Individual differences in learning predict the return of fear.

PubMed

Gershman, Samuel J; Hartley, Catherine A

2015-09-01

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

The Physiology of Fear: Reconceptualizing the Role of the Central Amygdala in Fear Learning

PubMed Central

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

2015-01-01

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

Caloric restriction enhances fear extinction learning in mice.

PubMed

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

2013-05-01

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

Vicarious extinction learning during reconsolidation neutralizes fear memory.

PubMed

Golkar, Armita; Tjaden, Cathelijn; Kindt, Merel

2017-05-01

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

The Physiology of Fear: Reconceptualizing the Role of the Central Amygdala in Fear Learning.

PubMed

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

2015-09-01

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

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.

3,4-Methylenedioxymethamphetamine facilitates fear extinction learning.

PubMed

Young, M B; Andero, R; Ressler, K J; Howell, L L

2015-09-15

Acutely administered 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') has been proposed to have long-term positive effects on post-traumatic stress disorder (PTSD) symptoms when combined with psychotherapy. No preclinical data support a mechanistic basis for these claims. Given the persistent nature of psychotherapeutic gains facilitated by MDMA, we hypothesized that MDMA improves fear extinction learning, a key process in exposure-based therapies for PTSD. In these experiments, mice were first exposed to cued fear conditioning and treated with drug vehicle or MDMA before extinction training 2 days later. MDMA was administered systemically and also directly targeted to brain structures known to contribute to extinction. In addition to behavioral measures of extinction, changes in mRNA levels of brain-derived neurotrophic factor (Bdnf) and Fos were measured after MDMA treatment and extinction. MDMA (7.8 mg kg(-1)) persistently and robustly enhanced long-term extinction when administered before extinction training. MDMA increased the expression of Fos in the amygdala and medial prefrontal cortex (mPFC), whereas increases in Bdnf expression were observed only in the amygdala after extinction training. Extinction enhancements were recapitulated when MDMA (1 μg) was infused directly into the basolateral complex of the amygdala (BLA), and enhancement was abolished when BDNF signaling was inhibited before extinction. These findings suggest that MDMA enhances fear memory extinction through a BDNF-dependent mechanism, and that MDMA may be a useful adjunct to exposure-based therapies for PTSD and other anxiety disorders characterized by altered fear learning.

AMYGDALA MICROCIRCUITS CONTROLLING LEARNED FEAR

PubMed Central

Duvarci, Sevil; Pare, Denis

2014-01-01

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

Developmental regulation of fear learning and anxiety behavior by endocannabinoids

PubMed Central

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

2015-01-01

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

Adult Hippocampal Neurogenesis Modulates Fear Learning through Associative and Nonassociative Mechanisms

PubMed Central

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

2015-01-01

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

Social Fear Learning: from Animal Models to Human Function.

PubMed

Debiec, Jacek; Olsson, Andreas

2017-07-01

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

Forming Competing Fear Learning and Extinction Memories in Adolescence Makes Fear Difficult to Inhibit

ERIC Educational Resources Information Center

Baker, Kathryn D.; Richardson, Rick

2015-01-01

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

Developmental regulation of fear learning and anxiety behavior by endocannabinoids.

