC) following fear reminder. Some brain regions such as dorsal anterior cingulate (dACC) and ventromedial prefrontal cortex (vmPFC) showed increased amplitude of LFF (ALFF) in the fear reminder group than the no reminder group following fear reminder. More importantly, there was much stronger functional connectivity between the amygdala and vmPFC in the fear reminder group than those in the no reminder group. These findings suggest that the strong functional connectivity between vmPFC and amygdala following a fear reminder could serve as a key role in the followed-up fear extinction stages, which may contribute to the erasing of fear memory. PMID:26576733

  2. Genetic dissection of an amygdala microcircuit that gates conditioned fear

    PubMed Central

    Haubensak, Wulf; Kunwar, Prabhat; Cai, Haijiang; Ciocchi, Stephane; Wall, Nicholas; Ponnusamy, Ravikumar; Biag, Jonathan; Dong, Hong-Wei; Deisseroth, Karl; Callaway, Edward M.; Fanselow, Michael S.; Lüthi, Andreas; Anderson, David J.

    2013-01-01

    The role of different amygdala nuclei (neuroanatomical subdivisions) in processing Pavlovian conditioned fear has been studied extensively, but the function of the heterogeneous neuronal subtypes within these nuclei remains poorly understood. We used molecular genetic approaches to map the functional connectivity of a subpopulation of GABAergic neurons, located in the lateral subdivision of the central amygdala (CEl), which express protein kinase C-delta (PKCδ). Channelrhodopsin-2 assisted circuit mapping in amygdala slices and cell-specific viral tracing indicate that PKCδ+ neurons inhibit output neurons in the medial CE (CEm), and also make reciprocal inhibitory synapses with PKCδ− neurons in CEl. Electrical silencing of PKCδ+ neurons in vivo suggests that they correspond to physiologically identified units that are inhibited by the conditioned stimulus (CS), called CEloff units (Ciocchi et al, this issue). This correspondence, together with behavioral data, defines an inhibitory microcircuit in CEl that gates CEm output to control the level of conditioned freezing. PMID:21068836

  3. The NMDA Agonist D-Cycloserine Facilitates Fear Memory Consolidation in Humans

    PubMed Central

    Holt, Beatrice; Petrovic, Predrag; De Martino, Benedetto; Klöppel, Stefan; Büchel, Christian; Dolan, Raymond J.

    2009-01-01

    Animal research suggests that the consolidation of fear and extinction memories depends on N-methyl D-aspartate (NMDA)-type glutamate receptors. Using a fear conditioning and extinction paradigm in healthy normal volunteers, we show that postlearning administration of the NMDA partial agonist D-cycloserine (DCS) facilitates fear memory consolidation, evidenced behaviorally by enhanced skin conductance responses, relative to placebo, for presentations of a conditioned stimulus (CS) at a memory test performed 72 h later. DCS also enhanced CS-evoked neural responses in a posterior hippocampus/collateral sulcus region and in the medial prefrontal cortex at test. Our data suggest a role for NMDA receptors in regulating fear memory consolidation in humans. PMID:18477687

  4. Extinction, generalization, and return of fear: a critical review of renewal research in humans.

    PubMed

    Vervliet, Bram; Baeyens, Frank; Van den Bergh, Omer; Hermans, Dirk

    2013-01-01

    The main behavioral signature of fear extinction is its fragility. This is exemplified by the renewal effect, where a change in the background context produces recovery of fear to a conditioned-and-extinguished stimulus. Renewal is the backbone of a widely accepted theory of extinction in animal research, as well as an important experimental model to screen novel treatment techniques. This has led to an explosion of fear renewal research in humans. However, the mere observation of return of fear in a renewal procedure is not sufficient to validate this particular theory of extinction in the tested sample/procedure. Here, we systematically outline a set of experimental tests that aid in evaluating alternative extinction/renewal mechanisms. We examine published renewal studies in human fear conditioning and conclude that the prevailing theory of extinction is often taken for granted, but critical tests are lacking. Including these tests in future research will not only reveal the fear extinction mechanism in humans, but also inspire further developments in extinction treatment research.

  5. Social buffering ameliorates conditioned fear responses in the presence of an auditory conditioned stimulus.

    PubMed

    Kiyokawa, Yasushi; Takeuchi, Yukari

    2017-01-01

    Social buffering is a phenomenon in which stress in an animal is ameliorated when the subject is accompanied by a conspecific animal(s) during exposure to distressing stimuli. Previous studies of social buffering of conditioned fear responses in rats have typically used a 3-s auditory conditioned stimulus (CS) as a stressor, observing stress responses during a specified experimental period. Because a 3-s CS is extremely short compared with a typical experimental period, freezing has thus been observed primarily in the absence of the CS. Therefore, it has been unclear whether social buffering ameliorates conditioned fear responses in the presence of the CS. To clarify this issue, the current study assessed the effects of social buffering on conditioned fear responses in the presence of a 20-s CS. We measured the percentage of time spent freezing during the 20-s period following the onset of the CS. When conditioned subjects were exposed to the 20-s CS alone, they exhibited a high percentage of freezing in the presence of the CS. The presence of another non-conditioned rat completely blocked this response. The same result was observed when freezing was observed primarily in the absence of the 3-s CS. In addition, we confirmed that the presence of an associate ameliorated conditioned fear responses induced by a 20-s CS or 3-s CS when the duration and frequency of fear responses was measured. These findings indicate that social buffering ameliorates conditioned fear responses in the presence of an auditory CS. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. Reward devaluation disrupts latent inhibition in fear conditioning.

    PubMed

    De la Casa, Luís Gonzalo; Mena, Auxiliadora; Ruiz-Salas, Juán Carlos; Quintero, Esperanza; Papini, Mauricio R

    2017-07-11

    Three experiments explored the link between reward shifts and latent inhibition (LI). Using consummatory procedures, rewards were either downshifted from 32% to 4% sucrose (Experiments 1-2), or upshifted from 4% to 32% sucrose (Experiment 3). In both cases, appropriate unshifted controls were also included. LI was implemented in terms of fear conditioning involving a single tone-shock pairing after extensive tone-only preexposure. Nonpreexposed controls were also included. Experiment 1 demonstrated a typical LI effect (i.e., disruption of fear conditioning after preexposure to the tone) in animals previously exposed only to 4% sucrose. However, the LI effect was eliminated by preexposure to a 32%-to-4% sucrose devaluation. Experiment 2 replicated this effect when the LI protocol was administered immediately after the reward devaluation event. However, LI was restored when preexposure was administered after a 60-min retention interval. Finally, Experiment 3 showed that a reward upshift did not affect LI. These results point to a significant role of negative emotion related to reward devaluation in the enhancement of stimulus processing despite extensive nonreinforced preexposure experience.

  7. 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.

  8. Antenatal Maternal Stress Alters Functional Brain Responses In Adult Offspring During Conditioned Fear

    PubMed Central

    Sadler, Theodore R.; Nguyen, Peter T.; Yang, Jun; Givrad, Tina K.; Mayer, Emeran A.; Maarek, Jean-Michel I.; Hinton, David R.; Holschneider, Daniel P.

    2011-01-01

    Antenatal maternal stress has been shown in rodent models and in humans to result in altered behavioral and neuroendocrine responses, yet little is known about its effects on functional brain activation. Pregnant female rats received a daily foot-shock stress or sham-stress two days after testing plug-positive and continuing for the duration of their pregnancy. Adult male offspring (age 14 weeks) with and without prior maternal stress (MS) were exposed to an auditory fear conditioning (CF) paradigm. Cerebral blood flow (CBF) was assessed during recall of the tone cue in the nonsedated, nontethered animal using the 14C-iodoantipyrine method, in which the tracer was administered intravenously by remote activation of an implantable minipump. Regional CBF distribution was examined by autoradiography and analyzed by statistical parametric mapping in the three-dimensionally reconstructed brains. Presence of fear memory was confirmed by behavioral immobility (‘freezing’). Corticosterone plasma levels during the CF paradigm were measured by ELISA in a separate group of rats. Antenatal MS exposure altered functional brain responses to the fear conditioned cue in adult offspring. Rats with prior MS exposure compared to those without demonstrated heightened fear responsivity, exaggerated and prolonged corticosterone release, increased functional cerebral activation of limbic/paralimbic regions (amygdala, ventral hippocampus, insula, ventral striatum, nucleus acumbens), the locus coeruleus, and white matter, and deactivation of medial prefrontal cortical regions. Dysregulation of corticolimbic circuits may represent risk factors in the future development of anxiety disorders and associated alterations in emotional regulation. PMID:21300034

  9. Phasic vs Sustained Fear in Rats and Humans: Role of the Extended Amygdala in Fear vs Anxiety

    PubMed Central

    Davis, Michael; Walker, David L; Miles, Leigh; Grillon, Christian

    2010-01-01

    Data will be reviewed using the acoustic startle reflex in rats and humans based on our attempts to operationally define fear vs anxiety. Although the symptoms of fear and anxiety are very similar, they also differ. Fear is a generally adaptive state of apprehension that begins rapidly and dissipates quickly once the threat is removed (phasic fear). Anxiety is elicited by less specific and less predictable threats, or by those that are physically or psychologically more distant. Thus, anxiety is a more long-lasting state of apprehension (sustained fear). Rodent studies suggest that phasic fear is mediated by the amygdala, which sends outputs to the hypothalamus and brainstem to produce symptoms of fear. Sustained fear is also mediated by the amygdala, which releases corticotropin-releasing factor, a stress hormone that acts on receptors in the bed nucleus of the stria terminalis (BNST), a part of the so-called ‘extended amygdala.' The amygdala and BNST send outputs to the same hypothalamic and brainstem targets to produce phasic and sustained fear, respectively. In rats, sustained fear is more sensitive to anxiolytic drugs. In humans, symptoms of clinical anxiety are better detected in sustained rather than phasic fear paradigms. PMID:19693004

  10. Oxytocin and Social Support as Synergistic Inhibitors of Aversive Fear Conditioning and Fear-Potentiated Startle in Male Rats

    DTIC Science & Technology

    2010-09-01

    disorder. Psychoneuroendocrinology 34: 917-923. Heinrichs M, Baumgartner T, Kirschbaum C, Ehlert U (2003). Social support and oxytocin interact to...TITLE: Oxytocin and Social Support as Synergistic Inhibitors of Aversive Fear Conditioning and Fear-Potentiated Startle in Male Rats PRINCIPAL...Annual 3. DATES COVERED (From - To) 4. TITLE AND SUBTITLE Oxytocin and Social Support as Synergistic Inhibitors of 5a. CONTRACT NUMBER

  11. Conditioning- and time-dependent increases in context fear and generalization.

    PubMed

    Poulos, Andrew M; Mehta, Nehali; Lu, Bryan; Amir, Dorsa; Livingston, Briana; Santarelli, Anthony; Zhuravka, Irina; Fanselow, Michael S

    2016-07-01

    A prominent feature of fear memories and anxiety disorders is that they endure across extended periods of time. Here, we examine how the severity of the initial fear experience influences incubation, generalization, and sensitization of contextual fear memories across time. Adult rats were presented with either five, two, one, or zero shocks (1.2 mA, 2 sec) during contextual fear conditioning. Following a recent (1 d) or remote (28 d) retention interval all subjects were returned to the original training context to measure fear memory and/or to a novel context to measure the specificity of fear conditioning. Our results indicate rats that received two or five shocks show an "incubation"-like enhancement of fear between recent and remote retention intervals, while single-shocked animals show stable levels of context fear memory. Moreover, when fear was tested in a novel context, 1 and 2 shocked groups failed to freeze, whereas five shocked rats showed a time-dependent generalization of context memory. Stress enhancement of fear learning to a second round of conditioning was evident in all previously shocked animals. Based on these results, we conclude that the severity or number of foot shocks determines not only the level of fear memory, but also the time-dependent incubation of fear and its generalization across distinct contexts. © 2016 Poulos et al.; Published by Cold Spring Harbor Laboratory Press.

  12. Trace and contextual fear conditioning require neural activity and NMDA receptor-dependent transmission in the medial prefrontal cortex

    PubMed Central

    Gilmartin, Marieke R.; Helmstetter, Fred J.

    2010-01-01

    The contribution of the medial prefrontal cortex (mPFC) to the formation of memory is a subject of considerable recent interest. Notably, the mechanisms supporting memory acquisition in this structure are poorly understood. The mPFC has been implicated in the acquisition of trace fear conditioning, a task that requires the association of a conditional stimulus (CS) and an aversive unconditional stimulus (UCS) across a temporal gap. In both rat and human subjects, frontal regions show increased activity during the trace interval separating the CS and UCS. We investigated the contribution of prefrontal neural activity in the rat to the acquisition of trace fear conditioning using microinfusions of the γ-aminobutyric acid type A (GABAA) receptor agonist muscimol. We also investigated the role of prefrontal N-methyl-d-aspartate (NMDA) receptor-mediated signaling in trace fear conditioning using the NMDA receptor antagonist 2-amino-5-phosphonovaleric acid (APV). Temporary inactivation of prefrontal activity with muscimol or blockade of NMDA receptor-dependent transmission in mPFC impaired the acquisition of trace, but not delay, conditional fear responses. Simultaneously acquired contextual fear responses were also impaired in drug-treated rats exposed to trace or delay, but not unpaired, training protocols. Our results support the idea that synaptic plasticity within the mPFC is critical for the long-term storage of memory in trace fear conditioning. PMID:20504949

  13. Benzodiazepines have no effect on fear-potentiated startle in humans.

    PubMed

    Baas, Johanna M P; Grillon, Christian; Böcker, Koen B E; Brack, Anouk A; Morgan, Charles A; Kenemans, J Leon; Verbaten, Marinus N

    2002-05-01

    Pre-clinical and clinical investigations have provided a great deal of evidence that the fear-potentiated startle paradigm represents a valid model for the objective assessment of emotional states of anxiety and fear. The four studies presented in this report sought to further validate the "threat of shock" paradigm as a human analogue to fear-potentiated startle in rats, by examining the effect of benzodiazepine administration on both baseline and fear-potentiated startle. Three studies, conducted at Utrecht University, evaluated the effects of oxazepam and of diazepam on baseline and fear-potentiated startle, whereas a fourth study, conducted at Yale University, evaluated the effect of diazepam on baseline, contextual and cue-specific fear-potentiated startle. The threat of shock paradigm consisted of verbal instruction about two visual cues (the threat cue predicted the possible administration of electric shock, the other predicted a safe period), followed by a series of presentations of these cues. During these conditions, acoustic startle stimuli were presented in order to elicit startle responses. The magnitude of the startle response was used to index the degree of fear or alarm experienced during the periods of threat and safety. The fourth study examined the effect of IV administration of diazepam in a similar threat of shock paradigm except that there were two additional context manipulations: electrode placement and darkness. None of the drug manipulations affected specific threat-cue potentiation of startle. However, reductions in baseline startle were observed. Further, startle potentiation by darkness was inhibited by diazepam. At least one type of fear-potentiated startle, i.e. potentiation by a cue-specific fear manipulation, is not susceptible to benzodiazepine treatment. In contrast, effects of manipulations more akin to anxiety (darkness, context) appear sensitive to benzodiazepines. Human experimental models differentiating between these cue

  14. Effects of Neonatal Amygdala Lesions on Fear Learning, Conditioned Inhibition, and Extinction in Adult Macaques

    PubMed Central

    Kazama, Andy M.; Heuer, Eric; Davis, Michael; Bachevalier, Jocelyne

    2013-01-01

    Fear conditioning studies have demonstrated the critical role played by the amygdala in emotion processing. Although all lesion studies until now investigated the effect of adult-onset damage on fear conditioning, the current study assessed fear-learning abilities, as measured by fear-potentiated startle, in adult monkeys that had received neonatal neurotoxic amygdala damage or sham-operations. After fear acquisition, their abilities to learn and use a safety cue to modulate their fear to the conditioned cue, and, finally, to extinguish their response to the fear conditioned cue were measured with the AX+/BX− Paradigm. Neonatal amygdala damage retarded, but did not completely abolish, the acquisition of a learned fear. After acquisition of the fear signal, four of the six animals with neonatal amygdala lesions discriminated between the fear and safety cues and were also able to use the safety signal to reduce the potentiated-startle response and to extinguish the fear response when the air-blast was absent. In conclusion, the present results support the critical contribution of the amygdala during the early phases of fear conditioning that leads to quick, robust responses to potentially threatening stimuli, a highly adaptive process across all species and likely to be present in early infancy. The neonatal amygdala lesions also indicated the presence of amygdala-independent alternate pathways that are capable to support fear learning in the absence of a functional amygdala. This parallel processing of fear responses within these alternate pathways was also sufficient to support the ability to flexibly modulate the magnitude of the fear responses. PMID:22642884

  15. Effects of neonatal amygdala lesions on fear learning, conditioned inhibition, and extinction in adult macaques.

    PubMed

    Kazama, Andy M; Heuer, Eric; Davis, Michael; Bachevalier, Jocelyne

    2012-06-01

    Fear conditioning studies have demonstrated the critical role played by the amygdala in emotion processing. Although all lesion studies until now investigated the effect of adult-onset damage on fear conditioning, the current study assessed fear-learning abilities, as measured by fear-potentiated startle, in adult monkeys that had received neonatal neurotoxic amygdala damage or sham-operations. After fear acquisition, their abilities to learn and use a safety cue to modulate their fear to the conditioned cue, and, finally, to extinguish their response to the fear conditioned cue were measured with the AX+/BX- Paradigm. Neonatal amygdala damage retarded, but did not completely abolish, the acquisition of a learned fear. After acquisition of the fear signal, four of the six animals with neonatal amygdala lesions discriminated between the fear and safety cues and were also able to use the safety signal to reduce the potentiated-startle response and to extinguish the fear response when the air-blast was absent. In conclusion, the present results support the critical contribution of the amygdala during the early phases of fear conditioning that leads to quick, robust responses to potentially threatening stimuli, a highly adaptive process across all species and likely to be present in early infancy. The neonatal amygdala lesions also indicated the presence of amygdala-independent alternate pathways that are capable to support fear learning in the absence of a functional amygdala. This parallel processing of fear responses within these alternate pathways was also sufficient to support the ability to flexibly modulate the magnitude of the fear responses. © 2012 American Psychological Association

  16. Contextual and auditory fear conditioning continue to emerge during the periweaning period in rats.

    PubMed

    Burman, Michael A; Erickson, Kristen J; Deal, Alex L; Jacobson, Rose E

    2014-01-01

    Anxiety disorders often emerge during childhood. Rodent models using classical fear conditioning have shown that different types of fear depend upon different neural structures and may emerge at different stages of development. For example, some work has suggested that contextual fear conditioning generally emerges later in development (postnatal day 23-24) than explicitly cued fear conditioning (postnatal day 15-17) in rats. This has been attributed to an inability of younger subjects to form a representation of the context due to an immature hippocampus. However, evidence that contextual fear can be observed in postnatal day 17 subjects and that cued fear conditioning continues to emerge past this age raises questions about the nature of this deficit. The current studies examine this question using both the context pre-exposure facilitation effect for immediate single-shock contextual fear conditioning and traditional cued fear conditioning using Sprague-Dawley rats. The data suggest that both cued and contextual fear conditioning are continuing to develop between PD 17 and 24, consistent with development occurring the in essential fear conditioning circuit.

  17. D-cycloserine does not facilitate fear extinction by reducing conditioned stimulus processing or promoting conditioned inhibition to contextual cues.

    PubMed

    Baker, Kathryn D; McNally, Gavan P; Richardson, Rick

    2012-09-14

    The NMDA receptor partial agonist d-cycloserine (DCS) enhances the extinction of learned fear in rats and exposure therapy in humans with anxiety disorders. Despite these benefits, little is known about the mechanisms by which DCS promotes the loss of fear. The present study examined whether DCS augments extinction retention (1) through reductions in conditioned stimulus (CS) processing or (2) by promoting the development of conditioned inhibition to contextual cues. Rats administered DCS prior to extinction showed enhanced long-term extinction retention (Experiments 3 and 4). The same nonreinforced CS procedure used in extinction also reduced freezing at test when presented as pre-exposure before conditioning, demonstrating latent inhibition (Experiment 1). DCS administered shortly prior to pre-exposure had no effect on latent inhibition using parameters which produced weak (Experiment 2) or strong (Experiment 3) expression of latent inhibition. Therefore, DCS facilitated learning involving CS-alone exposures, but only when these exposures occurred after (extinction) and not before (latent inhibition) conditioning. We also used a retardation test procedure to examine whether the extinction context gained inhibitory properties for rats given DCS prior to extinction. With three different footshock intensities, there was no evidence that DCS promoted accrual of associative inhibition to the extinction context (Experiment 4). The present findings demonstrate that DCS does not facilitate extinction by reducing CS processing or causing the extinction context to become a conditioned inhibitor. Investigations into the mechanisms underlying the augmentation of extinction by DCS are valuable for understanding how fear can be inhibited.

  18. Human fear acquisition deficits in relation to genetic variants of the corticotropin releasing hormone receptor 1 and the serotonin transporter.

    PubMed

    Heitland, Ivo; Groenink, Lucianne; Bijlsma, Elisabeth Y; Oosting, Ronald S; Baas, Johanna M P

    2013-01-01

    The ability to identify predictors of aversive events allows organisms to appropriately respond to these events, and failure to acquire these fear contingencies can lead to maladaptive contextual anxiety. Recently, preclinical studies demonstrated that the corticotropin-releasing factor and serotonin systems are interactively involved in adaptive fear acquisition. Here, 150 healthy medication-free human subjects completed a cue and context fear conditioning procedure in a virtual reality environment. Fear potentiation of the eyeblink startle reflex (FPS) was measured to assess both uninstructed fear acquisition and instructed fear expression. All participants were genotyped for polymorphisms located within regulatory regions of the corticotropin releasing hormone receptor 1 (CRHR1 - rs878886) and the serotonin transporter (5HTTLPR). These polymorphisms have previously been linked to panic disorder and anxious symptomology and personality, respectively. G-allele carriers of CRHR1 (rs878886) showed no acquisition of fear conditioned responses (FPS) to the threat cue in the uninstructed phase, whereas fear acquisition was present in C/C homozygotes. Moreover, carrying the risk alleles of both rs878886 (G-allele) and 5HTTLPR (short allele) was associated with increased FPS to the threat context during this phase. After explicit instructions regarding the threat contingency were given, the cue FPS and context FPS normalized in all genotype groups. The present results indicate that genetic variability in the corticotropin-releasing hormone receptor 1, especially in interaction with the 5HTTLPR, is involved in the acquisition of fear in humans. This translates prior animal findings to the human realm.

  19. Fibroblast growth factor-2 enhances extinction and reduces renewal of conditioned fear.

    PubMed

    Graham, Bronwyn M; Richardson, Rick

    2010-05-01

    Anxiety disorders are increasingly prevalent in society; hence, there is a need to improve on existing treatments for such disorders. Fibroblast growth factor-2 (FGF2), a mitogen that is involved in brain development and regeneration, has been shown to both facilitate long-term extinction of fear and reduce stress-precipitated relapse in rats. Extinction is the laboratory analog of exposure-based therapies in humans. In this study, we continued to investigate the clinical potential of FGF2 as a pharmacological enhancer of extinction by examining its effect on renewal, a common type of relapse. In all experiments, rats were trained to fear a white noise-conditioned stimulus, and then this learned fear was extinguished the following day. Rats received systemic injections of FGF2 or vehicle immediately after extinction training. At test, on the day after extinction training, levels of freezing elicited by the white noise in either the extinction context or the original training context were measured. FGF2-treated rats showed less renewal of fear when tested in the original training context than did vehicle-treated rats. This pattern occurred even when vehicle rats were given double the amount of extinction training, and when FGF2-treated rats were given equivalent exposure to the extinction context. These results show that FGF2 facilitates long-term extinction and attenuates relapse, and thus highlight its potential as a novel pharmacological adjunct to exposure therapy.

  20. Medial prefrontal pathways for the contextual regulation of extinguished fear in humans

    PubMed Central

    Åhs, Fredrik; Kragel, Philip A.; Zielinski, David J.; Brady, Rachael; LaBar, Kevin S.

    2015-01-01

    The maintenance of anxiety disorders is thought to depend, in part, on deficits in extinction memory, possibly due to reduced contextual control of extinction that leads to fear renewal. Animal studies suggest that the neural circuitry responsible fear renewal includes the hippocampus, amygdala, and dorsomedial (dmPFC) and ventromedial (vmPFC) prefrontal cortex. However, the neural mechanisms of context-dependent fear renewal in humans remain poorly understood. We used functional magnetic resonance imaging (fMRI), combined with psychophysiology and immersive virtual reality, to elucidate how the hippocampus, amygdala, and dmPFC and vmPFC interact to drive the context-dependent renewal of extinguished fear. Healthy human participants encountered dynamic fear-relevant conditioned stimuli (CSs) while navigating through 3-D virtual reality environments in the MRI scanner. Conditioning and extinction were performed in two different virtual contexts. Twenty-four hours later, participants were exposed to the CSs without reinforcement while navigating through both contexts in the MRI scanner. Participants showed enhanced skin conductance responses (SCRs) to the previously-reinforced CS+ in the acquisition context on Day 2, consistent with fear renewal, and sustained responses in the dmPFC. In contrast, participants showed low SCRs to the CSs in the extinction context on Day 2, consistent with extinction recall, and enhanced vmPFC activation to the non-reinforced CS−. Structural equation modeling revealed that the dmPFC fully mediated the effect of the hippocampus on right amygdala activity during fear renewal, whereas the vmPFC partially mediated the effect of the hippocampus on right amygdala activity during extinction recall. These results indicate dissociable contextual influences of the hippocampus on prefrontal pathways, which, in turn, determine the level of reactivation of fear associations. PMID:26220745

  1. Medial prefrontal pathways for the contextual regulation of extinguished fear in humans.

    PubMed

    Åhs, Fredrik; Kragel, Philip A; Zielinski, David J; Brady, Rachael; LaBar, Kevin S

    2015-11-15

    The maintenance of anxiety disorders is thought to depend, in part, on deficits in extinction memory, possibly due to reduced contextual control of extinction that leads to fear renewal. Animal studies suggest that the neural circuitry responsible fear renewal includes the hippocampus, amygdala, and dorsomedial (dmPFC) and ventromedial (vmPFC) prefrontal cortex. However, the neural mechanisms of context-dependent fear renewal in humans remain poorly understood. We used functional magnetic resonance imaging (fMRI), combined with psychophysiology and immersive virtual reality, to elucidate how the hippocampus, amygdala, and dmPFC and vmPFC interact to drive the context-dependent renewal of extinguished fear. Healthy human participants encountered dynamic fear-relevant conditioned stimuli (CSs) while navigating through 3-D virtual reality environments in the MRI scanner. Conditioning and extinction were performed in two different virtual contexts. Twenty-four hours later, participants were exposed to the CSs without reinforcement while navigating through both contexts in the MRI scanner. Participants showed enhanced skin conductance responses (SCRs) to the previously-reinforced CS+ in the acquisition context on Day 2, consistent with fear renewal, and sustained responses in the dmPFC. In contrast, participants showed low SCRs to the CSs in the extinction context on Day 2, consistent with extinction recall, and enhanced vmPFC activation to the non-reinforced CS-. Structural equation modeling revealed that the dmPFC fully mediated the effect of the hippocampus on right amygdala activity during fear renewal, whereas the vmPFC partially mediated the effect of the hippocampus on right amygdala activity during extinction recall. These results indicate dissociable contextual influences of the hippocampus on prefrontal pathways, which, in turn, determine the level of reactivation of fear associations.

  2. Differential roles of the dorsal and ventral hippocampus in predator odor contextual fear conditioning.

    PubMed

    Wang, Melissa E; Fraize, Nicolas P; Yin, Linda; Yuan, Robin K; Petsagourakis, Despina; Wann, Ellen G; Muzzio, Isabel A

    2013-06-01

    The study of fear memory is important for understanding various anxiety disorders in which patients experience persistent recollections of traumatic events. These memories often involve associations of contextual cues with aversive events; consequently, Pavlovian classical conditioning is commonly used to study contextual fear learning. The use of predator odor as a fearful stimulus in contextual fear conditioning has become increasingly important as an animal model of anxiety disorders. Innate fear responses to predator odors are well characterized and reliable; however, attempts to use these odors as unconditioned stimuli in fear conditioning paradigms have proven inconsistent. Here we characterize a contextual fear conditioning paradigm using coyote urine as the unconditioned stimulus. We found that contextual conditioning induced by exposure to coyote urine produces long-term freezing, a stereotypic response to fear observed in mice. This paradigm is context-specific and parallels shock-induced contextual conditioning in that it is responsive to extinction training and manipulations of predator odor intensity. Region-specific lesions of the dorsal and ventral hippocampus indicate that both areas are independently required for the long-term expression of learned fear. These results in conjunction with c-fos immunostaining data suggest that while both the dorsal and ventral hippocampus are required for forming a contextual representation, the ventral region also modulates defensive behaviors associated with predators. This study provides information about the individual contributions of the dorsal and ventral hippocampus to ethologically relevant fear learning.

  3. Dendritic structural plasticity in the basolateral amygdala after fear conditioning and its extinction in mice.

    PubMed

    Heinrichs, Stephen C; Leite-Morris, Kimberly A; Guy, Marsha D; Goldberg, Lisa R; Young, Angela J; Kaplan, Gary B

    2013-07-01

    Previous research suggests that morphology and arborization of dendritic spines change as a result of fear conditioning in cortical and subcortical brain regions. This study uniquely aims to delineate these structural changes in the basolateral amygdala (BLA) after both fear conditioning and fear extinction. C57BL/6 mice acquired robust conditioned fear responses (70-80% cued freezing behavior) after six pairings with a tone cue associated with footshock in comparison to unshocked controls. During fear acquisition, freezing behavior was significantly affected by both shock exposure and trial number. For fear extinction, mice were exposed to the conditioned stimulus tone in the absence of shock administration and behavioral responses significantly varied by shock treatment. In the retention tests over 3 weeks, the percentage time spent freezing varied with the factor of extinction training. In all treatment groups, alterations in dendritic plasticity were analyzed using Golgi-Cox staining of dendrites in the BLA. Spine density differed between the fear conditioned group and both the fear extinction and control groups on third order dendrites. Spine density was significantly increased in the fear conditioned group compared to the fear extinction group and controls. Similarly in Sholl analyses, fear conditioning significantly increased BLA spine numbers and dendritic intersections while subsequent extinction training reversed these effects. In summary, fear extinction produced enduring behavioral plasticity that is associated with a reversal of alterations in BLA dendritic plasticity produced by fear conditioning. These neuroplasticity findings can inform our understanding of structural mechanisms underlying stress-related pathology can inform treatment research into these disorders.

  4. Dendritic structural plasticity in the basolateral amygdala after fear conditioning and its extinction in mice

    PubMed Central

    Heinrichs, Stephen C.; Leite-Morris, Kimberly A.; Guy, Marsha D.; Goldberg, Lisa R.; Young, Angela J.; Kaplan, Gary B.

    2015-01-01

    Previous research suggests that morphology and arborization of dendritic spines change as a result of fear conditioning in cortical and subcortical brain regions. This study uniquely aims to delineate these structural changes in the basolateral amygdala (BLA) after both fear conditioning and fear extinction. C57BL/6 mice acquired robust conditioned fear responses (70–80% cued freezing behavior) after six pairings with a tone cue associated with footshock in comparison to unshocked controls. During fear acquisition, freezing behavior was significantly affected by both shock exposure and trial number. For fear extinction, mice were exposed to the conditioned stimulus tone in the absence of shock administration and behavioral responses significantly varied by shock treatment. In the retention tests over 3 weeks, the percentage time spent freezing varied with the factor of extinction training. In all treatment groups, alterations in dendritic plasticity were analyzed using Golgi–Cox staining of dendrites in the BLA. Spine density differed between the fear conditioned group and both the fear extinction and control groups on third order dendrites. Spine density was significantly increased in the fear conditioned group compared to the fear extinction group and controls. Similarly in Sholl analyses, fear conditioning significantly increased BLA spine numbers and dendritic intersections while subsequent extinction training reversed these effects. In summary, fear extinction produced enduring behavioral plasticity that is associated with a reversal of alterations in BLA dendritic plasticity produced by fear conditioning. These neuroplasticity findings can inform our understanding of structural mechanisms underlying stress-related pathology can inform treatment research into these disorders. PMID:23570859

  5. Effects of Recent Exposure to a Conditioned Stimulus on Extinction of Pavlovian Fear Conditioning

    ERIC Educational Resources Information Center

    Chan, Wan Yee Macy; Leung, Hiu T.; Westbrook, R. Frederick; McNally, Gavan P.

    2010-01-01

    In six experiments we studied the effects of a single re-exposure to a conditioned stimulus (CS; "retrieval trial") prior to extinction training (extinction-reconsolidation boundary) on the development of and recovery from fear extinction. A single retrieval trial prior to extinction training significantly augmented the renewal and reinstatement…

  6. Effects of Recent Exposure to a Conditioned Stimulus on Extinction of Pavlovian Fear Conditioning

    ERIC Educational Resources Information Center

    Chan, Wan Yee Macy; Leung, Hiu T.; Westbrook, R. Frederick; McNally, Gavan P.

    2010-01-01

    In six experiments we studied the effects of a single re-exposure to a conditioned stimulus (CS; "retrieval trial") prior to extinction training (extinction-reconsolidation boundary) on the development of and recovery from fear extinction. A single retrieval trial prior to extinction training significantly augmented the renewal and reinstatement…

  7. Neuropeptide S reduces fear and avoidance of con-specifics induced by social fear conditioning and social defeat, respectively.

    PubMed

    Zoicas, Iulia; Menon, Rohit; Neumann, Inga D

    2016-09-01

    Neuropeptide S (NPS) has anxiolytic effects and facilitates extinction of cued fear in rodents. Here, we investigated whether NPS reverses social fear and social avoidance induced by social fear conditioning (SFC) and acute social defeat (SD), respectively, in male CD1 mice. Our results revealed that intracerebroventricular NPS (icv; 10 and 50 nmol/2 μl) reversed fear of unknown con-specifics induced by SFC and dose-dependently reduced avoidance of known aggressive con-specifics induced by SD. While 50 nmol of NPS completely reversed social avoidance and reinstated social preference, 10 nmol of NPS reduced social avoidance, but did not completely reinstate social preference in socially-defeated mice. Further, a lower dose (1 nmol/2 μl) of NPS facilitated the within-session extinction of cued fear, while a higher dose (10 nmol/2 μl) reduced the expression of cued fear. We could also confirm the anxiolytic effects of NPS (1, 10 and 50 nmol/2 μl) on the elevated plus-maze (EPM), which were not accompanied by alterations in locomotor activity either on the EPM or in the home cage. Finally, we could show that icv infusion of the NPS receptor 1 antagonist D-Cys((t)Bu)(5)-NPS (10 nmol/2 μl) did not alter SFC-induced social fear, general anxiety and locomotor activity. Taken together, our study extends the potent anxiolytic profile of NPS to a social context by demonstrating the reduction of social fear and social avoidance, thus providing the framework for studies investigating the involvement of the NPS system in the regulation of different types of social behaviour. Copyright © 2016 Elsevier Ltd. All rights reserved.

  8. The CRH1 antagonist GSK561679 increases human fear but not anxiety as assessed by startle.

    PubMed

    Grillon, Christian; Hale, Elizabeth; Lieberman, Lynne; Davis, Andrew; Pine, Daniel S; Ernst, Monique

    2015-03-13

    Fear to predictable threat and anxiety to unpredictable threat reflect distinct processes mediated by different brain structures, the central nucleus of the amygdala and the bed nucleus of the stria terminalis (BNST), respectively. This study tested the hypothesis that the corticotropin-releasing factor (CRF1) antagonist GSK561679 differentially reduces anxiety but increases fear in humans. A total of 31 healthy females received each of four treatments: placebo, 50 mg GSK561679 (low-GSK), 400 mg GSK561679 (high-GSK), and 1 mg alprazolam in a crossover design. Participants were exposed to three conditions during each of the four treatments. The three conditions included one in which predictable aversive shocks were signaled by a cue, a second during which shocks were administered unpredictably, and a third condition without shock. Fear and anxiety were assessed using the acoustic startle reflex. High-GSK had no effect on startle potentiation during unpredictable threat (anxiety) but increased startle potentiation during the predictable condition (fear). Low-GSK did not affect startle potentiation across conditions. Consistent with previous findings, alprazolam reduced startle potentiation during unpredictable threat but not during predictable threat. The increased fear by high-GSK replicates animal findings and suggests a lift of the inhibitory effect of the BNST on the amygdala by the CRF1 antagonist.

  9. The CRH1 Antagonist GSK561679 Increases Human Fear But Not Anxiety as Assessed by Startle

    PubMed Central

    Grillon, Christian; Hale, Elizabeth; Lieberman, Lynne; Davis, Andrew; Pine, Daniel S; Ernst, Monique

    2015-01-01

    Fear to predictable threat and anxiety to unpredictable threat reflect distinct processes mediated by different brain structures, the central nucleus of the amygdala and the bed nucleus of the stria terminalis (BNST), respectively. This study tested the hypothesis that the corticotropin-releasing factor (CRF1) antagonist GSK561679 differentially reduces anxiety but increases fear in humans. A total of 31 healthy females received each of four treatments: placebo, 50 mg GSK561679 (low-GSK), 400 mg GSK561679 (high-GSK), and 1 mg alprazolam in a crossover design. Participants were exposed to three conditions during each of the four treatments. The three conditions included one in which predictable aversive shocks were signaled by a cue, a second during which shocks were administered unpredictably, and a third condition without shock. Fear and anxiety were assessed using the acoustic startle reflex. High-GSK had no effect on startle potentiation during unpredictable threat (anxiety) but increased startle potentiation during the predictable condition (fear). Low-GSK did not affect startle potentiation across conditions. Consistent with previous findings, alprazolam reduced startle potentiation during unpredictable threat but not during predictable threat. The increased fear by high-GSK replicates animal findings and suggests a lift of the inhibitory effect of the BNST on the amygdala by the CRF1 antagonist. PMID:25430779

  10. 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…

  11. 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…

  12. Conditioned fear in adult rats is facilitated by the prior acquisition of a classically conditioned motor response

    PubMed Central

    Lindquist, Derick H.; Mahoney, Luke P.; Steinmetz, Joseph E.

    2010-01-01

    Early in eyeblink classical conditioning, amygdala-dependent fear responding is reported to facilitate acquisition of the cerebellar-dependent eyeblink conditioned response (CR), in accord with the two-process model of conditioning (Konorski, 1967). In the current study, we predicted that the conditioned fear (e.g., freezing) observed during eyeblink conditioning may become autonomous of the eyeblink CR and amenable to further associative modification. Conditioned freezing was assessed during and following Pavlovian fear conditioning in Long-Evans rats that had or had not undergone eight prior sessions of eyeblink conditioning. The amplitude and frequency of the tone conditioned stimulus (CS) was held constant across both forms of conditioning. Following fear conditioning in Experiment 1, freezing to the tone CS, but not the context, was facilitated in rats that previously experienced CS-unconditioned stimulus (US) paired eyeblink conditioning. In Experiment 2, freezing immediately following each fear conditioning trial was enhanced in rats subjected to the antecedent eyeblink conditioning, indicating a faster acquisition rate. Finally, in Experiment 3, faster acquisition was seen only in those rats fear conditioned in the same context used for the prior eyeblink conditioning. Taken together, the data indicate that the conditioned fear associated with the context and CS as a result of eyeblink conditioning can be built upon or strengthened during subsequent learning. PMID:20493273

  13. The conditioning and extinction of fear in youths: what's sex got to do with it?

    PubMed

    Chauret, Mélissa; La Buissonnière-Ariza, Valérie; Lamoureux Tremblay, Vickie; Suffren, Sabrina; Servonnet, Alice; Pine, Daniel S; Maheu, Françoise S

    2014-07-01

    Adult work shows differences in emotional processing influenced by sexes of both the viewer and expresser of facial expressions. We investigated this in 120 healthy youths (57 boys; 10-17 years old) randomly assigned to fear conditioning and extinction tasks using either neutral male or female faces as the conditioned threat and safety cues, and a fearful face paired with a shrieking scream as the unconditioned stimulus. Fear ratings and skin conductance responses (SCRs) were assessed. Male faces triggered increased fear ratings in all participants during conditioning and extinction. Greater differential SCRs were observed in boys viewing male faces and in girls viewing female faces during conditioning. During extinction, differential SCR findings remained significant in boys viewing male faces. Our findings demonstrate how sex of participant and sex of target interact to shape fear responses in youths, and how the type of measure may lead to distinct profiles of fear responses. Copyright © 2014 Elsevier B.V. All rights reserved.

  14. 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.

  15. 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…

  16. 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…

  17. Altered fear learning across development in both mouse and human

    PubMed Central

    Pattwell, Siobhan S.; Duhoux, Stéphanie; Hartley, Catherine A.; Johnson, David C.; Jing, Deqiang; Elliott, Mark D.; Ruberry, Erika J.; Powers, Alisa; Mehta, Natasha; Yang, Rui R.; Soliman, Fatima; Glatt, Charles E.; Casey, B. J.; Ninan, Ipe; Lee, Francis S.