PubMed

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

2016-01-01

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

3,4-Methylenedioxymethamphetamine facilitates fear extinction learning

PubMed Central

Young, M B; Andero, R; Ressler, K J; Howell, L L

2015-01-01

Acutely administered 3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy') has been proposed to have long-term positive effects on post-traumatic stress disorder (PTSD) symptoms when combined with psychotherapy. No preclinical data support a mechanistic basis for these claims. Given the persistent nature of psychotherapeutic gains facilitated by MDMA, we hypothesized that MDMA improves fear extinction learning, a key process in exposure-based therapies for PTSD. In these experiments, mice were first exposed to cued fear conditioning and treated with drug vehicle or MDMA before extinction training 2 days later. MDMA was administered systemically and also directly targeted to brain structures known to contribute to extinction. In addition to behavioral measures of extinction, changes in mRNA levels of brain-derived neurotrophic factor (Bdnf) and Fos were measured after MDMA treatment and extinction. MDMA (7.8 mg kg−1) persistently and robustly enhanced long-term extinction when administered before extinction training. MDMA increased the expression of Fos in the amygdala and medial prefrontal cortex (mPFC), whereas increases in Bdnf expression were observed only in the amygdala after extinction training. Extinction enhancements were recapitulated when MDMA (1  μg) was infused directly into the basolateral complex of the amygdala (BLA), and enhancement was abolished when BDNF signaling was inhibited before extinction. These findings suggest that MDMA enhances fear memory extinction through a BDNF-dependent mechanism, and that MDMA may be a useful adjunct to exposure-based therapies for PTSD and other anxiety disorders characterized by altered fear learning. PMID:26371762

Complementary roles for amygdala and periaqueductal gray in temporal-difference fear learning.

PubMed

Cole, Sindy; McNally, Gavan P

2009-01-01

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

Forming competing fear learning and extinction memories in adolescence makes fear difficult to inhibit

PubMed Central

Richardson, Rick

2015-01-01

Fear inhibition is markedly impaired in adolescent rodents and humans. The present experiments investigated whether this impairment is critically determined by the animal's age at the time of fear learning or their age at fear extinction. Male rats (n = 170) were tested for extinction retention after conditioning and extinction at different ages. We examined neural correlates of impaired extinction retention by detection of phosphorylated mitogen-activated protein kinase immunoreactivity (pMAPK-IR) in several brain regions. Unexpectedly, adolescent rats exhibited good extinction retention if fear was acquired before adolescence. Further, fear acquired in adolescence could be successfully extinguished in adulthood but not within adolescence. Adolescent rats did not show extinction-induced increases in pMAPK-IR in the medial prefrontal cortex or the basolateral amygdala, or a pattern of reduced caudal central amygdala pMAPK-IR, as was observed in juveniles. This dampened prefrontal and basolateral amygdala MAPK activation following extinction in adolescence occurred even when there was no impairment in extinction retention. In contrast, only adolescent animals that exhibited impaired extinction retention showed elevated pMAPK-IR in the posterior paraventricular thalamus. These data suggest that neither the animal's age at the time of fear acquisition or extinction determines whether impaired extinction retention is exhibited. Rather, it appears that forming competing fear conditioning and extinction memories in adolescence renders this a vulnerable developmental period in which fear is difficult to inhibit. Furthermore, even under conditions that promote good extinction, the neural correlates of extinction in adolescence are different than those recruited in animals of other ages. PMID:26472643

A novel perceptual discrimination training task: Reducing fear overgeneralization in the context of fear learning.

PubMed

Ginat-Frolich, Rivkah; Klein, Zohar; Katz, Omer; Shechner, Tomer

2017-06-01

Generalization is an adaptive learning mechanism, but it can be maladaptive when it occurs in excess. A novel perceptual discrimination training task was therefore designed to moderate fear overgeneralization. We hypothesized that improvement in basic perceptual discrimination would translate into lower fear overgeneralization in affective cues. Seventy adults completed a fear-conditioning task prior to being allocated into training or placebo groups. Predesignated geometric shape pairs were constructed for the training task. A target shape from each pair was presented. Thereafter, participants in the training group were shown both shapes and asked to identify the image that differed from the target. Placebo task participants only indicated the location of each shape on the screen. All participants then viewed new geometric pairs and indicated whether they were identical or different. Finally, participants completed a fear generalization test consisting of perceptual morphs ranging from the CS + to the CS-. Fear-conditioning was observed through physiological and behavioural measures. Furthermore, the training group performed better than the placebo group on the assessment task and exhibited decreased fear generalization in response to threat/safety cues. The findings offer evidence for the effectiveness of the novel discrimination training task, setting the stage for future research with clinical populations. Copyright © 2017 Elsevier Ltd. All rights reserved.

Sensitive periods in fear learning and memory.

PubMed

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

2014-01-01

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

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

Learning from other people’s fear: amygdala-based social reference learning in social anxiety disorder

PubMed Central

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

2016-01-01

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

The Effect of Disgust and Fear Modeling on Children’s Disgust and Fear for Animals

PubMed Central

2014-01-01

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

A common neural network differentially mediates direct and social fear learning.

PubMed

Lindström, Björn; Haaker, Jan; Olsson, Andreas

2018-02-15

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

Sensitive periods in fear learning and memory

PubMed Central

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

2015-01-01

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

Zinc transporter 3 is involved in learned fear and extinction, but not in innate fear.

PubMed

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

2010-11-01

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

Associative fear learning and perceptual discrimination: a perceptual pathway in the development of chronic pain.

PubMed

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

2015-04-01

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

Complementary Roles for Amygdala and Periaqueductal Gray in Temporal-Difference Fear Learning

ERIC Educational Resources Information Center

Cole, Sindy; McNally, Gavan P.

2009-01-01

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

Anxiety symptoms and children's eye gaze during fear learning.

PubMed

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

2017-11-01

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

Lifelong disturbance of serotonin transporter functioning results in fear learning deficits: Reversal by blockade of CRF1 receptors.

PubMed

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

2015-10-01

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

Neonatal Odor-Shock Conditioning Alters the Neural Network Involved in Odor Fear Learning at Adulthood

ERIC Educational Resources Information Center

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

2008-01-01

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

Nonlinear Developmental trajectory of fear learning and memory

PubMed Central

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

2013-01-01

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

Cholinergic regulation of fear learning and extinction.

PubMed

Wilson, Marlene A; Fadel, Jim R

2017-03-01

Cholinergic activation regulates cognitive function, particularly long-term memory consolidation. This Review presents an overview of the anatomical, neurochemical, and pharmacological evidence supporting the cholinergic regulation of Pavlovian contextual and cue-conditioned fear learning and extinction. Basal forebrain cholinergic neurons provide inputs to neocortical regions and subcortical limbic structures such as the hippocampus and amygdala. Pharmacological manipulations of muscarinic and nicotinic receptors support the role of cholinergic processes in the amygdala, hippocampus, and prefrontal cortex in modulating the learning and extinction of contexts or cues associated with threat. Additional evidence from lesion studies and analysis of in vivo acetylcholine release with microdialysis similarly support a critical role of cholinergic neurotransmission in corticoamygdalar or corticohippocampal circuits during acquisition of fear extinction. Although a few studies have suggested a complex role of cholinergic neurotransmission in the cellular plasticity essential for extinction learning, more work is required to elucidate the exact cholinergic mechanisms and physiological role of muscarinic and nicotinic receptors in these fear circuits. Such studies are important for elucidating the role of cholinergic neurotransmission in disorders such as posttraumatic stress disorder that involve deficits in extinction learning as well as for developing novel therapeutic approaches for such disorders. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Extinction of Conditioned Fear is Better Learned and Recalled in the Morning than in the Evening

PubMed Central

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

2013-01-01

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

Extinction of conditioned fear is better learned and recalled in the morning than in the evening.

PubMed

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

2013-11-01

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

A role for the interoceptive insular cortex in the consolidation of learned fear.

PubMed

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

2016-01-01

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

Inhibition of Fear by Learned Safety Signals: minisymposium review

PubMed Central

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

2012-01-01

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

Persistent Prelimbic Cortex Activity Contributes to Enhanced Learned Fear Expression in Females

ERIC Educational Resources Information Center

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

2014-01-01

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

Contingency learning in human fear conditioning involves the ventral striatum.

PubMed

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

2009-11-01

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

Fear conditioning to subliminal fear relevant and non fear relevant stimuli.

PubMed

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

2014-01-01

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

Nothing is safe: Intolerance of uncertainty is associated with compromised fear extinction learning.

PubMed

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

2016-12-01

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

Social modulation of associative fear learning by pheromone communication

PubMed Central

Bredy, Timothy W.; Barad, Mark

2009-01-01

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

Social modulation of associative fear learning by pheromone communication.