    2012-01-01

    The only evidence-based behavioral treatment for anxiety and stress-related disorders involves desensitization techniques that rely on principles of extinction learning. However, 40% of patients do not respond to this treatment. Efforts have focused on individual differences in treatment response, but have not examined when, during development, such treatments may be most effective. We examined fear-extinction learning across development in mice and humans. Parallel behavioral studies revealed attenuated extinction learning during adolescence. Probing neural circuitry in mice revealed altered synaptic plasticity of prefrontal cortical regions implicated in suppression of fear responses across development. The results suggest a lack of synaptic plasticity in the prefrontal regions, during adolescence, is associated with blunted regulation of fear extinction. These findings provide insight into optimizing treatment outcomes for when, during development, exposure therapies may be most effective. PMID:22988092

  18. Effects of pre- or post-training entorhinal cortex AP5 injection on fear conditioning.

    PubMed

    Schenberg, Eduardo Ekman; Soares, Juliana Carlota Kramer; Oliveira, Maria Gabriela Menezes

    2005-11-15

    Fear conditioning is one of the most studied paradigms to assess the neural basis of emotional memory. The circuitry involves NMDA receptor activation in the amygdala and, in the case of contextual conditioning, in the hippocampus. Entorhinal cortex is one of the major input/output structures to the hippocampus and also projects to the amygdala, both through glutamatergic transmission. Other learning tasks involving hippocampus and amygdala, such as inhibitory avoidance, require entorhinal cortex during acquisition and consolidation. However, the involvement of NMDA receptors mediated transmission in entorhinal cortex in fear conditioning acquisition and consolidation is not clear. To investigate that issue, rats were trained in fear conditioning to both contextual and tone conditioned stimulus. Immediately before, immediately, 30 or 90 min after training they received NMDA antagonist AP5 or saline injections bilaterally in the entorhinal cortex (AP-6.8 mm, L +/-5.0 mm DV-6.8 mm). Contextual fear conditioning was measured 24 h after training, and tone fear conditioning 48 h after training. AP5 injections selectively impaired contextual fear conditioning only when injected pre-training. Post-training injections had no effect. These findings suggest that entorhinal cortex NMDA receptors are necessary for acquisition, but not for consolidation, of contextual fear conditioning. On the other hand, both acquisition and consolidation of tone fear conditioning seem to be independent of NMDA receptors in the entorhinal cortex.

  19. Neurotoxic lesions of the dorsal hippocampus and Pavlovian fear conditioning in rats.

    PubMed

    Maren, S; Aharonov, G; Fanselow, M S

    1997-11-01

    Electrolytic lesions of the dorsal hippocampus (DH) produce deficits in both the acquisition and expression of conditional fear to contextual stimuli in rats. To assess whether damage to DH neurons is responsible for these deficits, we performed three experiments to examine the effects of neurotoxic N-methyl-D-aspartate (NMDA) lesions of the DH on the acquisition and expression of fear conditioning. Fear conditioning consisted of the delivery of signaled or unsignaled footshocks in a novel conditioning chamber and freezing served as the measure of conditional fear. In Experiment 1, posttraining DH lesions produced severe retrograde deficits in context fear when made either 1 or 28, but not 100, days following training. Pretraining DH lesions made 1 week before training did not affect contextual fear conditioning. Tone fear was impaired by DH lesions at all training-to-lesion intervals. In Experiment 2, posttraining (1 day), but not pretraining (1 week), DH lesions produced substantial deficits in context fear using an unsignaled shock procedure. In Experiment 3, pretraining electrolytic DH lesions produced modest deficits in context fear using the same signaled and unsignaled shock procedures used in Experiments 1 and 2, respectively. Electrolytic, but not neurotoxic, lesions also increased pre-shock locomotor activity. Collectively, this pattern of results reveals that neurons in the DH are not required for the acquisition of context fear, but have a critical and time-limited role in the expression of context fear. The normal acquisition and expression of context fear in rats with neurotoxic DH lesions made before training may be mediated by conditioning to unimodal cues in the context, a process that may rely less on the hippocampal memory system.

  20. Modulation of cannabinoid signaling by hippocampal 5-HT4 serotonergic system in fear conditioning.

    PubMed

    Nasehi, Mohammad; Farrahizadeh, Maryam; Ebrahimi-Ghiri, Mohaddeseh; Zarrindast, Mohammad-Reza

    2016-09-01

    Behavioral studies have suggested a key role for the cannabinoid system in the modulation of conditioned fear memory. Likewise, much of the literature has revealed that the serotonergic system affects Pavlovian fear conditioning and extinction. A high level of functional overlap between the serotonin and cannabinoid systems has also been reported. To clarify the interaction between the hippocampal serotonin (5-HT4) receptor and the cannabinoid CB1 receptor in the acquisition of fear memory, the effects of 5-HT4 agents, arachidonylcyclopropylamide (ACPA; CB1 receptor agonist), and the combined use of these drugs on fear learning were studied in a fear conditioning task in adult male NMRI mice. Pre-training intraperitoneal administration of ACPA (0.1 mg/kg) decreased the percentage of freezing time in both context- and tone-dependent fear conditions, suggesting impairment of the acquisition of fear memory. Pre-training, intra-hippocampal (CA1) microinjection of RS67333, a 5-HT4 receptor agonist, at doses of 0.1 and 0.2 or 0.2 µg/mouse impaired contextual and tone fear memory, respectively. A subthreshold dose of RS67333 (0.005 µg/mouse) did not alter the ACPA response in either condition. Moreover, intra-CA1 microinjection of RS23597 as a 5-HT4 receptor antagonist did not alter context-dependent fear memory acquisition, but it did impair tone-dependent fear memory acquisition. However, a subthreshold dose of the RS23597 (0.01 µg/mouse) potentiated ACPA-induced fear memory impairment in both conditions. Therefore, we suggest that the blockade of hippocampal 5-HT4 serotonergic system modulates cannabinoid signaling induced by the activation of CB1 receptors in conditioned fear. © The Author(s) 2016.

  1. Modeling fear‐conditioned bradycardia in humans

    PubMed Central

    Tzovara, Athina; Staib, Matthias; Paulus, Philipp C.; Hofer, Nicolas; Bach, Dominik R.

    2016-01-01

    Abstract Across species, cued fear conditioning is a common experimental paradigm to investigate aversive Pavlovian learning. While fear‐conditioned stimuli (CS+) elicit overt behavior in many mammals, this is not the case in humans. Typically, autonomic nervous system activity is used to quantify fear memory in humans, measured by skin conductance responses (SCR). Here, we investigate whether heart period responses (HPR) evoked by the CS, often observed in humans and small mammals, are suitable to complement SCR as an index of fear memory in humans. We analyze four datasets involving delay and trace conditioning, in which heart beats are identified via electrocardiogram or pulse oximetry, to show that fear‐conditioned heart rate deceleration (bradycardia) is elicited and robustly distinguishes CS+ from CS−. We then develop a psychophysiological model (PsPM) of fear‐conditioned HPR. This PsPM is inverted to yield estimates of autonomic input into the heart. We show that the sensitivity to distinguish CS+ and CS− (predictive validity) is higher for model‐based estimates than peak‐scoring analysis, and compare this with SCR. Our work provides a novel tool to investigate fear memory in humans that allows direct comparison between species. PMID:26950648

  2. Withdrawal from Chronic Nicotine Administration Impairs Contextual Fear Conditioning in C57BL/6 Mice

    PubMed Central

    Davis, Jennifer A.; James, John R.; Siegel, Steven J.; Gould, Thomas J.

    2009-01-01

    The effects of acute nicotine administration (0.09 mg/kg nicotine), chronic nicotine administration (6.3 mg/kg/d nicotine for 14 d), and withdrawal from chronic nicotine administration on fear conditioning in C57BL/6 mice were examined. Mice were trained using two coterminating conditioned stimulus (30 s; 85 dB white noise)– unconditioned stimulus (2 s; 0.57 mA foot shock) pairings and tested 24 h later for contextual and cued fear conditioning. Acute nicotine administration enhanced contextual fear conditioning, chronic nicotine administration had no effect on contextual fear conditioning, and withdrawal from chronic nicotine administration impaired contextual fear conditioning. Plasma nicotine concentrations were similar after acute and chronic treatment and were within the range reported for smokers. During withdrawal, concentrations of nicotine were undetectable. An acute dose of nicotine (0.09 mg/kg) during withdrawal from chronic nicotine treatment reversed withdrawal-associated deficits in contextual fear conditioning. The results suggest that tolerance to the effects of nicotine on contextual fear conditioning develops with chronic nicotine treatment at a physiologically relevant dose, and withdrawal from this chronic nicotine treatment is associated with impairments in contextual fear conditioning. These findings provide a model of how the effects of nicotine on learning may contribute to the development and maintenance of nicotine addiction. PMID:16177040

  3. Hemodynamic responses in amygdala and hippocampus distinguish between aversive and neutral cues during Pavlovian fear conditioning in behaving rats.

    PubMed

    McHugh, Stephen B; Marques-Smith, Andre; Li, Jennifer; Rawlins, J N P; Lowry, John; Conway, Michael; Gilmour, Gary; Tricklebank, Mark; Bannerman, David M

    2013-02-01

    Lesion and electrophysiological studies in rodents have identified the amygdala and hippocampus (HPC) as key structures for Pavlovian fear conditioning, but human functional neuroimaging studies have not consistently found activation of these structures. This could be because hemodynamic responses cannot detect the sparse neuronal activity proposed to underlie conditioned fear. Alternatively, differences in experimental design or fear levels could account for the discrepant findings between rodents and humans. To help distinguish between these alternatives, we used tissue oxygen amperometry to record hemodynamic responses from the basolateral amygdala (BLA), dorsal HPC (dHPC) and ventral HPC (vHPC) in freely-moving rats during the acquisition and extinction of conditioned fear. To enable specific comparison with human studies we used a discriminative paradigm, with one auditory cue [conditioned stimulus (CS)+] that was always followed by footshock, and another auditory cue (CS-) that was never followed by footshock. BLA tissue oxygen signals were significantly higher during CS+ than CS- trials during training and early extinction. In contrast, they were lower during CS+ than CS- trials by the end of extinction. dHPC and vHPC tissue oxygen signals were significantly lower during CS+ than CS- trials throughout extinction. Thus, hemodynamic signals in the amygdala and HPC can detect the different patterns of neuronal activity evoked by threatening vs. neutral stimuli during fear conditioning. Discrepant neuroimaging findings may be due to differences in experimental design and/or fear levels evoked in participants. Our methodology offers a way to improve translation between rodent models and human neuroimaging. © 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

  4. Empirical support for an involvement of the mesostriatal dopamine system in human fear extinction.

    PubMed

    Raczka, K A; Mechias, M-L; Gartmann, N; Reif, A; Deckert, J; Pessiglione, M; Kalisch, R

    2011-06-07

    Exposure therapy for anxiety disorders relies on the principle of confronting a patient with the triggers of his fears, allowing him to make the unexpected safety experience that his fears are unfounded and resulting in the extinction of fear responses. In the laboratory, fear extinction is modeled by repeatedly presenting a fear-conditioned stimulus (CS) in the absence of the aversive unconditioned stimulus (UCS) to which it had previously been associated. Classical associative learning theory considers extinction to be driven by an aversive prediction error signal that expresses the expectation violation when not receiving an expected UCS and establishes a prediction of CS non-occurrence. Insufficiencies of this account in explaining various extinction-related phenomena could be resolved by assuming that extinction is an opponent appetitive-like learning process that would be mediated by the mesostriatal dopamine (DA) system. In accordance with this idea, we find that a functional polymorphism in the DA transporter gene, DAT1, which is predominantly expressed in the striatum, significantly affects extinction learning rates. Carriers of the 9-repeat (9R) allele, thought to confer enhanced phasic DA release, had higher learning rates. Further, functional magnetic resonance imaging revealed stronger hemodynamic appetitive prediction error signals in the ventral striatum in 9R carriers. Our results provide a first hint that extinction learning might indeed be conceptualized as an appetitive-like learning process and suggest DA as a new candidate neurotransmitter for human fear extinction. They open up perspectives for neurobiological therapy augmentation.

  5. Olfactory-Mediated Fear Conditioning in Mice: Simultaneous Measurements of Fear-Potentiated Startle and Freezing

    PubMed Central

    Jones, Seth V.; Heldt, Scott A.; Davis, Michael; Ressler, Kerry J.

    2010-01-01

    This study demonstrates that mice display olfactory-cued fear as measured with both freezing and fear-potentiated startle. Following a preconditioning test to measure any unconditioned responses to odor, mice received 5 pairings of a 10-s odor with a 0.25-s, 0.4-mA footshock. The next day, startle and freezing were measured in the presence and absence of the odor. Both fear measures increased after training with amyl acetate (Experiment 1) and acetophenone (Experiment 2). The enhancement of startle did not occur when the same number of odors and shocks were presented in an unpaired fashion (Experiment 3). Furthermore, mice were able to discriminate between an odor paired with shock and a nonreinforced odor (Experiment 4). PMID:15727538

  6. Adversity-induced relapse of fear: neural mechanisms and implications for relapse prevention from a study on experimentally induced return-of-fear following fear conditioning and extinction.

    PubMed

    Scharfenort, R; Menz, M; Lonsdorf, T B

    2016-07-19

    The efficacy of current treatments for anxiety disorders is limited by high relapse rates. Relapse of anxiety disorders and addiction can be triggered by exposure to life adversity, but the underlying mechanisms remain unexplored. Seventy-six healthy adults were a priori selected for the presence or absence of adverse experiences during childhood (CA) and recent past (RA; that is, past 12 months). Participants underwent fear conditioning (day 1) and fear extinction and experimental return-of-fear (ROF) induction through reinstatement (a model for adversity-induced relapse; day 2). Ratings, autonomic (skin conductance response) and neuronal activation measures (functional magnetic resonance imaging (fMRI)) were acquired. Individuals exposed to RA showed a generalized (that is, not CS- specific) fear recall and ROF, whereas unexposed individuals showed differential (that is, CS+ specific) fear recall and ROF on an autonomic level despite no group differences during fear acquisition and extinction learning. These group differences in ROF were accompanied by corresponding activation differences in brain areas known to be involved in fear processing and differentiability/generalization of ROF (that is, hippocampus). In addition, dimensional measures of RA, CA and lifetime adversity were negatively correlated with differential skin conductance responses (SCRs) during ROF and hippocampal activation. As discriminating signals of danger and safety, as well as a tendency for overgeneralization, are core features in clinically anxious populations, these deficits may specifically contribute to relapse risk following exposure to adversity, in particular to recent adversity. Hence, our results may provide first and novel insights into the possible mechanisms mediating enhanced relapse risk following exposure to (recent) adversity, which may guide the development of effective pre- and intervention programs.

  7. Involvement of GluD2 in Fear-Conditioned Bradycardia in Mice

    PubMed Central

    Kotajima-Murakami, Hiroko; Narumi, Sakae; Yuzaki, Michisuke; Yanagihara, Dai

    2016-01-01

    Lesions in the cerebellar vermis abolish acquisition of fear-conditioned bradycardia in animals and human patients. The δ2 glutamate receptor (GluD2) is predominantly expressed in cerebellar Purkinje cells. The mouse mutant ho15J carries a spontaneous mutation in GluD2 and these mice show a primary deficiency in parallel fiber-Purkinje cell synapses, multiple innervations of Purkinje cells by climbing fibers, and impairment of long-term depression. In the present study, we used ho15J mice to investigate the role of the cerebellum in fear-conditioned bradycardia. We recorded changes in heart rate of ho15J mice induced by repeated pairing of an acoustic (conditioned) stimulus (CS) with an aversive (unconditioned) stimulus (US). The mice acquired conditioned bradycardia on Day 1 of the CS-US phase, similarly to wild-type mice. However, the magnitude of the conditioned bradycardia was not stable in the mutant mice, but rather was exaggerated on Days 2–5 of the CS-US phase. We examined the effects of reversibly inactivating the cerebellum by injection of an antagonist against the α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor (AMPAR). The antagonist abolished expression of conditioned responses in both wild-type and ho15J mice. We conclude that the GluD2 mutation in the ho15J mice affects stable retention of the acquired conditioned bradycardia. PMID:27820843

  8. Contextual and Cued Fear Conditioning Test Using a Video Analyzing System in Mice

    PubMed Central

    Shoji, Hirotaka; Takao, Keizo; Hattori, Satoko; Miyakawa, Tsuyoshi

    2014-01-01

    The contextual and cued fear conditioning test is one of the behavioral tests that assesses the ability of mice to learn and remember an association between environmental cues and aversive experiences. In this test, mice are placed into a conditioning chamber and are given parings of a conditioned stimulus (an auditory cue) and an aversive unconditioned stimulus (an electric footshock). After a delay time, the mice are exposed to the same conditioning chamber and a differently shaped chamber with presentation of the auditory cue. Freezing behavior during the test is measured as an index of fear memory. To analyze the behavior automatically, we have developed a video analyzing system using the ImageFZ application software program, which is available as a free download at http://www.mouse-phenotype.org/. Here, to show the details of our protocol, we demonstrate our procedure for the contextual and cued fear conditioning test in C57BL/6J mice using the ImageFZ system. In addition, we validated our protocol and the video analyzing system performance by comparing freezing time measured by the ImageFZ system or a photobeam-based computer measurement system with that scored by a human observer. As shown in our representative results, the data obtained by ImageFZ were similar to those analyzed by a human observer, indicating that the behavioral analysis using the ImageFZ system is highly reliable. The present movie article provides detailed information regarding the test procedures and will promote understanding of the experimental situation. PMID:24637495

  9. Antagonism of Lateral Amygdala Alpha1-Adrenergic Receptors Facilitates Fear Conditioning and Long-Term Potentiation

    ERIC Educational Resources Information Center

    Lazzaro, Stephanie C.; Hou, Mian; Cunha, Catarina; LeDoux, Joseph E.; Cain, Christopher K.

    2010-01-01

    Norepinephrine receptors have been studied in emotion, memory, and attention. However, the role of alpha1-adrenergic receptors in fear conditioning, a major model of emotional learning, is poorly understood. We examined the effect of terazosin, an alpha1-adrenergic receptor antagonist, on cued fear conditioning. Systemic or intra-lateral amygdala…

  10. The Amygdala Is Critical for Trace, Delay, and Contextual Fear Conditioning

    ERIC Educational Resources Information Center

    Kochli, Daniel E.; Thompson, Elaine C.; Fricke, Elizabeth A.; Postle, Abagail F.; Quinn, Jennifer J.

    2015-01-01

    Numerous investigations have definitively shown amygdalar involvement in delay and contextual fear conditioning. However, much less is known about amygdala contributions to trace fear conditioning, and what little evidence exists is conflicting as noted in previous studies. This discrepancy may result from selective targeting of individual nuclei…

  11. A Discrete Population of Neurons in the Lateral Amygdala Is Specifically Activated by Contextual Fear Conditioning

    ERIC Educational Resources Information Center

    Wilson, Yvette M.; Murphy, Mark

    2009-01-01

    There is no clear identification of the neurons involved in fear conditioning in the amygdala. To search for these neurons, we have used a genetic approach, the "fos-tau-lacZ" (FTL) mouse, to map functionally activated expression in neurons following contextual fear conditioning. We have identified a discrete population of neurons in the lateral…

  12. Dissociated Roles for the Lateral and Medial Septum in Elemental and Contextual Fear Conditioning

    ERIC Educational Resources Information Center

    Calandreau, Ludovic; Jaffard, Robert; Desmedt, Aline

    2007-01-01

    Extensive evidence indicates that the septum plays a predominant role in fear learning, yet the direction of this control is still a matter of debate. Increasing data suggest that the medial (MS) and lateral septum (LS) would be differentially required in fear conditioning depending on whether a discrete conditional stimulus (CS) predicts, or not,…

  13. Dissociated Roles for the Lateral and Medial Septum in Elemental and Contextual Fear Conditioning

    ERIC Educational Resources Information Center

    Calandreau, Ludovic; Jaffard, Robert; Desmedt, Aline

    2007-01-01

    Extensive evidence indicates that the septum plays a predominant role in fear learning, yet the direction of this control is still a matter of debate. Increasing data suggest that the medial (MS) and lateral septum (LS) would be differentially required in fear conditioning depending on whether a discrete conditional stimulus (CS) predicts, or not,…

  14. 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

  15. Chronic stress and sex differences on the recall of fear conditioning and extinction.

    PubMed

    Baran, Sarah E; Armstrong, Charles E; Niren, Danielle C; Hanna, Jeffery J; Conrad, Cheryl D

    2009-03-01

    Chronic stress effects and sex differences were examined on conditioned fear extinction. Male and female Sprague-Dawley rats were chronically stressed by restraint (6 h/d/21 d), conditioned to tone and footshock, followed by extinction after 1 h and 24 h delays. Chronic stress impaired the recall of fear extinction in males, as evidenced by high freezing to tone after the 24 h delay despite exposure to the previous 1 h delay extinction trials, and this effect was not due to ceiling effects from overtraining during conditioning. In contrast, chronic stress attenuated the recall of fear conditioning acquisition in females, regardless of exposure to the 1 h extinction exposure. Since freezing to tone was reinstated following unsignalled footshocks, the deficit in the stressed rats reflected impaired recall rather than impaired consolidation. Sex differences in fear conditioning and extinction were observed in nonstressed controls as well, with control females resisting extinction to tone. Analysis of contextual freezing showed that all groups (control, stress, male, female) increased freezing immediately after the first tone extinction trial, demonstrating contextual discrimination. These findings show that chronic stress and sex interact to influence fear conditioning, with chronic stress impairing the recall of delayed fear extinction in males to implicate the medial prefrontal cortex, disrupting the recall of the fear conditioning acquisition in females to implicate the amygdala, and nonstressed controls exhibiting sex differences in fear conditioning and extinction, which may involve the amygdala and/or corticosterone levels.

  16. Antagonism of Lateral Amygdala Alpha1-Adrenergic Receptors Facilitates Fear Conditioning and Long-Term Potentiation

    ERIC Educational Resources Information Center

    Lazzaro, Stephanie C.; Hou, Mian; Cunha, Catarina; LeDoux, Joseph E.; Cain, Christopher K.