PubMed

Bredy, Timothy W; Barad, Mark

2009-01-01

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

Cannabinoid modulation of zebrafish fear learning and its functional analysis investigated by c-Fos expression.

PubMed

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

2017-02-01

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

Morphine prevents the development of stress-enhanced fear learning.

PubMed

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

2013-01-01

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

Zinc Transporter 3 Is Involved in Learned Fear and Extinction, but Not in Innate Fear

ERIC Educational Resources Information Center

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

2010-01-01

Synaptically released Zn[superscript 2+] is a potential modulator of neurotransmission and synaptic plasticity in fear-conditioning pathways. Zinc transporter 3 (ZnT3) knock-out (KO) mice are well suited to test the role of zinc in learned fear, because ZnT3 is colocalized with synaptic zinc, responsible for its transport to synaptic vesicles,…

Fear in the Classroom: An Examination of Teachers' Use of Fear Appeals and Students' Learning Outcomes

ERIC Educational Resources Information Center

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

2006-01-01

This study examined the impact of teachers' use of fear appeals and efficacy statements on student affective learning, motivation, likelihood of taking a course with the instructor, and likelihood of visiting with the instructor for help. The results suggest that fear and efficacy interact to more positively influence students' perceptions of…

Opioid receptors mediate direct predictive fear learning: evidence from one-trial blocking.

PubMed

Cole, Sindy; McNally, Gavan P

2007-04-01

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

Time Determines the Neural Circuit Underlying Associative Fear Learning

PubMed Central

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

2011-01-01

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

Deficient inhibitory processing in trait anxiety: Evidence from context-dependent fear learning, extinction recall and renewal.

PubMed

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

2015-10-01

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

Social learning of fear and safety is determined by the demonstrator's racial group.

PubMed

Golkar, Armita; Castro, Vasco; Olsson, Andreas

2015-01-01

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

Modeling startle eyeblink electromyogram to assess fear learning.

PubMed

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

2017-02-01

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

Age-Dependent Deficits in Fear Learning in Heterozygous BDNF Knock-Out Mice

ERIC Educational Resources Information Center

Endres, Thomas; Lessmann, Volkmar

2012-01-01

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

Fear learning circuitry is biased toward generalization of fear associations in posttraumatic stress disorder

PubMed Central

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

2015-01-01

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

Vicarious learning of children's social-anxiety-related fear beliefs and emotional Stroop bias.

PubMed

Askew, Chris; Hagel, Anna; Morgan, Julie

2015-08-01

Models of social anxiety suggest that negative social experiences contribute to the development of social anxiety, and this is supported by self-report research. However, there is relatively little experimental evidence for the effects of learning experiences on social cognitions. The current study examined the effect of observing a social performance situation with a negative outcome on children's (8 to 11 years old) fear-related beliefs and cognitive processing. Two groups of children were each shown 1 of 2 animated films of a person trying to score in basketball while being observed by others; in 1 film, the outcome was negative, and in the other, it was neutral. Children's fear-related beliefs about performing in front of others were measured before and after the film and children were asked to complete an emotional Stroop task. Results showed that social fear beliefs increased for children who saw the negative social performance film. In addition, these children showed an emotional Stroop bias for social-anxiety-related words compared to children who saw the neutral film. The findings have implications for our understanding of social anxiety disorder and suggest that vicarious learning experiences in childhood may contribute to the development of social anxiety. (c) 2015 APA, all rights reserved).

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

ERIC Educational Resources Information Center

Cole, Sindy; McNally, Gavan P.

2007-01-01

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

Learned Helplessness and "Fear of Success" in College Women.

ERIC Educational Resources Information Center

Ris, Martin D.; Woods, Donald J.

1983-01-01

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

Threatening social context facilitates pain-related fear learning.