    2010-01-01

    Norepinephrine receptors have been studied in emotion, memory, and attention. However, the role of alpha1-adrenergic receptors in fear conditioning, a major model of emotional learning, is poorly understood. We examined the effect of terazosin, an alpha1-adrenergic receptor antagonist, on cued fear conditioning. Systemic or intra-lateral amygdala…

  17. A Discrete Population of Neurons in the Lateral Amygdala Is Specifically Activated by Contextual Fear Conditioning

    ERIC Educational Resources Information Center

    Wilson, Yvette M.; Murphy, Mark

    2009-01-01

    There is no clear identification of the neurons involved in fear conditioning in the amygdala. To search for these neurons, we have used a genetic approach, the "fos-tau-lacZ" (FTL) mouse, to map functionally activated expression in neurons following contextual fear conditioning. We have identified a discrete population of neurons in the lateral…

  18. The Amygdala Is Critical for Trace, Delay, and Contextual Fear Conditioning

    ERIC Educational Resources Information Center

    Kochli, Daniel E.; Thompson, Elaine C.; Fricke, Elizabeth A.; Postle, Abagail F.; Quinn, Jennifer J.

    2015-01-01

    Numerous investigations have definitively shown amygdalar involvement in delay and contextual fear conditioning. However, much less is known about amygdala contributions to trace fear conditioning, and what little evidence exists is conflicting as noted in previous studies. This discrepancy may result from selective targeting of individual nuclei…

  19. Exposure to a novel context after extinction causes a renewal of extinguished conditioned responses: implications for the treatment of fear.

    PubMed

    Neumann, David L; Kitlertsirivatana, Edward

    2010-06-01

    Renewal gives an experimental model for the relapse of fear symptoms following exposure therapy. While renewal of extinguished fear in humans has been observed following a return to the original context in which fear was acquired (ABA design), it has been more difficult to show upon presentation of a novel context (ABC design). The present experiment used a particularly strong context manipulation in a fear conditioning procedure. Context was manipulated by using large photographs of real environments taken from various angles and was present throughout the entire experiment. A renewal of cognitive expectancy was found in both ABA and ABC renewal designs, although it was larger in the former than in the latter. Response times in making the expectancy judgments increased when there was a change to a new context. The results demonstrate consistency in fear renewal effects between human and animal studies and suggest that relapse following exposure therapy via renewal remains a danger when people encounter a previously feared object in a novel context. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

  20. Chronic cannabis use is associated with impaired fear extinction in humans.

    PubMed

    Papini, Santiago; Ruglass, Lesia M; Lopez-Castro, Teresa; Powers, Mark B; Smits, Jasper A J; Hien, Denise A

    2017-01-01

    The use of fear conditioning and extinction paradigms to examine intermediate phenotypes of anxiety and stress-related disorders has facilitated the identification of neurobiological mechanisms that underlie specific components of abnormal psychological functioning. Across species, acute pharmacologic manipulation of the endogenous cannabinoid system has provided evidence of its critical role in fear extinction, but the effects of chronic cannabis on extinction are relatively understudied. In rats, chronic cannabinoid administration impairs fear extinction in a drug-free state. Here we examine whether chronic cannabis use is associated with impaired fear extinction in humans. Participants were healthy chronic cannabis users (n = 20) and nonuser controls with minimal lifetime cannabis use (n = 20) matched on age, sex, and race who all screened negative for psychiatric disorders. A 2-day differential fear conditioning paradigm was used to test the hypothesis that chronic cannabis use would be associated with impaired extinction of the skin conductance response. Consistent with hypotheses, chronic cannabis use was associated with reduced within-session extinction of skin conductance response on Day 1 (d = 0.78), and between-session extinction on Day 2 (d = 0.76). Unexpectedly, cannabis use was also associated with reduced subjective differentiation between threat and safety stimuli during conditioning. Replication and translation of findings are necessary to test potential mechanisms directly and examine whether impairments can be reversed pharmacologically or after a period of cannabis abstinence. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

  1. Memory and psychostimulants: Modulation of Pavlovian fear conditioning by amphetamine

    PubMed Central

    Wood, Suzanne C.; Anagnostaras, Stephan G.

    2010-01-01

    Rationale and Objectives With prescriptions of stimulants on the rise, it is important to examine the cognitive effects of low and moderate doses of stimulants, rather than only those typical of addicts. Methods The present study examined the effects a range of doses (0.005 – 8 mg/kg) of d-amphetamine sulfate on cued and contextual Pavlovian fear conditioning in mice. Results In agreement with previous research, subjects administered a moderately high dose of amphetamine (8 mg/kg) pre-training, typical of what addicts might take, displayed impaired memory when tested, off-drug. Alternately, subjects injected with a very low dose of amphetamine (0.005, 0.025, or 0.05 mg/kg), pre-training, similar to the therapeutic doses for attention deficit hyperactivity disorder, displayed enhanced memory when tested, off-drug. A control study showed these effects were not due to state-dependent learning. Conclusions Thus, dose is a critical determinant of the cognitive effects of psychostimulants. PMID:18478205

  2. Endogenous co-agonists of the NMDA receptor modulate contextual fear in trace conditioning.

    PubMed

    Basu, Alo C; Puhl, Matthew D; Coyle, Joseph T

    2016-12-01

    We have used mutant mice to probe the roles of the endogenous co-agonists of the NMDA receptor (NMDAR), D-serine and glycine, in fear learning and memory. Serine racemase knockout (SR-/-) mice have less than 15% of wild type forebrain levels of D-serine, whereas glycine transporter 1 heterozygous knockout (GlyT1+/-) mice have elevated synaptic glycine. While cued fear was normal in both delay and trace conditioned mice of both mutant genotypes, contextual fear was affected in trace conditioned subjects: SR-/- mice showed decreased contextual freezing, whereas GlyT1+/- mice showed elevated contextual freezing. These results indicate that endogenous co-agonists of the NMDAR modulate the conditioning of contextual fear responses, particularly in trace conditioning. They further suggest that endogenous glycine can compensate for the D-serine deficiency in cued and contextual fear following delay conditioning. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. 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,…

  4. 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,…

  5. Origins of fear of dogs in adults and children: the role of conditioning processes and prior familiarity with dogs.

    PubMed

    Doogan, S; Thomas, G V

    1992-07-01

    One hundred adults and 30 children completed questionnaires to investigate fear of dogs. Dog fearful adults asked to recall the origins of their fear reported classical conditioning experiences more frequently than vicarious acquisition or informational transmission. Overall, however, there was no difference in the frequency of attacks reported by the fearful and non-fearful groups. Significantly more fearful than non-fearful adults reported little contact with dogs prior to the onset of their fear which suggests that early non-eventful exposure to dogs may prevent a conditioning event from producing a dog phobia. Most adults reported that their fear began in childhood, and dog fear were more frequently reported by children than by adults. In the aggregate, however, dog-fearful adults and children differed in several ways; children were more likely than adults to report having received warnings about dogs, but also to recognize the potential attractiveness of a friendly dog. Unlike dog-fearful children, dog-fearful adults reported many other fears in addition to their fear of dogs. A better understanding of fear of dogs in adults may depend on discovering why some dog-fearful children, but not others, apparently lose their fear of dogs as they become older.

  6. The effects of cannabinoids on contextual conditioned fear in CB1 knockout and CD1 mice.

    PubMed

    Mikics, Eva; Dombi, Timea; Barsvári, Beáta; Varga, Balázs; Ledent, Catherine; Freund, Tamás F; Haller, József

    2006-05-01

    We studied the effects of cannabinoids on contextual conditioned fear responses. CB1 knockout and wild-type (CD1) mice were exposed to a brief session of electric shocks, and their behavior was studied in the same context 24 h later. In wild-type mice, shock exposure increased freezing and resting, and decreased locomotion and exploration. The genetic disruption of the CB1 receptor abolished the conditioned fear response. The CB1 antagonist AM-251 reduced the peak of the conditioned fear response when applied 30 min before behavioral testing (i.e. 24 h after shocks) in CD1 (wild-type) mice. The cannabinoid agonist WIN-55,212-2 markedly increased the conditioned fear response in CD1 mice, the effect of which was potently antagonized by AM-251. Thus, cannabinoid receptor activation appears to strongly promote the expression of contextual conditioned fear. In earlier experiments, cannabinoids did not interfere with the expression of cue-induced conditioned fear but strongly promoted its extinction. Considering the primordial role of the amygdala in simple associative learning (e.g. in cue-induced fear) and the role of the hippocampus in learning more complex stimulus relationships (e.g. in contextual fear), the present and earlier findings are not necessarily contradictory, but suggest that cannabinoid signaling plays different roles in the two structures. Data are interpreted in terms of the potential involvement of cannabinoids in trauma-induced behavioral changes.

  7. 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.

  8. 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

  9. The effects of fear and hunger on food neophobia in humans.

    PubMed

    Pliner, P; Eng, A; Krishnan, K

    1995-08-01

    We examined the effects of hunger and fear on food neophobia in humans. Subjects came to the experiment five or more hours food-deprived (high hunger) or two or less hours food-deprived (low hunger) and were assigned either to give a speech (high fear) or to listen to a speech (low fear). All subjects were then given the task of selecting for tasting one member of each of ten pairs of foods, each pair consisting of one novel and one familiar food. The number of novel foods chosen was the measure of food neophobia (with fewer choices indicative of greater neophobia). The results indicated that subjects were least neophobic in the low fear-low hunger condition and were tentatively interpreted in terms of Hull's (1943) theory of behavior. That is, it was assumed that fear and hunger summated to produce different levels of drive in the various conditions, which combined with responses of different habit strength (the tendency to approach novel stimuli and the tendency to approach familiar stimuli) to produce the results obtained.

  10. 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.

  11. The central nucleus of the amygdala is essential for acquiring and expressing conditional fear after overtraining.

    PubMed

    Zimmerman, Joshua M; Rabinak, Christine A; McLachlan, Ian G; Maren, Stephen

    2007-09-01

    The basolateral complex of the amygdala (BLA) is critical for the acquisition and expression of Pavlovian fear conditioning in rats. Nonetheless, rats with neurotoxic BLA lesions can acquire conditional fear after overtraining (75 trials). The capacity of rats with BLA lesions to acquire fear memory may be mediated by the central nucleus of the amygdala (CEA). To examine this issue, we examined the influence of neurotoxic CEA lesions or reversible inactivation of the CEA on the acquisition and expression of conditional freezing after overtraining in rats. Rats with pretraining CEA lesions (whether alone or in combination with BLA lesions) did not acquire conditional freezing to either the conditioning context or an auditory conditional stimulus after extensive overtraining. Similarly, post-training lesions of the CEA or BLA prevented the expression of overtrained fear. Lastly, muscimol infusions into the CEA prevented both the acquisition and the expression of overtrained fear, demonstrating that the effects of CEA lesions are not likely due to the destruction of en passant axons. These results suggest that the CEA is essential for conditional freezing after Pavlovian fear conditioning. Moreover, overtraining may engage a compensatory fear conditioning circuit involving the CEA in animals with damage to the BLA.

  12. Impaired contextual fear-conditioning in MAM rodent model of schizophrenia.

    PubMed

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

    2017-09-15

    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.

  13. D-Cycloserine Does Not Facilitate Fear Extinction by Reducing Conditioned Stimulus Processing or Promoting Conditioned Inhibition to Contextual Cues

    ERIC Educational Resources Information Center

    Baker, Kathryn D.; McNally, Gavan P.; Richardson, Rick

    2012-01-01

    The NMDA receptor partial agonist d-cycloserine (DCS) enhances the extinction of learned fear in rats and exposure therapy in humans with anxiety disorders. Despite these benefits, little is known about the mechanisms by which DCS promotes the loss of fear. The present study examined whether DCS augments extinction retention (1) through reductions…

  14. D-Cycloserine Does Not Facilitate Fear Extinction by Reducing Conditioned Stimulus Processing or Promoting Conditioned Inhibition to Contextual Cues

    ERIC Educational Resources Information Center

    Baker, Kathryn D.; McNally, Gavan P.; Richardson, Rick

    2012-01-01

    The NMDA receptor partial agonist d-cycloserine (DCS) enhances the extinction of learned fear in rats and exposure therapy in humans with anxiety disorders. Despite these benefits, little is known about the mechanisms by which DCS promotes the loss of fear. The present study examined whether DCS augments extinction retention (1) through reductions…

  15. L-type voltage-gated calcium channels in conditioned fear: A genetic and pharmacological analysis

    PubMed Central

    McKinney, Brandon C.; Sze, Wilson; White, Jessica A.; Murphy, Geoffrey G.

    2008-01-01

    Using pharmacological approaches, others have suggested that L-type voltage-gated calcium channels (L-VGCCs) mediate both consolidation and extinction of conditioned fear. In the absence of L-VGCC isoform-specific antagonists, we have begun to investigate the subtype-specific role of LVGCCs in consolidation and extinction of conditioned fear using a molecular genetics approach. Previously, we used this approach to demonstrate that the Cav1.3 isoform mediates consolidation, but not extinction, of contextually conditioned fear. Here, we used mice in which the gene for the L-VGCC pore-forming subunit Cav1.2 was conditionally deleted in forebrain excitatory neurons (Cav1.2cKO mice) to address the role of Cav1.2 in consolidation and extinction of conditioned fear. We demonstrate that Cav1.2cKO mice consolidate and extinguish conditioned fear as well as control littermates. These data suggest that Cav1.2 is not critical for these processes and together with our previous data argue against a role for either of the brain-expressed L-VGCCs (Cav1.2 or Cav1.3) in extinction of conditioned fear. Additionally, we present data demonstrating that the L-VGCC antagonist nifedipine, which has been used in previous conditioned fear extinction studies, impairs locomotion, and induces an aversive state. We further demonstrate that this aversive state can enter into associations with conditioned stimuli that are present at the time that it is experienced, suggesting that previous studies using nifedipine were likely confounded by drug toxicity. Taken together, our genetic and pharmacological data argue against a role for Cav1.2 in consolidation of conditioned fear as well as a role for L-VGCCs in extinction of conditioned fear. PMID:18441291

  16. Time-dependent involvement of the dorsal hippocampus in trace fear conditioning in mice.

    PubMed

    Misane, Ilga; Tovote, Philip; Meyer, Michael; Spiess, Joachim; Ogren, Sven Ove; Stiedl, Oliver

    2005-01-01

    Hippocampal and amygdaloid neuroplasticity are important substrates for Pavlovian fear conditioning. The hippocampus has been implicated in trace fear conditioning. However, a systematic investigation of the significance of the trace interval has not yet been performed. Therefore, this study analyzed the time-dependent involvement of N-methyl-D-aspartate (NMDA) receptors in the dorsal hippocampus in one-trial auditory trace fear conditioning in C57BL/6J mice. The NMDA receptor antagonist APV was injected bilaterally into the dorsal hippocampus 15 min before training. Mice were exposed to tone (conditioned stimulus [CS]) and footshock (unconditioned stimulus [US]) in the conditioning context without delay (0 s) or with CS-US (trace) intervals of 1-45 s. Conditioned auditory fear was determined 24 h after training by the assessment of freezing and computerized evaluation of inactivity in a new context; 2 h later, context-dependent memory was tested in the conditioning context. NMDA receptor blockade by APV markedly impaired conditioned auditory fear at trace intervals of 15 s and 30 s, but not at shorter trace intervals. A 45-s trace interval prevented the formation of conditioned tone-dependent fear. Context-dependent memory was always impaired by APV treatment independent of the trace interval. The results indicate that the dorsal hippocampus and its NMDA receptors play an important role in auditory trace fear conditioning at trace intervals of 15-30-s length. In contrast, NMDA receptors in the dorsal hippocampus are unequivocally involved in contextual fear conditioning independent of the trace interval. The results point at a time-dependent role of the dorsal hippocampus in encoding of noncontingent explicit stimuli. Preprocessing of long CS-US contingencies in the hippocampus appears to be important for the final information processing and execution of fear memories through amygdala circuits.

  17. A multi-pathway hypothesis for human visual fear signaling

    PubMed Central

    Silverstein, David N.; Ingvar, Martin

    2015-01-01

    A hypothesis is proposed for five visual fear signaling pathways in humans, based on an analysis of anatomical connectivity from primate studies and human functional connectvity and tractography from brain imaging studies. Earlier work has identified possible subcortical and cortical fear pathways known as the “low road” and “high road,” which arrive at the amygdala independently. In addition to a subcortical pathway, we propose four cortical signaling pathways in humans along the visual ventral stream. All four of these traverse through the LGN to the visual cortex (VC) and branching off at the inferior temporal area, with one projection directly to the amygdala; another traversing the orbitofrontal cortex; and two others passing through the parietal and then prefrontal cortex, one excitatory pathway via the ventral-medial area and one regulatory pathway via the ventral-lateral area. These pathways have progressively longer propagation latencies and may have progressively evolved with brain development to take advantage of higher-level processing. Using the anatomical path lengths and latency estimates for each of these five pathways, predictions are made for the relative processing times at selective ROIs and arrival at the amygdala, based on the presentation of a fear-relevant visual stimulus. Partial verification of the temporal dynamics of this hypothesis might be accomplished using experimental MEG analysis. Possible experimental protocols are suggested. PMID:26379513

  18. Electrolytic lesions of the dorsal hippocampus disrupt renewal of conditional fear after extinction.

    PubMed

    Ji, Jinzhao; Maren, Stephen

    2005-01-01

    There is a growing body of evidence that the hippocampus is critical for context-dependent memory retrieval. In the present study, we used Pavlovian fear conditioning in rats to examine the role of the dorsal hippocampus (DH) in the context-specific expression of fear memory after extinction (i.e., renewal). Pre-training electrolytic lesions of the DH blunted the expression of conditional freezing to an auditory conditional stimulus (CS), but did not affect the acquisition of extinction to that CS. In contrast, DH lesions impaired the context-specific expression of extinction, eliminating the renewal of fear normally observed to a CS presented outside of the extinction context. Post-extinction DH lesions also eliminated the context dependence of fear extinction. These results are consistent with those using pharmacological inactivation of the DH and suggest that the DH is required for using contextual stimuli to regulate the expression of fear to a Pavlovian CS after extinction.

  19. Factors governing single-trial contextual fear conditioning in the weanling rat

    PubMed Central

    Burman, M.A.; Murawski, N.J.; Schiffino, F.L.; Rosen, J.B.; Stanton, M.E.

    2014-01-01

    Although contextual fear conditioning emerges later in development than explicit-cue fear conditioning, little is known about the stimulus parameters and biological substrates required at early ages. The current experiments adapted methods for investigating hippocampus function in adult rodents to identify determinants of contextual fear conditioning in developing rats. Experiment 1 examined the duration of exposure required by weanling rats at postnatal day (PND) 23 to demonstrate contextual fear conditioning. This experiment demonstrated that 30 s of context exposure is sufficient to support conditioning. Furthermore, preexposure enhanced conditioning to an immediate footshock, the context preexposure facilitation effect (CPFE), but had no effect on contextual conditioning to a delayed shock. Experiment 2 demonstrated that NMDA receptor inactivation during preexposure impairs contextual learning at PND 23. Thus, the conjuctive representations underlying the CPFE are NMDA-dependent as early as PND23 in the rat. PMID:19824781

  20. Factors Regulating the Effects of Hippocampal Inactivation on Renewal of Conditional Fear after Extinction

    ERIC Educational Resources Information Center

    Corcoran, Kevin A.; Maren, Stephen

    2004-01-01

    After extinction of fear to a Pavlovian conditional stimulus (CS), contextual stimuli come to regulate the expression of fear to that CS. There is growing evidence that the context dependence of memory retrieval after extinction involves the hippocampus. In the present experiment, we examine whether hippocampal involvement in memory retrieval…

  1. Individual Differences in the Expression of Conditioned Fear Are Associated with Endogenous Fibroblast Growth Factor 2

    ERIC Educational Resources Information Center

    Graham, Bronwyn M.; Richardson, Rick

    2016-01-01

    These experiments examined the relationship between the neurotrophic factor fibroblast growth factor 2 (FGF2) and individual differences in the expression of conditioned fear. Experiments 1 and 2 demonstrated that rats naturally expressing low levels of contextual or cued fear have higher levels of hippocampal FGF2 relative to rats that express…

  2. Exposure to Novelty Weakens Conditioned Fear in Long-Evans Rats

    ERIC Educational Resources Information Center

    Anderson, Matthew J.; Burpee, Tara E.; Wall, Matthew J.; McGraw, Justin J.

    2013-01-01

    The present study sought to determine whether post-training exposure to a novel or familiar object, encountered in either the location of the original fear conditioning (black compartment of a passive avoidance {PA} chamber) or in a neutral setting (open field where initial object training had occurred) would prove capable of reducing fear at…

  3. 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…

  4. 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…

  5. Individual Differences in the Expression of Conditioned Fear Are Associated with Endogenous Fibroblast Growth Factor 2

    ERIC Educational Resources Information Center

    Graham, Bronwyn M.; Richardson, Rick

    2016-01-01

    These experiments examined the relationship between the neurotrophic factor fibroblast growth factor 2 (FGF2) and individual differences in the expression of conditioned fear. Experiments 1 and 2 demonstrated that rats naturally expressing low levels of contextual or cued fear have higher levels of hippocampal FGF2 relative to rats that express…

  6. 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…

  7. Electrolytic Lesions of the Dorsal Hippocampus Disrupt Renewal of Conditional Fear after Extinction

    ERIC Educational Resources Information Center

    Ji, Jinzhao; Maren, Stephen

    2005-01-01

    There is a growing body of evidence that the hippocampus is critical for context-dependent memory retrieval. In the present study, we used Pavlovian fear conditioning in rats to examine the role of the dorsal hippocampus (DH) in the context-specific expression of fear memory after extinction (i.e., renewal). Pre-training electrolytic lesions of…

  8. Electrolytic Lesions of the Dorsal Hippocampus Disrupt Renewal of Conditional Fear after Extinction

    ERIC Educational Resources Information Center

    Ji, Jinzhao; Maren, Stephen

    2005-01-01

    There is a growing body of evidence that the hippocampus is critical for context-dependent memory retrieval. In the present study, we used Pavlovian fear conditioning in rats to examine the role of the dorsal hippocampus (DH) in the context-specific expression of fear memory after extinction (i.e., renewal). Pre-training electrolytic lesions of…

  9. Factors Regulating the Effects of Hippocampal Inactivation on Renewal of Conditional Fear after Extinction

    ERIC Educational Resources Information Center

    Corcoran, Kevin A.; Maren, Stephen

    2004-01-01

    After extinction of fear to a Pavlovian conditional stimulus (CS), contextual stimuli come to regulate the expression of fear to that CS. There is growing evidence that the context dependence of memory retrieval after extinction involves the hippocampus. In the present experiment, we examine whether hippocampal involvement in memory retrieval…

  10. Brain Region-Specific Activity Patterns after Recent or Remote Memory Retrieval of Auditory Conditioned Fear

    ERIC Educational Resources Information Center

    Kwon, Jeong-Tae; Jhang, Jinho; Kim, Hyung-Su; Lee, Sujin; Han, Jin-Hee

    2012-01-01

    Memory is thought to be sparsely encoded throughout multiple brain regions forming unique memory trace. Although evidence has established that the amygdala is a key brain site for memory storage and retrieval of auditory conditioned fear memory, it remains elusive whether the auditory brain regions may be involved in fear memory storage or…

  11. Brain Region-Specific Activity Patterns after Recent or Remote Memory Retrieval of Auditory Conditioned Fear

    ERIC Educational Resources Information Center

    Kwon, Jeong-Tae; Jhang, Jinho; Kim, Hyung-Su; Lee, Sujin; Han, Jin-Hee

    2012-01-01

    Memory is thought to be sparsely encoded throughout multiple brain regions forming unique memory trace. Although evidence has established that the amygdala is a key brain site for memory storage and retrieval of auditory conditioned fear memory, it remains elusive whether the auditory brain regions may be involved in fear memory storage or…

  12. Predicting fear of heights, snakes, and public speaking from multimodal classical conditioning events.

    PubMed

    Wu, Ning Ying; Conger, Anthony J; Dygdon, Judith A

    2006-04-01

    Two hundred fifty one men and women participated in a study of the prediction of fear of heights, snakes, and public speaking by providing retrospective accounts of multimodal classical conditioning events involving those stimuli. The fears selected for study represent those believed by some to be innate (i.e., heights), prepared (i.e., snakes), and purely experientially learned (i.e., public speaking). This study evaluated the extent to which classical conditioning experiences in direct, observational, and verbal modes contributed to the prediction of the current level of fear severity. Subjects were asked to describe their current level of fear and to estimate their experience with fear response-augmenting events (first- and higher-order aversive pairings) and fear response-moderating events (first- and higher-order appetitive pairings, and pre- and post-conditioning neutral presentations) in direct, observational, and verbal modes. For each stimulus, fear was predictable from direct response-augmenting events and prediction was enhanced by the inclusion of response-moderating events. Furthermore, for each fear, maximum prediction was attained by the addition of variables tapping experiences in the observational and/or verbal modes. Conclusions are offered regarding the importance of including response-augmenting and response-moderating events in all three modes in both research and clinical applications of classical conditioning.

  13. Metabotropic glutamate subtype 5 receptors modulate fear-conditioning induced enhancement of prepulse inhibition in rats.

    PubMed

    Zou, Dan; Huang, Juan; Wu, Xihong; Li, Liang

    2007-02-01

    Non-startling acoustic events presented shortly before an intense startling sound can inhibit the acoustic startle reflex. This phenomenon is called prepulse inhibition (PPI), and is widely used as a model of sensorimotor gating. The present study investigated whether PPI can be modulated by fear conditioning, whose acquisition can be blocked by the specific antagonist of metabotropic glutamate receptors subtype 5 (mGluR5), 2-methyl-6-(phenylethynyl)-pyridine (MPEP). The results show that a gap embedded in otherwise continuous noise sounds, which were delivered by two spatially separated loudspeakers, could inhibit the startle reflex induced by an intense sound that was presented 50 ms after the gap. The inhibitory effect depended on the duration of the gap, and was enhanced by fear conditioning that was introduced by temporally pairing the gap with footshock. Intraperitoneal injection of MPEP (0.5 or 5mg/kg) 30 min before fear conditioning blocked the enhancing effect of fear conditioning on PPI, but did not affect either the baseline startle magnitude or PPI if no fear conditioning was introduced. These results indicate that PPI is enhanced when the prepulse signifies an aversive event after fear conditioning. Also, mGlu5Rs play a role in preserving the fear-conditioning-induced enhancement of PPI.

  14. 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.

  15. The roles of Eph receptors in contextual fear conditioning memory formation.

    PubMed

    Dines, Monica; Grinberg, Svetlana; Vassiliev, Maria; Ram, Alon; Tamir, Tal; Lamprecht, Raphael

    2015-10-01

    Eph receptors regulate glutamate receptors functions, neuronal morphology and synaptic plasticity, cellular events believed to be involved in memory formation. In this study we aim to explore the roles of Eph receptors in learning and memory. Toward that end, we examined the roles of EphB2 and EphA4 receptors, key regulators of synaptic functions, in fear conditioning memory formation. We show that mice lacking EphB2 (EphB2(-/-)) are impaired in short- and long-term contextual fear conditioning memory. Mice that express a carboxy-terminally truncated form of EphB2 that lacks forward signaling, instead of the full EphB2, are impaired in long-term, but not short-term, contextual fear conditioning memory. Long-term contextual fear conditioning memory is attenuated in CaMKII-cre;EphA4(lx/-) mice where EphA4 is removed from all pyramidal neurons of the forebrain. Mutant mice with targeted kinase-dead EphA4 (EphA4(KD)) exhibit intact long-term contextual fear conditioning memory showing that EphA4 kinase-mediated forward signaling is not needed for contextual fear memory formation. The ability to form long-term conditioned taste aversion (CTA) memory is not impaired in the EphB2(-/-) and CaMKII-cre;EphA4(lx/-) mice. We conclude that EphB2 forward signaling is required for long-term contextual fear conditioning memory formation. In contrast, EphB2 mediates short-term contextual fear conditioning memory formation in a forward signaling-independent manner. EphA4 mediates long-term contextual fear conditioning memory formation in a kinase-independent manner.

  16. DHEA-S selectively impairs contextual-fear conditioning: support for the antiglucocorticoid hypothesis.

    PubMed

    Fleshner, M; Pugh, C R; Tremblay, D; Rudy, J W

    1997-06-01

    The authors had reported that glucocorticoids play a selective role in fear conditioning. The adrenal steroid dehydroepiandrosterone (DHEA) has been reported to act as a functional antiglucocorticoid. If DHEA has antiglucocorticoid properties, then its effects on fear conditioning might resemble those produced by adrenalectomy. The authors now report that chronic exposure to high levels of dehydroepiandrosterone sulfate (DHEA-S; converted in vivo to DHEA) produced the same pattern of results as adrenalectomy. Specifically, treatment with DHEA-S impaired contextual fear conditioning 24 hr after conditioning but not immediately after conditioning, and like adrenalectomy, DHEA-S had no effect on auditory-cue fear conditioning. Preexposure to the context before drug treatment eliminated the amnestic effects of DHEA-S, suggesting that, like adrenalectomy, DHEA-S exerted its effect by interfering with the construction of a contextual memory representation. Thus, DHEA appears to act as a functional antiglucocorticoid in the processes that mediate learning and memory.

  17. Dual role of dopamine D(2)-like receptors in the mediation of conditioned and unconditioned fear.

    PubMed

    Brandão, Marcus Lira; de Oliveira, Amanda Ribeiro; Muthuraju, Sangu; Colombo, Ana Caroline; Saito, Viviane Mitsuko; Talbot, Teddy

    2015-11-14

    A reduction of dopamine release or D2 receptor blockade in the terminal fields of the mesolimbic system, particularly the amygdala, clearly reduces conditioned fear. Similar D2 receptor antagonism in the neural substrates of fear in the midbrain tectum attenuates the processing of unconditioned aversive information. However, the implications of the interplay between opposing actions of dopamine in the rostral and caudal segments of the dopaminergic system are still unclear. Previous studies from this laboratory have reported the effects of dopaminergic drugs on behavior in rats in the elevated plus maze, auditory-evoked potentials (AEPs) recorded from the midbrain tectum, fear-potentiated startle, and conditioned freezing. These findings led to an interesting framework on the functional roles of dopamine in both anxiety and fear states. Dopamine D2 receptor inhibition in the terminal fields of the mesolimbic dopamine system generally causes anxiolytic-like effects, whereas the activity of midbrain substrates of unconditioned fear are enhanced by D2 receptor antagonists, suggesting that D2 receptor-mediated mechanisms play opposing roles in fear/anxiety processes, depending on the brain region under study. Dopamine appears to mediate conditioned fear by acting at rostral levels of the brain and regulate unconditioned fear at the midbrain level, likely by reducing the sensorimotor gating of aversive events. Copyright © 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  18. The impact of a context switch and context instructions on the return of verbally conditioned fear.

    PubMed

    Mertens, Gaëtan; De Houwer, Jan

    2016-06-01

    Repeated exposure to a conditioned stimulus can lead to a reduction of conditioned fear responses towards this stimulus (i.e., extinction). However, this reduction is often fragile and sensitive to contextual changes. In the current study, we investigated whether extinction of fear responses established through verbal threat instructions is also sensitive to contextual changes. We additionally examined whether verbal instructions can strengthen the effects of a context change. Fifty-two participants were informed that one colored rectangle would be predictive of an electrocutaneous stimulus, while another colored rectangle was instructed to be safe. Half of these participants were additionally informed that this contingency would only hold when the background of the computer screen had a particular color but not when it had another color. After these instructions, the participants went through an unannounced extinction phase that was followed by a context switch. Results indicate that extinguished verbally conditioned fear responses can return after a context switch, although only as indexed by self-reported expectancy ratings. This effect was stronger when participants were told that CS-US contingency would depend on the background color, in which case a return of fear was also observed on physiological measures of fear. Extinction was not very pronounced in this study, possibly limiting the extent to which return of fear could be observed on physiological measures. Contextual cues can impact the return of fear established via verbal instructions. Verbal instructions can further strengthen the contextual control of fear. Copyright © 2015 Elsevier Ltd. All rights reserved.

  19. Influence of cued-fear conditioning and its impairment on NREM sleep.

    PubMed

    Kumar, Tankesh; Jha, Sushil K

    2017-10-01

    Many studies suggest that fear conditioning influences sleep. It is, however, not known if the changes in sleep architecture after fear conditioning are essentially associated with the consolidation of fearful memory or with fear itself. Here, we have observed that within sleep, NREM sleep consistently remained augmented after the consolidation of cued fear-conditioned memory. But a similar change did not occur after impairing memory consolidation by blocking new protein synthesis and glutamate transmission between glial-neuronal loop in the lateral amygdala (LA). Anisomycin (a protein synthesis inhibitor) and DL-α-amino-adipic acid (DL- α -AA) (a glial glutamine synthetase enzyme inhibitor) were microinjected into the LA soon after cued fear-conditioning to induce memory impairment. On the post-conditioning day, animals in both the groups exhibited significantly less freezing. In memory-consolidated groups (vehicle groups), NREM sleep significantly increased during 2nd to 5th hours after training compared to their baseline days. However, in memory impaired groups (anisomycin and DL- α -AA microinjected groups), similar changes were not observed. Our results thus suggest that changes in sleep architecture after cued fear-conditioning are indeed a consolidation dependent event. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. High-alcohol-drinking rats exhibit persistent freezing responses to discrete cues following Pavlovian fear conditioning.

    PubMed

    Rorick, Linda M; Finn, Peter R; Steinmetz, Joseph E

    2003-09-01

    We previously reported that high-alcohol-drinking (HAD) rats exhibited selective deficits in active avoidance learning and that those deficits were partially reversed by moderate doses of ethanol under certain training conditions [Pharmacol. Biochem. Behav. 75 (2003) 89]. In that study, we hypothesized that HAD deficits resulted from exaggerated fear in the conditioning context and that the anxiolytic properties of ethanol, along with prior exposure to the conditioning apparatus, were responsible for the facilitated avoidance learning that was observed in HAD rats following moderate doses of ethanol. The current study was designed to test whether HAD rats exhibit behaviors consistent with increased fear in aversive learning contexts. We used a standard Pavlovian fear conditioning paradigm to assess behavioral freezing in HAD (HAD-1 and HAD-2) and low-alcohol-drinking (LAD; LAD-1 and LAD-2) rats. No significant differences were observed between HAD-1 and HAD-2 or between LAD-1 and LAD-2 rats, indicating that the replicate lines performed similarly in this study. Both HAD and LAD rats exhibited robust fear conditioning during training. Although no differences were observed between HAD and LAD rats during fear training, HAD rats failed to extinguish freezing behavior in response to the discrete tone conditional stimulus during subsequent fear retention tests. Thus, HAD rats demonstrated prolonged cue-elicited fear that was resistant to extinction.

  1. Hippocampus and Pavlovian fear conditioning in rats: muscimol infusions into the ventral, but not dorsal, hippocampus impair the acquisition of conditional freezing to an auditory conditional stimulus.

    PubMed

    Maren, Stephen; Holt, William G

    2004-02-01

    The authors compared the effects of pharmacological inactivation of the dorsal hippocampus (DH) or ventral hippocampus (VH) on Pavlovian fear conditioning in rats. Freezing behavior served as the measure of fear. Pretraining infusions of muscimol, a GABAA receptor agonist, into the VH disrupted auditory, but not contextual, fear conditioning; DH infusions did not affect fear conditioning. Pretesting inactivation of the VH or DH did not affect the expression of conditional freezing. Pretraining electrolytic lesions of the VH reproduced the effects of muscimol infusions, whereas posttraining VH lesions disrupted both auditory and contextual freezing. Hence, neurons in the VH are importantly involved in the acquisition of auditory fear conditioning and the expression of auditory and contextual fear under some conditions.

  2. An organization of visual and auditory fear conditioning in the lateral amygdala.

    PubMed

    Bergstrom, Hadley C; Johnson, Luke R

    2014-12-01

    Pavlovian fear conditioning is an evolutionary conserved and extensively studied form of associative learning and memory. In mammals, the lateral amygdala (LA) is an essential locus for Pavlovian fear learning and memory. Despite significant progress unraveling the cellular mechanisms responsible for fear conditioning, very little is known about the anatomical organization of neurons encoding fear conditioning in the LA. One key question is how fear conditioning to different sensory stimuli is organized in LA neuronal ensembles. Here we show that Pavlovian fear conditioning, formed through either the auditory or visual sensory modality, activates a similar density of LA neurons expressing a learning-induced phosphorylated extracellular signal-regulated kinase (p-ERK1/2). While the size of the neuron population specific to either memory was similar, the anatomical distribution differed. Several discrete sites in the LA contained a small but significant number of p-ERK1/2-expressing neurons specific to either sensory modality. The sites were anatomically localized to different levels of the longitudinal plane and were independent of both memory strength and the relative size of the activated neuronal population, suggesting some portion of the memory trace for auditory and visually cued fear conditioning is allocated differently in the LA. Presenting the visual stimulus by itself did not activate the same p-ERK1/2 neuron density or pattern, confirming the novelty of light alone cannot account for the specific pattern of activated neurons after visual fear conditioning. Together, these findings reveal an anatomical distribution of visual and auditory fear conditioning at the level of neuronal ensembles in the LA.

  3. Fear conditioning and stimulus generalization in patients with social anxiety disorder.

    PubMed

    Ahrens, Lea M; Pauli, Paul; Reif, Andreas; Mühlberger, Andreas; Langs, Gernot; Aalderink, Tim; Wieser, Matthias J

    2016-12-01

    Although overgeneralization seems to be a hallmark of several anxiety disorders, this until now has not been investigated in social anxiety disorder (SAD). Therefore, we examined fear generalization in 26 SAD patients and 29 healthy controls (HC) using two faces as conditioned stimuli (CS+, CS-), and a loud scream and a fearful face as unconditioned stimulus (US). Generalization was tested by presenting both CS and four morphs of the two faces (generalization stimuli [GSs]), while ratings, heart rate (HR) and skin conductance responses (SCR) were recorded. Results revealed that SAD patients rated all stimuli as less pleasant and more arousing compared to HC. Moreover, ratings and SCR indicated that both groups generalized their acquired fear from the CS+ to GSs. Remarkably, only SAD patients showed generalization in HR responses (fear bradycardia). Overall, SAD seems not to be characterized by strong overgeneralization but discrepancies in fear responses to both conditioned and generalized threat stimuli. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. Social fear conditioning as an animal model of social anxiety disorder.

    PubMed

    Toth, Iulia; Neumann, Inga D; Slattery, David A

    2013-01-01

    Social fear and avoidance of social situations represent the main behavioral symptoms of social anxiety disorder (SAD), a disorder that is poorly elucidated and has rather unsatisfactory therapeutic options. Therefore, animal models are needed to study the underlying etiology of the disorder and possible novel treatment approaches. However, the current paradigms modeling SAD-like symptoms in rodents are not specific, as they induce numerous other behavioral deficits in addition to social fear and avoidance. Here, we describe the protocol for the social fear conditioning paradigm, an animal model of SAD that specifically induces social fear of unfamiliar con-specifics without potentially confounding alterations in other behavioral measures. Theoretical and practical considerations for performing the social fear conditioning paradigm in both rats and mice, as well as for the analysis and interpretation of the obtained data, are described in detail.

  5. Generalized anxiety disorder is associated with overgeneralization of classically conditioned fear.

    PubMed

    Lissek, Shmuel; Kaczkurkin, Antonia N; Rabin, Stephanie; Geraci, Marilla; Pine, Daniel S; Grillon, Christian

    2014-06-01

    Meta-analytic results of fear-conditioning studies in the anxiety disorders implicate generalization of conditioned fear to stimuli resembling the conditioned danger cue as one of the more robust conditioning markers of anxiety pathology. Due to the absence of conditioning studies assessing generalization in generalized anxiety disorder (GAD), results of this meta-analysis do not reveal whether such generalization abnormalities also apply to GAD. The current study fills this gap by behaviorally and psychophysiologically assessing levels of conditioned fear generalization across adults with and without GAD. Twenty-two patients with a DSM-IV-Text Revision diagnosis of GAD and 26 healthy comparison subjects were recruited and tested. The employed generalization paradigm consisted of quasi-randomly presented rings of gradually increasing size, with extreme sizes serving as conditioned danger cues (CS+) and conditioned safety cues. The rings of intermediary size served as generalization stimuli, creating a continuum of similarity between CS+ and conditioned safety cues across which to assess response slopes, referred to as generalization gradients. Primary outcome variables included slopes for fear-potentiated startle (electromyography) and self-reported risk ratings. Behavioral and psychophysiological findings demonstrated overgeneralization of conditioned fear among patients with GAD. Specifically, generalization gradients were abnormally shallow among GAD patients, reflecting less degradation of the conditioned fear response as the presented stimulus differentiated from the CS+. Overgeneralization of conditioned fear to safe encounters resembling feared situations may contribute importantly to the psychopathology of GAD by proliferating anxiety cues in the individual's environment that are then capable of evoking and maintaining anxiety and worry associated with GAD. Copyright © 2014 Society of Biological Psychiatry. All rights reserved.

  6. Impaired extinction of fear conditioning after REM deprivation is magnified by rearing in an enriched environment.

    PubMed

    Hunter, Amy Silvestri

    2015-07-01

    Evidence from both human and animal studies indicates that rapid eye movement sleep (REM) is essential for the acquisition and retention of information, particularly of an emotional nature. Learning and memory can also be impacted by manipulation of housing condition such as exposure to an enriched environment (EE). This study investigated the effects of REM deprivation and EE, both separately and combined, on the extinction of conditioned fear in rats. Consistent with prior studies, conditioning was enhanced in EE-reared rats and extinction was impaired in REM deprived rats. In addition, rats exposed to both REM deprivation and EE showed the greatest impairment in extinction, with effects persisting through the first two days of extinction training. This study is the first to explore the combination of REM deprivation and EE and suggests that manipulations that alter sleep, particularly REM, can have persisting deleterious effects on emotional memory processing.

  7. Amygdalar unit activity during three learning tasks: eyeblink classical conditioning, Pavlovian fear conditioning, and signaled avoidance conditioning.

    PubMed

    Rorick-Kehn, Linda M; Steinmetz, Joseph E

    2005-10-01

    Neural activity in central and basolateral amygdala nuclei (CeA and BLA, respectively) was recorded during delay eyeblink conditioning, Pavlovian fear conditioning, and signaled barpress avoidance. During paired training, the CeA exhibited robust learning-related excitatory activity during all 3 tasks. By contrast, the BLA exhibited minimal activity during eyeblink conditioning, while demonstrating pronounced increases in learning-related excitatory responsiveness during fear conditioning and barpress avoidance. In addition, the relative amount of amygdalar activation observed appeared to be related to the relative intensity of the unconditioned stimulus and somatic requirements of the task. Results suggest the CeA mediates the Pavlovian association between sensory stimuli and the BLA mediates the modulation of instrumental responding through the assignment of motivational value to the unconditioned stimulus.

  8. Cannabinoid modulation of prefrontal-limbic activation during fear extinction learning and recall in humans.

    PubMed

    Rabinak, Christine A; Angstadt, Mike; Lyons, Maryssa; Mori, Shoko; Milad, Mohammed R; Liberzon, Israel; Phan, K Luan

    2014-09-01

    Pre-extinction administration of Δ9-tetrahydrocannibinol (THC) facilitates recall of extinction in healthy humans, and evidence from animal studies suggest that this likely occurs via enhancement of the cannabinoid system within the ventromedial prefrontal cortex (vmPFC) and hippocampus (HIPP), brain structures critical to fear extinction. However, the effect of cannabinoids on the underlying neural circuitry of extinction memory recall in humans has not been demonstrated. We conducted a functional magnetic resonance imaging (fMRI) study using a randomized, double-blind, placebo-controlled, between-subjects design (N=14/group) coupled with a standard Pavlovian fear extinction paradigm and an acute pharmacological challenge with oral dronabinol (synthetic THC) in healthy adult volunteers. We examined the effects of THC on vmPFC and HIPP activation when tested for recall of extinction learning 24 h after extinction learning. Compared to subjects who received placebo, participants who received THC showed increased vmPFC and HIPP activation to a previously extinguished conditioned stimulus (CS+E) during extinction memory recall. This study provides the first evidence that pre-extinction administration of THC modulates prefrontal-limbic circuits during fear extinction in humans and prompts future investigation to test if cannabinoid agonists can rescue or correct the impaired behavioral and neural function during extinction recall in patients with PTSD. Ultimately, the cannabinoid system may serve as a promising target for innovative intervention strategies (e.g. pharmacological enhancement of exposure-based therapy) in PTSD and other fear learning-related disorders.

  9. Long-term effects of traumatic stress on subsequent contextual fear conditioning in rats.

    PubMed

    Ryoke, Rie; Yamada, Kazuo; Ichitani, Yukio

    2014-04-22

    Exposure to stressful events affects subsequent sensitivity to fear. We investigated the long-term effects of a traumatic experience on subsequent contextual fear conditioning and anxiety-like behaviors in rats (Experiment 1). In addition, we tested whether the administration of the glucocorticoid synthesis inhibitor metyrapone (MET) attenuated the sensitization of fear induced by traumatic stress (Experiment 2). Male rats were subjected to a multiple stress (MS) session, which consisted of 4 foot shocks (1mA, 1s) and forced swimming for 20min, followed by exposure to a situational reminder 7days after the MS session. MET (25 or 100mg/kg, intraperitoneal) was administered 30min before MS. The contextual fear conditioning was performed 14days after MS. MS enhanced the conditioned fear response for at least 14days after the conditioning, and pretreatment with MET did not affect the enhancement of conditioned fear. These results suggest that glucocorticoid secretion triggered by MS is not involved in regulating the long-term stress-induced sensitization of fear.

  10. Tone conditioning potentiates rather than overshadows context fear in adult animals following adolescent ethanol exposure.

    PubMed

    Broadwater, Margaret A; Spear, Linda P

    2014-07-01

    We have shown that adults exposed to ethanol during adolescence exhibit a deficit in the retention of context fear, reminiscent of that normally seen in preweanling rats. However, preweanlings have been reported to exhibit a potentiation of context fear when they are conditioned in the presence of a tone. Therefore, this study examined context retention 24 hr after tone or context conditioning in male Sprague-Dawley rats exposed intragastrically to 4 g/kg ethanol or water every 48 hr (total of 11 exposures) during adolescence [Postnatal day (P) 28-48] or adulthood (P70-90). Approximately 3 weeks following exposure, retention of fear to the context in animals exposed to ethanol during adolescence was attenuated after context conditioning, but enhanced after tone conditioning. Comparable adult ethanol exposure groups showed typical overshadowing of context fear retention after tone conditioning. These data suggest that adolescent ethanol exposure may induce an immature pattern of cognitive processing.

  11. Fear conditioning enhances γ oscillations and their entrainment of neurons representing the conditioned stimulus.

    PubMed

    Headley, Drew B; Weinberger, Norman M

    2013-03-27

    Learning alters the responses of neurons in the neocortex, typically strengthening their encoding of behaviorally relevant stimuli. These enhancements are studied extensively in the auditory cortex by characterizing changes in firing rates and evoked potentials. However, synchronous activity is also important for the processing of stimuli, especially the relationship between gamma oscillations in the local field potential and spiking. We investigated whether tone/shock fear conditioning in rats, a task known to alter responses in auditory cortex, also modified the relationship between gamma and unit activity. A boost in gamma oscillations developed, especially at sites tuned near the tone, and strengthened across multiple conditioning sessions. Unit activity became increasingly phase-locked to gamma, with sites tuned near the tone developing enhanced phase-locking during the tone, whereas those tuned away maintained a tendency to decrease their phase-locking. Enhancements in the coordination of spiking between sites tuned near the tone developed within the first conditioning session and remained throughout the rest of training. Enhanced cross-covariances in unit activity were strongest for subjects that exhibited robust conditioned fear. These results illustrate that changes in sensory cortex during associative learning extend to the coordination of neurons encoding the relevant stimulus, with implications for how it is processed downstream.

  12. Resting heart rate variability is associated with inhibition of conditioned fear.

    PubMed

    Wendt, Julia; Neubert, Jörg; Koenig, Julian; Thayer, Julian F; Hamm, Alfons O

    2015-09-01

    Startle blink as well as skin conductance responses (SCR) are widely used indices of learning processes associated with fear conditioning and extinction. During safety learning, the amygdala is under top-down inhibitory control by the prefrontal cortex (PFC). The capacity of the PFC to exert inhibitory control over subcortical brain structures may be indexed by resting state vagally mediated heart rate variability (HRV). The present study investigated the association of resting HRV with startle blink and SCR during conditioned fear inhibition and extinction. Participants first learned to discriminate a threat cue (A) signaling an aversive unconditioned stimulus from a safety signal (B), which were each presented together with a third stimulus X (AX+/BX-). Then, both the threat and safety signal were presented together (AB) to test whether the presence of the learned safety signal inhibits the fear response to the danger signal. Finally, AX was presented without reinforcement (AX-) to investigate fear extinction. Higher HRV was associated with pronounced fear inhibition and fear extinction. Resting HRV levels were associated with fear extinction as indexed by startle blink potentiation but not SCR, which presumably reflect more cognitive aspects of learning. Resting HRV may reflect the capacity of the prefrontal cortex to inhibit subcortical fear responses in the presence of safety or when former threat cues are presented in the absence of threat.

  13. The GABA-synthetic enzyme GAD65 controls circadian activation of conditioned fear pathways.

    PubMed

    Bergado-Acosta, Jorge R; Müller, Iris; Richter-Levin, Gal; Stork, Oliver

    2014-03-01

    Circadian fluctuations of fear and anxiety symptoms are observable in persons with post-traumatic stress disorder, generalized anxiety, and panic disorder; however, the underlying neurobiological mechanisms are not sufficiently understood. In the present study, we investigated the putative role of inhibitory neurotransmission in the circadian fluctuation of fear symptoms, using mice with genetic ablation of the γ-amino butyric acid (GABA) synthesizing isoenzyme, glutamic acid decarboxylase GAD65. We observed in these mutant mice an altered expression of conditioned fear with a profound reduction of freezing, and an increase of hyperactivity bouts occurring only when both fear conditioning training and retrieval testing were done at the beginning of their active phase. Mutants further showed an increased arousal response at this time of the day, although, circadian rhythm of home cage activity was unaltered. Hyperactivity and reduced freezing during fear memory retrieval were accompanied by an increased induction of the immediate early gene cFos suggesting hyperactivation of the hippocampus, amygdala, and medial hypothalamus. Our data suggest a role of GAD65-mediated GABA synthesis in the encoding of circadian information to fear memory. GAD65 deficits in a state-dependent manner result in increased neural activation in fear circuits and elicit panic-like flight responses during fear memory retrieval.

  14. Conditioned fear is modulated by CRF mechanisms in the periaqueductal gray columns.

    PubMed

    Borelli, Karina G; Albrechet-Souza, Lucas; Fedoce, Alessandra G; Fabri, Denise S; Resstel, Leonardo B; Brandão, Marcus L

    2013-05-01

    The periaqueductal gray (PAG) columns have been implicated in controlling stress responses through corticotropin-releasing factor (CRF), which is a neuropeptide with a prominent role in the etiology of fear- and anxiety-related psychopathologies. Several studies have investigated the involvement of dorsal PAG (dPAG) CRF mechanisms in models of unconditioned fear. However, less is known about the role of this neurotransmission in the expression of conditioned fear memories in the dPAG and ventrolateral PAG (vlPAG) columns. We assessed the effects of ovine CRF (oCRF 0.25 and 1.0 μg/0.2 μL) locally administered into the dPAG and vlPAG on behavioral (fear-potentiated startle and freezing) and autonomic (arterial pressure and heart rate) responses in rats subjected to contextual fear conditioning. The lower dose injected into the columns promoted proaversive effects, enhanced contextual freezing, increased the blood pressure and heart rate and decreased tail temperature. The lower dose of oCRF into the vlPAG, but not into the dPAG, produced a pronounced enhancement of the fear-potentiated startle response. The results imply that the PAG is a heterogeneous structure that is involved in the coordination of distinct behaviors and autonomic control, suggest PAG involvement in the expression of contextual fear memory as well as implicate the CRF as an important modulator of the neural substrates of fear in the PAG.

  15. Nonassociative learning processes determine expression and extinction of conditioned fear in mice.

    PubMed

    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 suppression of the expression of fear. This study challenges these concepts for auditory fear conditioning in mice. We show that acquisition of conditioned fear by a few tone-shock pairings is accompanied by a nonassociative sensitization process. As a consequence, the freezing response of conditioned mice seems to be determined by both associative and nonassociative memory components. Our data suggest that the intensity of freezing as a function of footshock intensity is primarily determined by the nonassociative component, whereas the associative component is more or less categorical. We next demonstrate that the decrease in freezing on repeated nonreinforced tone presentation following conditioning shows fundamental properties of habituation. Thus, it might be regarded as a habituation-like process, which abolishes the influence of sensitization on the freezing response to the tone without affecting the expression of the associative memory component. Taken together, this study merges the dual-process theory of habituation with the concept of classical fear conditioning and demonstrates that sensitization and habituation as two nonassociative learning processes may critically determine the expression of conditioned fear in mice.

  16. Microstimulation reveals opposing influences of prelimbic and infralimbic cortex on the expression of conditioned fear.

    PubMed

    Vidal-Gonzalez, Ivan; Vidal-Gonzalez, Benjamín; Rauch, Scott L; Quirk, Gregory J

    2006-01-01

    Recent studies using lesion, infusion, and unit-recording techniques suggest that the infralimbic (IL) subregion of medial prefrontal cortex (mPFC) is necessary for the inhibition of conditioned fear following extinction. Brief microstimulation of IL paired with conditioned tones, designed to mimic neuronal tone responses, reduces the expression of conditioned fear to the tone. In the present study we used microstimulation to investigate the role of additional mPFC subregions: the prelimbic (PL), dorsal anterior cingulate (ACd), and medial precentral (PrCm) cortices in the expression and extinction of conditioned fear. These are tone-responsive areas that have been implicated in both acquisition and extinction of conditioned fear. In contrast to IL, microstimulation of PL increased the expression of conditioned fear and prevented extinction. Microstimulation of ACd and PrCm had no effect. Under low-footshock conditions (to avoid ceiling levels of freezing), microstimulation of PL and IL had opposite effects, respectively increasing and decreasing freezing to the conditioned tone. We suggest that PL excites amygdala output and IL inhibits amygdala output, providing a mechanism for bidirectional modulation of fear expression.

  17. Long-term changes in the CA3 associative network of fear-conditioned mice.

    PubMed

    Çalışkan, Gürsel; Albrecht, Anne; Hollnagel, Jan O; Rösler, Anton; Richter-Levin, Gal; Heinemann, Uwe; Stork, Oliver

    2015-01-01

    The CA3 associative network plays a critical role in the generation of network activity patterns related to emotional state and fear memory. We investigated long-term changes in the corticosterone (CORT)-sensitive function of this network following fear conditioning and fear memory reactivation. In acute slice preparations from mice trained in either condition, the ratio of orthodromic population spike (PS) to antidromic PS was reduced compared to unconditioned animals, indicating a decrease in efficacy of neuronal coupling within the associative CA3 network. However, spontaneous sharp wave-ripples (SW-R), which are thought to arise from this network, remained unaltered. Following CORT application, we observed an increase in orthodromic PS and a normalization to control levels of their ratio to antidromic PS, while SW-R increased in slices of fear conditioned and fear reactivated mice, but not in slices of unconditioned controls. Together with our previous observations of altered hippocampal gamma activity under these learning paradigms, these data suggest that fear conditioning and fear reactivation lastingly alters the CORT-sensitive configuration of different network activity patterns generated by the CA3 associational network. Observed changes in the mRNA expression of receptors for glutamate, GABA and cannabinoids in the stratum pyramidale of area CA3 may provide a molecular mechanism for these adaptive changes.

  18. Fluoxetine pretreatment promotes neuronal survival and maturation after auditory fear conditioning in the rat amygdala.

    PubMed

    Jiang, Lizhu; Liu, Chen; Tong, Jianbin; Mao, Rongrong; Chen, Dan; Wang, Hui; Huang, Jufang; Li, Lingjiang

    2014-01-01

    The amygdala is a critical brain region for auditory fear conditioning, which is a stressful condition for experimental rats. Adult neurogenesis in the dentate gyrus (DG) of the hippocampus, known to be sensitive to behavioral stress and treatment of the antidepressant fluoxetine (FLX), is involved in the formation of hippocampus-dependent memories. Here, we investigated whether neurogenesis also occurs in the amygdala and contributes to auditory fear memory. In rats showing persistent auditory fear memory following fear conditioning, we found that the survival of new-born cells and the number of new-born cells that differentiated into mature neurons labeled by BrdU and NeuN decreased in the amygdala, but the number of cells that developed into astrocytes labeled by BrdU and GFAP increased. Chronic pretreatment with FLX partially rescued the reduction in neurogenesis in the amygdala and slightly suppressed the maintenance of the long-lasting auditory fear memory 30 days after the fear conditioning. The present results suggest that adult neurogenesis in the amygdala is sensitive to antidepressant treatment and may weaken long-lasting auditory fear memory.

  19. Fluoxetine Pretreatment Promotes Neuronal Survival and Maturation after Auditory Fear Conditioning in the Rat Amygdala

    PubMed Central

    Jiang, Lizhu; Liu, Chen; Tong, Jianbin; Mao, Rongrong; Chen, Dan; Wang, Hui; Huang, Jufang; Li, Lingjiang

    2014-01-01

    The amygdala is a critical brain region for auditory fear conditioning, which is a stressful condition for experimental rats. Adult neurogenesis in the dentate gyrus (DG) of the hippocampus, known to be sensitive to behavioral stress and treatment of the antidepressant fluoxetine (FLX), is involved in the formation of hippocampus-dependent memories. Here, we investigated whether neurogenesis also occurs in the amygdala and contributes to auditory fear memory. In rats showing persistent auditory fear memory following fear conditioning, we found that the survival of new-born cells and the number of new-born cells that differentiated into mature neurons labeled by BrdU and NeuN decreased in the amygdala, but the number of cells that developed into astrocytes labeled by BrdU and GFAP increased. Chronic pretreatment with FLX partially rescued the reduction in neurogenesis in the amygdala and slightly suppressed the maintenance of the long-lasting auditory fear memory 30 days after the fear conditioning. The present results suggest that adult neurogenesis in the amygdala is sensitive to antidepressant treatment and may weaken long-lasting auditory fear memory. PMID:24551236

  20. Human proprioceptive adaptations during states of height-induced fear and anxiety.

    PubMed

    Davis, Justin R; Horslen, Brian C; Nishikawa, Kei; Fukushima, Katie; Chua, Romeo; Inglis, J Timothy; Carpenter, Mark G

    2011-12-01

    Clinical and experimental research has demonstrated that the emotional experience of fear and anxiety impairs postural stability in humans. The current study investigated whether changes in fear and anxiety can also modulate spinal stretch reflexes and the gain of afferent inputs to the primary somatosensory cortex. To do so, two separate experiments were performed on two separate groups of participants while they stood under conditions of low and high postural threat. In experiment 1, the proprioceptive system was probed using phasic mechanical stimulation of the Achilles tendon while simultaneously recording the ensuing tendon reflexes in the soleus muscle and cortical-evoked potentials over the somatosensory cortex during low and high threat conditions. In experiment 2, phasic electrical stimulation of the tibial nerve was used to examine the effect of postural threat on somatosensory evoked potentials. Results from experiment 1 demonstrated that soleus tendon reflex excitability was facilitated during states of height-induced fear and anxiety while the magnitude of the tendon-tap-evoked cortical potential was not significantly different between threat conditions. Results from experiment 2 demonstrated that the amplitudes of somatosensory-evoked potentials were also unchanged between threat conditions. The results support the hypothesis that muscle spindle sensitivity in the triceps surae muscles may be facilitated when humans stand under conditions of elevated postural threat, although the presumed increase in spindle sensitivity does not result in higher afferent feedback gain at the level of the somatosensory cortex.

  1. 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.

  2. Human Fear Acquisition Deficits in Relation to Genetic Variants of the Corticotropin Releasing Hormone Receptor 1 and the Serotonin Transporter

    PubMed Central

    Heitland, Ivo; Groenink, Lucianne; Bijlsma, Elisabeth Y.; Oosting, Ronald S.; Baas, Johanna M. P.

    2013-01-01

    The ability to identify predictors of aversive events allows organisms to appropriately respond to these events, and failure to acquire these fear contingencies can lead to maladaptive contextual anxiety. Recently, preclinical studies demonstrated that the corticotropin-releasing factor and serotonin systems are interactively involved in adaptive fear acquisition. Here, 150 healthy medication-free human subjects completed a cue and context fear conditioning procedure in a virtual reality environment. Fear potentiation of the eyeblink startle reflex (FPS) was measured to assess both uninstructed fear acquisition and instructed fear expression. All participants were genotyped for polymorphisms located within regulatory regions of the corticotropin releasing hormone receptor 1 (CRHR1 - rs878886) and the serotonin transporter (5HTTLPR). These polymorphisms have previously been linked to panic disorder and anxious symptomology and personality, respectively. G-allele carriers of CRHR1 (rs878886) showed no acquisition of fear conditioned responses (FPS) to the threat cue in the uninstructed phase, whereas fear acquisition was present in C/C homozygotes. Moreover, carrying the risk alleles of both rs878886 (G-allele) and 5HTTLPR (short allele) was associated with increased FPS to the threat context during this phase. After explicit instructions regarding the threat contingency were given, the cue FPS and context FPS normalized in all genotype groups. The present results indicate that genetic variability in the corticotropin-releasing hormone receptor 1, especially in interaction with the 5HTTLPR, is involved in the acquisition of fear in humans. This translates prior animal findings to the human realm. PMID:23717480

  3. Impairment of contextual conditioned fear extinction after microinjection of alpha-1-adrenergic blocker prazosin into the medial prefrontal cortex.

    PubMed

    Do-Monte, Fabrício H M; Allensworth, Melody; Carobrez, Antônio P

    2010-07-29

    Long-lasting memories of aversive or stressful events have been associated with the noradrenergic system activation. Alpha-1-adrenergic antagonist prazosin has successfully been used in the last years to treat anxiety disorders related to aversive memories recurrence in humans. Contextual conditioned fear extinction paradigm in rats has been used to better understand the mechanisms involved in the attenuation of defensive behaviour after a traumatic situation. Here we investigated the effects of systemic administration of prazosin in the fear extinction processes. Rats were previously paired in a contextual fear conditioning box (1 footshock, 1 mA, 2s duration), further returning to the same box during three consecutive days receiving an intraperitoneal injection of vehicle or prazosin 30 min before (acquisition of extinction; 0.1 or 0.5mg/kg) or immediately after (consolidation of extinction, 0.5 or 1.5mg/kg) each extinction session (10 min). On the last day, all animals were re-exposed undrugged to the apparatus. Since the medial prefrontal cortex (mPFC) has been described as a key structure in the modulation of conditioned fear extinction, the effects of intra-mPFC microinjection (0.2 microl per side) of vehicle (PBS) or prazosin (0.75 or 2.5 nmol) in the acquisition of fear extinction (10 min before extinction session 1) were further evaluated. Subjects were drug-free re-exposed to the same box in the next day (extinction session 2). The percentage of freezing time was used as the memory retention parameter. The results showed that either systemic or intra-mPFC-alpha-1-adrenergic blockade increased the freezing time in the last extinction sessions, suggesting impairment of the extinction of contextual conditioned fear in rats.

  4. Translational neuroscience measures of fear conditioning across development: applications to high-risk children and adolescents

    PubMed Central

    2013-01-01

    Several mental illnesses, including anxiety, can manifest during development, with onsets in late childhood. Understanding the neurobiological underpinnings of risk for anxiety is of crucial importance for early prevention and intervention approaches. Translational neuroscience offers tools to investigate such mechanisms in human and animal models. The current review describes paradigms derived from neuroscience, such as fear conditioning and extinction and overviews studies that have used these paradigms in animals and humans across development. The review also briefly discusses developmental trajectories of the relevant neural circuits and the emergence of clinical anxiety. Future studies should focus on developmental changes in these paradigms, paying close attention to neurobiological and hormonal changes associated with childhood and adolescence. PMID:24004567

  5. Role of Sleep Deprivation in Fear Conditioning and Extinction: Implications for Treatment of PTSD

    DTIC Science & Technology

    2015-10-01

    Award Number: W81XWH-11-2-0001 TITLE: “Role of Sleep Deprivation in Fear Conditioning and Extinction : Implications for Treatment of PTSD...Annual 3. DATES COVERED (From - To) 1 OCT 2014- 30 SEP 2015 4. TITLE AND SUBTITLE Role of Sleep Deprivation in Fear Conditioning and Extinction ...successful acquisition, consolidation, and recall of extinction memory are implicated in both the natural reduction of initial PTSD symptoms and as the

  6. Individual Differences in Discriminatory Fear Learning under Conditions of Ambiguity: A Vulnerability Factor for Anxiety Disorders?

    PubMed

    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.

  7. 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

  8. Social fear conditioning: a novel and specific animal model to study social anxiety disorder.

    PubMed

    Toth, Iulia; Neumann, Inga D; Slattery, David A

    2012-05-01

    Social anxiety disorder (SAD) is a major health concern with high lifetime prevalence. The current medication is rather unspecific and, despite considerable efforts, its efficacy is still unsatisfactory. However, there are no appropriate and specific animal models available to study the underlying etiology of the disorder. Therefore, we aimed to establish a model of specific social fear in mice and use this social fear conditioning (SFC) model to assess the therapeutic efficacy of the benzodiazepine diazepam and of the antidepressant paroxetine; treatments currently used for SAD patients. We show that by administering electric foot shocks (2-5, 1 s, 0.7 mA) during the investigation of a con-specific, the investigation of unfamiliar con-specifics was reduced for both the short- and long-term, indicating lasting social fear. The induced fear was specific to social stimuli and did not lead to other behavioral alterations, such as fear of novelty, general anxiety, depression, and impaired locomotion. We show that social fear was dose-dependently reversed by acute diazepam, at doses that were not anxiolytic in a non-social context, such as the elevated plus maze. Finally, we show that chronic paroxetine treatment reversed social fear. All in all, we demonstrated robust social fear after exposure to SFC in mice, which was reversed with both acute benzodiazepine and chronic antidepressant treatment. We propose the SFC model as an appropriate animal model to identify the underlying etiology of SAD and possible novel treatment approaches.

  9. p300/CBP-associated factor selectively regulates the extinction of conditioned fear

    PubMed Central

    Wei, Wei; Coelho, Carlos M.; Li, Xiang; Marek, Roger; Yan, Shanzhi; Anderson, Shawn; Meyers, David; Mukherjee, Chandrani; Sbardella, Gianluca; Castellano, Sabrina; Milite, Ciro; Rotili, Dante; Mai, Antonello; Cole, Philip A.; Sah, Pankaj; Kobor, Michael S.; Bredy, Timothy W.

    2012-01-01

    It is well established that the activity of chromatin-modifying enzymes is crucial for regulating gene expression associated with hippocampal-dependent memories. However, very little is known about how these epigenetic mechanisms influence the formation of cortically-dependent memory, particularly when there is competition between opposing memory traces such as that which occurs during the acquisition and extinction of conditioned fear. Here we demonstrate, in C57/Bl6 mice, that the activity of p300/CBP-associated factor (PCAF) within the infralimbic prefrontal cortex is required for long-term potentiation and is necessary for the formation of memory associated with fear extinction, but not for fear acquisition. Further, systemic administration of the PCAF activator SPV106 enhances memory for fear extinction and prevents fear renewal. The selective influence of PCAF on fear extinction is mediated, in part, by a transient recruitment of the repressive transcription factor ATF4 to the promoter of the immediate early gene zif268, which competitively inhibits its expression. Thus, within the context of fear extinction, PCAF functions as a transcriptional co-activator, which may facilitate the formation of memory for fear extinction by interfering with reconsolidation of the original memory trace. PMID:22933779

  10. Social Fear Conditioning: A Novel and Specific Animal Model to Study Social Anxiety Disorder

    PubMed Central

    Toth, Iulia; Neumann, Inga D; Slattery, David A

    2012-01-01

    Social anxiety disorder (SAD) is a major health concern with high lifetime prevalence. The current medication is rather unspecific and, despite considerable efforts, its efficacy is still unsatisfactory. However, there are no appropriate and specific animal models available to study the underlying etiology of the disorder. Therefore, we aimed to establish a model of specific social fear in mice and use this social fear conditioning (SFC) model to assess the therapeutic efficacy of the benzodiazepine diazepam and of the antidepressant paroxetine; treatments currently used for SAD patients. We show that by administering electric foot shocks (2–5, 1 s, 0.7 mA) during the investigation of a con-specific, the investigation of unfamiliar con-specifics was reduced for both the short- and long-term, indicating lasting social fear. The induced fear was specific to social stimuli and did not lead to other behavioral alterations, such as fear of novelty, general anxiety, depression, and impaired locomotion. We show that social fear was dose-dependently reversed by acute diazepam, at doses that were not anxiolytic in a non-social context, such as the elevated plus maze. Finally, we show that chronic paroxetine treatment reversed social fear. All in all, we demonstrated robust social fear after exposure to SFC in mice, which was reversed with both acute benzodiazepine and chronic antidepressant treatment. We propose the SFC model as an appropriate animal model to identify the underlying etiology of SAD and possible novel treatment approaches. PMID:22237310

  11. Human Neural Stem Cells Overexpressing Choline Acetyltransferase Restore Unconditioned Fear in Rats with Amygdala Injury

    PubMed Central

    Shin, Kyungha; Cha, Yeseul; Kim, Kwang Sei; Choi, Ehn-Kyoung; Choi, Youngjin; Guo, Haiyu; Ban, Young-Hwan; Kim, Jong-Choon; Park, Dongsun; Kim, Yun-Bae

    2016-01-01

    Amygdala is involved in the fear memory that recognizes certain environmental cues predicting threatening events. Manipulation of neurotransmission within the amygdala affects the expression of conditioned and unconditioned emotional memories such as fear freezing behaviour. We previously demonstrated that F3.ChAT human neural stem cells (NSCs) overexpressing choline acetyltransferase (ChAT) improve cognitive function of Alzheimer's disease model rats with hippocampal or cholinergic nerve injuries by increasing acetylcholine (ACh) level. In the present study, we examined the effect of F3.ChAT cells on the deficit of unconditioned fear freezing. Rats given N-methyl-d-aspartate (NMDA) in their amygdala 2 weeks prior to cat odor exposure displayed very short resting (freezing) time compared to normal animals. NMDA induced neuronal degeneration in the amygdala, leading to a decreased ACh concentration in cerebrospinal fluid. However, intracerebroventricular transplantation of F3.ChAT cells attenuated amygdala lesions 4 weeks after transplantation. The transplanted cells were found in the NMDA-injury sites and produced ChAT protein. In addition, F3.ChAT-receiving rats recuperated freezing time staying remote from the cat odor source, according to the recovery of brain ACh concentration. The results indicate that human NSCs overexpressing ChAT may facilitate retrieval of unconditioned fear memory by increasing ACh level. PMID:27087745

  12. Genetic background differences and nonassociative effects in mouse trace fear conditioning.

    PubMed

    Smith, Dani R; Gallagher, Michela; Stanton, Mark E

    2007-09-01

    Fear conditioning, including variants such as delay and trace conditioning that depend on different neural systems, is widely used to behaviorally characterize genetically altered mice. We present data from three strains of mice, C57/BL6 (C57), 129/SvlmJ (129), and a hybrid strain of the two (F(1) hybrids), trained on various versions of a trace fear-conditioning protocol. The initial version was taken from the literature but included unpaired control groups to assess nonassociative effects on test performance. We observed high levels of nonassociative freezing in both contextual and cued test conditions. In particular, nonassociative freezing in unpaired control groups was equivalent to freezing shown by paired groups in the tests for trace conditioning. A number of pilot studies resulted in a new protocol that yielded strong context conditioning and low levels of nonassociative freezing in all mouse strains. During the trace-CS test in this protocol, freezing in unpaired controls remained low in all strains, and both the C57s and F(1) hybrids showed reliable associative trace fear conditioning. Trace conditioning, however, was not obtained in the 129 mice. Our findings indicate that caution is warranted in interpreting mouse fear-conditioning studies that lack control conditions to address nonassociative effects. They also reveal a final set of parameters that are important for minimizing such nonassociative effects and demonstrate strain differences across performance in mouse contextual and trace fear conditioning.

  13. Interplay between serotonin and cannabinoid function in the amygdala in fear conditioning.

    PubMed

    Nasehi, Mohammad; Davoudi, Kamelia; Ebrahimi-Ghiri, Mohaddeseh; Zarrindast, Mohammad-Reza

    2016-04-01

    The possible interactions between the cannabinoid and serotonin systems in the regions of the brain involved in emotional learning and memory formation have been studied by some researchers. In view of the key role of the amygdala in the acquisition and expression of fear memory, we investigated the involvement of basolateral amygdala (BLA) serotonin 5-HT4 receptors in arachidonylcyclopropylamide (ACPA; selective CB1 cannabinoid receptor agonist)-induced fear memory consolidation impairment. In our study, a context and tone fear conditioning apparatus was used for testing fear conditioning in adult male NMRI mice. The results showed that intraperitoneal administration of ACPA 0.5 or 0.05, 0.1 and 0.5mg/kg immediately after training decreased the percentage of freezing time in context or tone fear conditioning respectively, suggesting a context- or tone-dependent fear memory consolidation impairment. Post-training intra-BLA microinjections of RS67333, as 5-HT4 serotonin receptor agonist, at doses of 0.025 and 0.05 µg/mouse also impaired context or tone memory consolidation, while RS23597, as 5-HT4 serotonin receptor antagonist, did not produce a marked difference in both fear memories as compared with the control group. Moreover, a subthreshold dose of RS67333 did not alter ACPA response in both fear conditionings. Interestingly, a subthreshold dose of RS23597 potentiated or reversed ACPA response at the dose of 0.01 or 0.05 respectively. It is concluded that BLA serotonin 5-HT4 receptors are involved in tone-dependent fear memory consolidation impairment induced by CB1 activation using ACPA, suggesting a modulatory role for serotonin 5-HT4 receptor.

  14. 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…

  15. 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…

  16. Acute Exercise Enhances the Consolidation of Fear Extinction Memory and Reduces Conditioned Fear Relapse in a Sex-Dependent Manner

    ERIC Educational Resources Information Center

    Bouchet, Courtney A.; Lloyd, Brian A.; Loetz, Esteban C.; Farmer, Caroline E.; Ostrovskyy, Mykola; Haddad, Natalie; Foright, Rebecca M.; Greenwood, Benjamin N.

    2017-01-01

    Fear extinction-based exposure therapy is the most common behavioral therapy for anxiety and trauma-related disorders, but fear extinction memories are labile and fear tends to return even after successful extinction. The relapse of fear contributes to the poor long-term efficacy of exposure therapy. A single session of voluntary exercise can…

  17. Corticotropin releasing factor type-1 receptor antagonism in the dorsolateral bed nucleus of the stria terminalis disrupts contextually conditioned fear, but not unconditioned fear to a predator odor.

    PubMed

    Asok, Arun; Schulkin, Jay; Rosen, Jeffrey B

    2016-08-01

    The bed nucleus of the stria terminalis (BNST) plays a critical role in fear and anxiety. The BNST is important for contextual fear learning, but the mechanisms regulating this function remain unclear. One candidate mechanism is corticotropin-releasing-factor (CRF) acting at CRF type 1 receptors (CRFr1s). Yet, there has been little progress in elucidating if CRFr1s in the BNST are involved in different types of fear (conditioned and/or unconditioned). Therefore, the present study investigated the effect of antalarmin, a potent CRFr1 receptor antagonist, injected intracerebroventricularly (ICV) and into the dorsolateral BNST (LBNST) during single trial contextual fear conditioning or exposure to the predator odor 2,5-dihydro-2,4,5-trimethylthiazoline (TMT). Neither ICV nor LBNST antalarmin disrupted unconditioned freezing to TMT. In contrast, ICV and LBNST antalarmin disrupted the retention of contextual fear when tested 24h later. Neither ICV nor LBNST antalarmin affected baseline or post-shock freezing-indicating antalarmin does not interfere with the early phases of contextual fear acquisition. Antalarmin did not (1) permanently affect the ability to learn and express contextual fear, (2) change responsivity to footshocks, or (3) affect the ability to freeze. Our findings highlight an important role for CRFr1s within the LBNST during contextually conditioned fear, but not unconditioned predator odor fear. Copyright © 2016 Elsevier Ltd. All rights reserved.

  18. Effects of acute exercise on fear extinction in rats and exposure therapy in humans: Null findings from five experiments.

    PubMed

    Jacquart, Jolene; Roquet, Rheall F; Papini, Santiago; Powers, Mark B; Rosenfield, David; Smits, Jasper A J; Monfils, Marie-H

    2017-08-01

    Exposure therapy is an established learning-based intervention for the treatment of anxiety disorders with an average response rate of nearly 50%, leaving room for improvement. Emerging strategies to enhance exposure therapy in humans and fear extinction retention in animal models are primarily pharmacological. These approaches are limited as many patients report preferring non-pharmacological approaches in therapy. With general cognitive enhancement effects, exercise has emerged as a plausible non-pharmacological augmentation strategy. The present study tested the hypothesis that fear extinction and exposure therapy would be enhanced by a pre-training bout of exercise. We conducted four experiments with rats that involved a standardized conditioning and extinction paradigm and a manipulation of exercise. In a fifth experiment, we manipulated vigorous-intensity exercise prior to a standardized virtual reality exposure therapy session among adults with fear of heights. In experiments 1-4, exercise did not facilitate fear extinction, long-term memory, or fear relapse tests. In experiment 5, human participants showed an overall reduction in fear of heights but exercise did not enhance symptom improvement. Although acute exercise prior to fear extinction or exposure therapy, as operationalized in the present 5 studies, did not enhance outcomes, these results must be interpreted within the context of a broader literature that includes positive findings. Taken all together, this suggests that more research is necessary to identify optimal parameters and key individual differences so that exercise can be implemented successfully to treat anxiety disorders. Copyright © 2017 Elsevier Ltd. All rights reserved.

  19. The narrow fellow in the grass: human infants associate snakes and fear.

    PubMed

    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 other animals. In the second study, 7- to 18-month-old infants associated snakes with fear: As predicted, they looked longer at films of snakes while listening to a frightened human voice than while listening to a happy voice. In the third study, infants did not look differentially to still photos of snakes and other animals, indicating that movement is crucial to infants' association of snakes with fear. These results offer support for the view that humans have a natural tendency to selectively associate snakes with fear.

  20. Identification of Functional Circuitry Between Retrosplenial and Postrhinal Cortices During Fear Conditioning

    PubMed Central

    Robinson, Siobhan; Poorman, Caroline E.; Marder, Thomas J.; Bucci, David J.

    2012-01-01

    The retrosplenial (RSP) and postrhinal (POR) cortices are heavily interconnected with medial temporal lobe structures involved in learning and memory. Previous studies indicate that RSP and POR are necessary for contextual fear conditioning, but it remains unclear whether these regions contribute individually or instead work together as a functional circuit to modulate learning and/or memory. In Experiment 1, learning-related neuronal activity was assessed in RSP from home-cage, shock-only, context-only or fear conditioned rats using real-time PCR and immunohistochemical methods to quantify immediate early gene expression. A significant increase in Arc (activity regulated cytoskeleton-associated protein) mRNA and Arc and c-Fos protein expression was detected in RSP from fear conditioned rats compared to all other groups. In Experiment 2, retrograde tracing combined with immunohistochemistry revealed that compared to controls, a significant proportion of cells projecting from RSP to POR were immunopositive for c-Fos in fear conditioned rats. These results demonstrate that neurons projecting from RSP to POR are indeed active during fear conditioning. In Experiment 3, a functional disconnection paradigm was used to further examine the interaction between RSP and POR during fear conditioning. Compared to controls, rats with unilateral lesions of RSP and POR on opposite sides of the brain exhibited impaired contextual fear memory whereas rats with unilateral lesions in the same hemisphere displayed intermediate levels of freezing compared to controls and rats with contralateral lesions. Collectively these results are the first to show that RSP and POR function as a cortical network necessary for contextual fear learning and memory. PMID:22933791

  1. Identification of functional circuitry between retrosplenial and postrhinal cortices during fear conditioning.

    PubMed

    Robinson, Siobhan; Poorman, Caroline E; Marder, Thomas J; Bucci, David J

    2012-08-29

    The retrosplenial cortex (RSP) and postrhinal cortex (POR) are heavily interconnected with medial temporal lobe structures involved in learning and memory. Previous studies indicate that RSP and POR are necessary for contextual fear conditioning, but it remains unclear whether these regions contribute individually or instead work together as a functional circuit to modulate learning and/or memory. In Experiment 1, learning-related neuronal activity was assessed in RSP from home cage, shock-only, context-only, or fear-conditioned rats using real-time PCR and immunohistochemical methods to quantify immediate-early gene expression. A significant increase in activity-regulated cytoskeleton-associated protein (Arc) mRNA and Arc and c-Fos protein expression was detected in RSP from fear-conditioned rats compared with all other groups. In Experiment 2, retrograde tracing combined with immunohistochemistry revealed that, compared with controls, a significant proportion of cells projecting from RSP to POR were immunopositive for c-Fos in fear-conditioned rats. These results demonstrate that neurons projecting from RSP to POR are indeed active during fear conditioning. In Experiment 3, a functional disconnection paradigm was used to further examine the interaction between RSP and POR during fear conditioning. Compared with controls, rats with unilateral lesions of RSP and POR on opposite sides of the brain exhibited impaired contextual fear memory, whereas rats with unilateral lesions in the same hemisphere displayed intermediate levels of freezing compared with controls and rats with contralateral lesions. Collectively, these results are the first to show that RSP and POR function as a cortical network necessary for contextual fear learning and memory.

  2. Entorhinal cortex contribution to contextual fear conditioning extinction and reconsolidation in rats.

    PubMed

    Baldi, Elisabetta; Bucherelli, Corrado

    2014-04-01

    During contextual fear conditioning a rat learns a temporal contiguity association between the exposition to a previously neutral context (CS) and an aversive unconditioned stimulus (US) as a footshock. This condition determines in the rat the freezing reaction during the subsequent re-exposition to the context. Potentially the re-exposition without US presentation initiates two opposing and competing processes: reconsolidation and extinction. Reconsolidation process re-stabilizes and strengthens the original memory and it is initiated by a brief re-exposure to context. Instead the extinction process leads to the decrease of the expression of the original memory and it is triggered by prolonged re-exposure to the context. Here we analyzed the entorhinal cortex (ENT) participation in contextual fear conditioning reconsolidation and extinction. The rats were trained in contextual fear conditioning and 24h later they were subjected either to a brief (2 min) reactivation session or to a prolonged (120 min) re-exposition to context to induce extinction of the contextual fear memory. Immediately after the reactivation or the extinction session, the animals were submitted to bilateral ENT TTX inactivation. Memory retention was assessed as conditioned freezing duration measured 72 h after TTX administration. The results showed that ENT inactivation both after reactivation and extinction session was followed by contextual freezing retention impairment. Thus, the present findings point out that ENT is involved in contextual fear memory reconsolidation and extinction. This neural structure might be part of parallel circuits underlying two phases of contextual fear memory processing.

  3. De novo fear conditioning across diagnostic groups in the affective disorders: evidence for learning impairments.

    PubMed

    Otto, Michael W; Moshier, Samantha J; Kinner, Dina G; Simon, Naomi M; Pollack, Mark H; Orr, Scott P

    2014-09-01

    De novo fear conditioning paradigms have served as a model for how clinical anxiety may be acquired and maintained. To further examine variable findings in the acquisition and extinction of fear responses between clinical and nonclinical samples, we assessed de novo fear conditioning outcomes in outpatients with either anxiety disorders or depression and healthy subjects recruited from the community. Overall, we found evidence for attenuated fear conditioning, as measured by skin conductance, among the patient sample, with significantly lower fear acquisition among patients with depression and posttraumatic stress disorder. These acquisition deficits were evident in both the simple (considering the CS+only) and differential (evaluating the CS+in relation to the CS-) paradigms. Examination of extinction outcomes were hampered by the low numbers of patients who achieved adequate conditioning, but the available data indicated slower extinction among the patient, primarily panic disorder, sample. Results are interpreted in the context of the cognitive deficits that are common to the anxiety and mood disorders, with attention to a range of potential factors, including mood comorbidity, higher-and lower-order cognitive processes and deficits, and medication use, that may modulate outcomes in fear conditioning studies, and, potentially, in exposure-based cognitive behavioral therapy. Copyright © 2014. Published by Elsevier Ltd.

  4. Intrinsic Neuronal Excitability Is Reversibly Altered by a Single Experience in Fear Conditioning

    PubMed Central

    Matthews, Elizabeth A.; Oliveira, Fernando A.; Disterhoft, John F.

    2009-01-01

    Learning is known to cause alterations in intrinsic cellular excitability but, to date, these changes have been seen only after multiple training trials. A powerful learning task that can be quickly acquired and extinguished with a single trial is fear conditioning. Rats were trained and extinguished on a hippocampus-dependent form of fear conditioning to determine whether learning-related changes in intrinsic excitability could be observed after a few training trials and a single extinction trial. Following fear training, hippocampal slices were made and intrinsic excitability was assayed via whole cell recordings from CA1 neurons. Alterations in intrinsic excitability, assayed by the postburst afterhyperpolarization and firing frequency accommodation, were observed after only three trials of contextual or trace-cued fear conditioning. Animals that had been trained in contextual and trace-cued fear were then extinguished. Context fear-conditioned animals extinguished in a single trial and the changes in intrinsic excitability were reversed. Trace-cue conditioned animals only partially extinguished in a single trial and reductions in excitability remained. Thus a single learning experience is sufficient to alter intrinsic excitability. This dramatically extends observations of learning-specific changes in intrinsic neuronal excitability previously observed in paradigms requiring many training trials, suggesting the excitability changes have a basic role in acquiring new information. PMID:19726729

  5. Fear conditioning suppresses large-conductance calcium-activated potassium channels in lateral amygdala neurons.

    PubMed

    Sun, P; Zhang, Q; Zhang, Y; Wang, F; Wang, L; Yamamoto, R; Sugai, T; Kato, N

    2015-01-01

    It was previously shown that depression-like behavior is accompanied with suppression of the large-conductance calcium activated potassium (BK) channel in cingulate cortex pyramidal cells. To test whether BK channels are also involved in fear conditioning, we studied neuronal properties of amygdala principal cells in fear conditioned mice. After behavior, we made brain slices containing the amygdala, the structure critically relevant to fear memory. The resting membrane potential in lateral amygdala (LA) neurons obtained from fear conditioned mice (FC group) was more depolarized than in neurons from naïve controls. The frequencies of spikes evoked by current injections were higher in neurons from FC mice, demonstrating that excitability of LA neurons was elevated by fear conditioning. The depolarization in neurons from FC mice was shown to depend on BK channels by using the BK channel blocker charybdotoxin. Suppression of BK channels in LA neurons from the FC group was further confirmed on the basis of the spike width, since BK channels affect the descending phase of spikes. Spikes were broader in the FC group than those in the naïve control in a manner dependent on BK channels. Consistently, quantitative real-time PCR revealed a decreased expression of BK channel mRNA. The present findings suggest that emotional disorder manifested in the forms of fear conditioning is accompanied with BK channel suppression in the amygdala, the brain structure critical to this emotional disorder.

  6. Computational search for hypotheses concerning the endocannabinoid contribution to the extinction of fear conditioning

    PubMed Central

    Anastasio, Thomas J.

    2013-01-01

    Fear conditioning, in which a cue is conditioned to elicit a fear response, and extinction, in which a previously conditioned cue no longer elicits a fear response, depend on neural plasticity occurring within the amygdala. Projection neurons in the basolateral amygdala (BLA) learn to respond to the cue during fear conditioning, and they mediate fear responding by transferring cue signals to the output stage of the amygdala. Some BLA projection neurons retain their cue responses after extinction. Recent work shows that activation of the endocannabinoid system is necessary for extinction, and it leads to long-term depression (LTD) of the GABAergic synapses that inhibitory interneurons make onto BLA projection neurons. Such GABAergic LTD would enhance the responses of the BLA projection neurons that mediate fear responding, so it would seem to oppose, rather than promote, extinction. To address this paradox, a computational analysis of two well-known conceptual models of amygdaloid plasticity was undertaken. The analysis employed exhaustive state-space search conducted within a declarative programming environment. The analysis reveals that GABAergic LTD actually increases the number of synaptic strength configurations that achieve extinction while preserving the cue responses of some BLA projection neurons in both models. The results suggest that GABAergic LTD helps the amygdala retain cue memory during extinction even as the amygdala learns to suppress the previously conditioned response. The analysis also reveals which features of both models are essential for their ability to achieve extinction with some cue memory preservation, and suggests experimental tests of those features. PMID:23761759

  7. Expatriates’ Multiple Fears, from Terrorism to Working Conditions: Development of a Model

    PubMed Central

    Giorgi, Gabriele; Montani, Francesco; Fiz-Perez, Javier; Arcangeli, Giulio; Mucci, Nicola

    2016-01-01

    Companies’ internationalization appears to be fundamental in the current globalized and competitive environment and seems important not only for organizational success, but also for societal development and sustainability. On one hand, global business increases the demand for managers for international assignment. On the other hand, emergent fears, such as terrorism, seem to be developing around the world, enhancing the risk of expatriates’ potential health problems. The purpose of this paper is to examine the relationships between the emergent concept of fear of expatriation with further workplace fears (economic crisis and dangerous working conditions) and with mental health problems. The study uses a quantitative design. Self-reported data were collected from 265 Italian expatriate workers assigned to both Italian and worldwide projects. Structural equation model analyses showed that fear of expatriation mediates the relationship of mental health with fear of economic crisis and with perceived dangerous working conditions. As expected, in addition to fear, worries of expatriation are also related to further fears. Although, the study is based on self-reports and the cross-sectional study design limits the possibility of making causal inferences, the new constructs introduced add to previous research. PMID:27790173

  8. Expatriates' Multiple Fears, from Terrorism to Working Conditions: Development of a Model.

    PubMed

    Giorgi, Gabriele; Montani, Francesco; Fiz-Perez, Javier; Arcangeli, Giulio; Mucci, Nicola

    2016-01-01

    Companies' internationalization appears to be fundamental in the current globalized and competitive environment and seems important not only for organizational success, but also for societal development and sustainability. On one hand, global business increases the demand for managers for international assignment. On the other hand, emergent fears, such as terrorism, seem to be developing around the world, enhancing the risk of expatriates' potential health problems. The purpose of this paper is to examine the relationships between the emergent concept of fear of expatriation with further workplace fears (economic crisis and dangerous working conditions) and with mental health problems. The study uses a quantitative design. Self-reported data were collected from 265 Italian expatriate workers assigned to both Italian and worldwide projects. Structural equation model analyses showed that fear of expatriation mediates the relationship of mental health with fear of economic crisis and with perceived dangerous working conditions. As expected, in addition to fear, worries of expatriation are also related to further fears. Although, the study is based on self-reports and the cross-sectional study design limits the possibility of making causal inferences, the new constructs introduced add to previous research.

  9. Dorsal hippocampus involvement in trace fear conditioning with long, but not short, trace intervals in mice.

    PubMed

    Chowdhury, Najwa; Quinn, Jennifer J; Fanselow, Michael S

    2005-10-01

    Placing a "trace" interval between a warning signal and an aversive shock makes consolidation of the memory for trace conditioning hippocampus dependent. To determine the trace at which memory consolidation requires the hippocampus, mice were trained with 0-s, 1-s, 3-s, or 20-s trace intervals and tested for freezing to context and tone. Posttraining dorsal hippocampus (DH) lesions decreased context conditioning regardless of trace interval. However, DH lesions attenuated only the 20-s trace tone freezing. Like eyeblink conditioning, the DH is necessary for trace fear conditioning only at long trace intervals, but the time scale for the effective interval in fear conditioning is about 40 times longer. Manipulations that alter trace fear conditioning with short trace intervals probably do not reflect altered DH function. Given this difference in time scale along with the use of posttraining DH lesions, hippocampus dependency of trace conditioning is not related to a bridging function or response timing.

  10. The Development of Skin Conductance Fear Conditioning in Children from Ages 3 to 8 Years

    PubMed Central

    Gao, Yu; Raine, Adrian; Venables, Peter H.; Dawson, Michael E.; Mednick, Sarnoff A.

    2009-01-01

    Although fear conditioning is an important psychological construct implicated in behavioral and emotional problems little is known about how it develops in early childhood. Using a differential, partial reinforcement conditioning paradigm, this longitudinal study assessed skin conductance conditioned responses in 200 children at ages 3, 4, 5, 6, and 8 years. Results demonstrated that in both boys and girls: (1) fear conditioning increased across age, particularly from ages 5 to 6 years, (2) the three components of skin conductance fear conditioning that reflect different degrees of automatic and controlled cognitive processes exhibited different developmental profiles, and (3) individual differences in arousal, orienting, and the unconditioned response were associated with individual differences in conditioning, with the influence of orienting increasing at later ages. This first longitudinal study of the development of skin conductance fear conditioning in children both demonstrates that children as young as age 3 years evidence fear conditioning in a difficult acquisition paradigm, and that different sub-components of skin conductance conditioning have different developmental trajectories. PMID:20121876

  11. Heart rate reactivity in HAD and LAD rats during Pavlovian fear conditioning.

    PubMed

    Rorick, Linda M; Finn, Peter R; Steinmetz, Joseph E

    2004-01-01

    Recently, we reported that High-Alcohol-Drinking (HAD) rats exhibited selective deficits in active avoidance learning under alcohol-naive conditions, and that administration of moderate doses of alcohol (0.5 and 1.0 g/kg) facilitated learning in these rats (Blankenship et al., 2000; Rorick et al., 2003b). We hypothesized that the deficits resulted from excessive fear in the aversive learning context and that the anxiolytic properties of alcohol may have contributed to the improved learning that was observed after alcohol administration. This hypothesis was supported by a recent study in which prolonged freezing in HAD rats was seen after a classical fear conditioning procedure (Rorick et al., 2003a). To provide additional evidence that HAD rats indeed exhibit behaviors consistent with the expression of increased fear in aversive learning contexts, we employed a Pavlovian fear conditioning task to measure heart rate in HAD and Low-Alcohol-Drinking (LAD) rats. In this study, HAD (HAD-1 and HAD-2) and LAD (LAD-1 and LAD-2) rats were assigned to one of three pre-exposure conditions: Context Only, Context/Tone, or Sequential (Context Only followed by Context/Tone) Pre-Exposure. Following pre-exposure, fear conditioning acquisition and extinction procedures were identical for all groups. Results indicated that although no baseline differences were observed between HAD and LAD rats, HAD rats receiving Context-Only pre-exposure exhibited excessive heart rate reactivity to the tone conditional stimulus during fear conditioning acquisition, compared to LAD rats receiving the same pre-exposure conditions. These findings support the hypothesis that HAD rats exhibit behaviors consistent with increased fear in aversive learning contexts, as measured by autonomic conditioning.

  12. Post-conditioning experience with acute or chronic inflammatory pain reduces contextual fear conditioning in the rat.

    PubMed

    Johnston, Ian N; Maier, Steven F; Rudy, Jerry W; Watkins, Linda R

    2012-01-15

    There is evidence that pain can impact cognitive function in people. The present study evaluated whether Pavlovian fear conditioning in rats would be reduced if conditioning were followed by persistent inflammatory pain induced by a subcutaneous injection of dilute formalin or complete Freund's adjuvant (CFA) on the dorsal lumbar surface of the back. Formalin-induced pain specifically impaired contextual fear conditioning but not auditory cue conditioning (Experiment 1A). Moreover, formalin pain only impaired contextual fear conditioning if it was initiated within 1h of conditioning and did not have a significant effect if initiated 2, 8 or 32 h after (Experiments 1A and 1B). Experiment 2 showed that formalin pain initiated after a session of context pre-exposure reduced the ability of that pre-exposure to facilitate contextual fear when the rat was limited to a brief exposure to the context during conditioning. Similar impairments in context- but not CS-fear conditioning were also observed if the rats received an immediate post-conditioning injection with CFA (Experiment 3). Finally, we confirmed that formalin and CFA injected s.c. on the back induced pain-indicative behaviours, hyperalgesia and allodynia with a similar timecourse to intraplantar injections (Experiment 4). These results suggest that persistent pain impairs learning in a hippocampus-dependent task, and may disrupt processes that encode experiences into long-term memory.

  13. The effect of yohimbine on the extinction of conditioned fear: a role for context.

    PubMed

    Morris, Richard W; Bouton, Mark E

    2007-06-01

    Six experiments with rat subjects examined the effect of yohimbine, an alpha-2 adrenergic autoreceptor antagonist, on the extinction of conditioned fear to a tone. Experiments 1 and 2 demonstrated that systemic administration of yohimbine (1.0 mg/kg) facilitated a long-term decrease in freezing after extinction, and this depended on pairing drug administration with extinction training. However, Experiments 3 and 4 demonstrated that yohimbine did not eradicate the original fear learning: Freezing was renewed when the tone was tested outside of the extinction context. Experiments 5 and 6 found that the contextually specific attenuation of fear produced by yohimbine transferred to another extinguished conditional stimulus (CS) and not to a nonextinguished CS. The results suggest that yohimbine, when administered in the presence of a neutral context, creates a form of inhibition in that context that allows that specific context to reduce fear of an extinguished CS.

  14. Evolution of human emotion: a view through fear.

    PubMed

    LeDoux, Joseph E

    2012-01-01

    Basic tendencies to detect and respond to significant events are present in the simplest single cell organisms and persist throughout all invertebrates and vertebrates. Within vertebrates, the overall brain plan is highly conserved, though differences in size and complexity also exist. The forebrain differs the most between mammals and other vertebrates. The classic notion that the evolution of mammals led to radical changes such that new forebrain structures (limbic system and neocortex) were added has not held up nor has the idea that so-called limbic areas are primarily involved in emotion. Modern efforts have focused on specific emotion systems, like the fear or defense system, rather than on the search for a general purpose emotion systems. Such studies have found that fear circuits are conserved in mammals, including humans. Animal work has been especially successful in determining how the brain detects and responds to danger. Caution should be exercised when attempting to discuss other aspects of emotion, namely subjective feelings, in animals since there are no scientific ways of verifying and measuring such states except in humans. Copyright © 2012 Elsevier B.V. All rights reserved.

  15. Signal transduction mechanisms within the entorhinal cortex that support latent inhibition of cued fear conditioning.

    PubMed

    Lewis, Michael C; Gould, Thomas J

    2007-10-01

    Latent inhibition is a phenomenon by which pre-exposure to a conditioned-stimulus (CS), prior to subsequent pairings of that same CS with an unconditioned-stimulus (US), results in decreased conditioned responding to the CS. Previous work in our laboratory has suggested that the entorhinal cortex is critically involved in the establishment of latent inhibition of cued fear conditioning. Furthermore, utilizing systemic pharmacology, we have demonstrated a role for of NMDA receptors, protein kinase A (PKA), and mitogen activated protein kinase (MAPK, also known as ERK) in latent inhibition of cued fear conditioning, but until now, where these cell signaling cascades are critically activated during latent inhibition of cued fear was unknown. Here, we use direct drug infusion to demonstrate that cell signaling via NMDA receptors, the cAMP/PKA pathway, and the MAPK pathway within the entorhinal cortex are critically involved in latent inhibition of cued fear conditioning. In the present study, CS pre-exposed mice received 20 CS pre-exposures 24h prior to two pairings of the same CS with a 0.53 mA foot shock US, while control animals receive no pre-exposure to the CS. The NMDA antagonist APV (0.25 or 2.5 microg/side), the cAMP inhibitor Rp-cAMP (1.8 or 18.0 microg/side), or the MAPK inhibitor U0126 (0.1 or 1.0 microg/side) were directly infused into the entorhinal cortex prior to pre-exposure. All three drugs produced dose-dependent disruptions in latent inhibition of cued fear conditioning. Importantly, none of the drugs had any effect on cued fear conditioning when administered on training day, suggesting that the effects of each of the drugs were specific to CS pre-exposure. These results are discussed in relation to the potential mechanisms of plasticity that support latent inhibition of cued fear conditioning.

  16. Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning.

    PubMed

    Catlow, Briony J; Song, Shijie; Paredes, Daniel A; Kirstein, Cheryl L; Sanchez-Ramos, Juan

    2013-08-01

    Drugs that modulate serotonin (5-HT) synaptic concentrations impact neurogenesis and hippocampal (HPC)-dependent learning. The primary objective is to determine the extent to which psilocybin (PSOP) modulates neurogenesis and thereby affects acquisition and extinction of HPC-dependent trace fear conditioning. PSOP, the 5-HT2A agonist 25I-NBMeO and the 5-HT2A/C antagonist ketanserin were administered via an acute intraperitoneal injection to mice. Trace fear conditioning was measured as the amount of time spent immobile in the presence of the conditioned stimulus (CS, auditory tone), trace (silent interval) and post-trace interval over 10 trials. Extinction was determined by the number of trials required to resume mobility during CS, trace and post-trace when the shock was not delivered. Neurogenesis was determined by unbiased counts of cells in the dentate gyrus of the HPC birth-dated with BrdU co-expressing a neuronal marker. Mice treated with a range of doses of PSOP acquired a robust conditioned fear response. Mice injected with low doses of PSOP extinguished cued fear conditioning significantly more rapidly than high-dose PSOP or saline-treated mice. Injection of PSOP, 25I-NBMeO or ketanserin resulted in significant dose-dependent decreases in number of newborn neurons in hippocampus. At the low doses of PSOP that enhanced extinction, neurogenesis was not decreased, but rather tended toward an increase. Extinction of "fear conditioning" may be mediated by actions of the drugs at sites other than hippocampus such as the amygdala, which is known to mediate the perception of fear. Another caveat is that PSOP is not purely selective for 5-HT2A receptors. PSOP facilitates extinction of the classically conditioned fear response, and this, and similar agents, should be explored as potential treatments for post-traumatic stress disorder and related conditions.

  17. Genome-wide association for fear conditioning in an advanced intercross mouse line.

    PubMed

    Parker, Clarissa C; Sokoloff, Greta; Cheng, Riyan; Palmer, Abraham A

    2012-05-01

    Fear conditioning (FC) may provide a useful model for some components of post-traumatic stress disorder (PTSD). We used a C57BL/6J × DBA/2J F(2) intercross (n = 620) and a C57BL/6J × DBA/2J F(8) advanced intercross line (n = 567) to fine-map quantitative trait loci (QTL) associated with FC. We conducted an integrated genome-wide association analysis in QTLRel and identified five highly significant QTL affecting freezing to context as well as four highly significant QTL associated with freezing to cue. The average percent decrease in QTL width between the F(2) and the integrated analysis was 59.2%. Next, we exploited bioinformatic sequence and expression data to identify candidate genes based on the existence of non-synonymous coding polymorphisms and/or expression QTLs. We identified numerous candidate genes that have been previously implicated in either fear learning in animal models (Bcl2, Btg2, Dbi, Gabr1b, Lypd1, Pam and Rgs14) or PTSD in humans (Gabra2, Oprm1 and Trkb); other identified genes may represent novel findings. The integration of F(2) and AIL data maintains the advantages of studying FC in model organisms while significantly improving resolution over previous approaches.

  18. Vagus nerve stimulation enhances extinction of conditioned fear and modulates plasticity in the pathway from the ventromedial prefrontal cortex to the amygdala

    PubMed Central

    Peña, David Frausto; Childs, Jessica E.; Willett, Shawn; Vital, Analicia; McIntyre, Christa K.; Kroener, Sven

    2014-01-01

    Fearful experiences can produce long-lasting and debilitating memories. Extinction of the fear response requires consolidation of new memories that compete with fearful associations. Subjects with posttraumatic stress disorder (PTSD) show impaired extinction of conditioned fear, which is associated with decreased ventromedial prefrontal cortex (vmPFC) control over amygdala activity. Vagus nerve stimulation (VNS) enhances memory consolidation in both rats and humans, and pairing VNS with exposure to conditioned cues enhances the consolidation of extinction learning in rats. Here we investigated whether pairing VNS with extinction learning facilitates plasticity between the infralimbic (IL) medial prefrontal cortex and the basolateral complex of the amygdala (BLA). Rats were trained on an auditory fear conditioning task, which was followed by a retention test and 1 day of extinction training. Vagus nerve stimulation or sham-stimulation was administered concurrently with exposure to the fear-conditioned stimulus and retention of fear conditioning was tested again 24 h later. Vagus nerve stimulation-treated rats demonstrated a significant reduction in freezing after a single extinction training session similar to animals that received 5× the number of extinction pairings. To study plasticity in the IL-BLA pathway, we recorded evoked field potentials (EFPs) in the BLA in anesthetized animals 24 h after retention testing. Brief burst stimulation in the IL produced LTD in the BLA field response in fear-conditioned and sham-treated animals. In contrast, the same stimulation resulted in potentiation of the IL-BLA pathway in the VNS-treated group. The present findin