PubMed

Karos, Kai; Meulders, Ann; Vlaeyen, Johan W S

2015-03-01

This study investigated the effects of a threatening and a safe social context on learning pain-related fear, a key factor in the development and maintenance of chronic pain. We measured self-reported pain intensity, pain expectancy, pain-related fear (verbal ratings and eyeblink startle responses), and behavioral measures of avoidance (movement-onset latency and duration) using an established differential voluntary movement fear conditioning paradigm. Participants (N = 42) performed different movements with a joystick: during fear acquisition, movement in one direction (CS+) was followed by a painful stimulus (pain-US) whereas movement in another direction (CS-) was not. For participants in the threat group, an angry face was continuously presented in the background during the task, whereas in the safe group, a happy face was presented. During the extinction phase the pain-US was omitted. As compared to the safe social context, a threatening social context led to increased contextual fear and facilitated differentiation between CS+ and CS- movements regarding self-reported pain expectancy, fear of pain, eyeblink startle responses, and movement-onset latency. In contrast, self-reported pain intensity was not affected by social context. These data support the modulation of pain-related fear by social context. A threatening social context leads to stronger acquisition of (pain-related) fear and simultaneous contextual fear but does not affect pain intensity ratings. This knowledge may aid in the prevention of chronic pain and anxiety disorders and shows that social context might modulate pain-related fear without immediately affecting pain intensity itself. Copyright © 2015 American Pain Society. Published by Elsevier Inc. All rights reserved.

The Future of Contextual Fear Learning for PTSD Research: A Methodological Review of Neuroimaging Studies.

PubMed

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

2017-10-21

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

Associative learning versus fear habituation as predictors of long-term extinction retention.

PubMed

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

2017-06-01

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

GABAergic interneurons: The orchestra or the conductor in fear learning and memory?

PubMed

Lucas, Elizabeth K; Clem, Roger L

2017-12-02

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

Matrix metalloproteinase (MMP) 9 transcription in mouse brain induced by fear learning.

PubMed

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

2013-07-19

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

Lmo4 in the Basolateral Complex of the Amygdala Modulates Fear Learning

PubMed Central

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

2012-01-01

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

Fear Conditioning in an Abdominal Pain Model: Neural Responses during Associative Learning and Extinction in Healthy Subjects

PubMed Central

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

2013-01-01

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

Learning and Judgment Can Be Affected by Predisposed Fearfulness in Laying Hens

PubMed Central

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

2017-01-01

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

Matrix Metalloproteinase (MMP) 9 Transcription in Mouse Brain Induced by Fear Learning*

PubMed Central

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

2013-01-01

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

Learned together, extinguished apart: reducing fear to complex stimuli

PubMed Central

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

2013-01-01

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

Persistence of Amygdala-Hippocampal Connectivity and Multi-Voxel Correlation Structures During Awake Rest After Fear Learning Predicts Long-Term Expression of Fear.

PubMed

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

2017-05-01

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

Fear learning and memory across adolescent development Hormones and Behavior Special Issue: Puberty and Adolescence

PubMed Central

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

2013-01-01

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

Fear learning and memory across adolescent development: Hormones and Behavior Special Issue: Puberty and Adolescence.

PubMed

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

2013-07-01

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

Combined effects of complex magnetic fields and agmatine for contextual fear learning deficits in rats.

PubMed

McKay, B E; Persinger, M A

2003-04-18

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

Gradients of fear: How perception influences fear generalization.

PubMed

Struyf, Dieter; Zaman, Jonas; Hermans, Dirk; Vervliet, Bram

2017-06-01

The current experiment investigated whether overgeneralization of fear could be due to an inability to perceptually discriminate the initial fear-evoking stimulus from similar stimuli, as fear learning-induced perceptual impairments have been reported but their influence on generalization gradients remain to be elucidated. Three hundred and sixty-eight healthy volunteers participated in a differential fear conditioning paradigm with circles of different sizes as conditioned stimuli (CS), of which one was paired to an aversive IAPS picture. During generalization, each subject was presented with one of 10 different sized circles including the CSs, and were asked to categorize the stimulus as either a CS or as novel after fear responses were recorded. Linear mixed models were used to investigate differences in fear generalization gradients depending on the participant's perception of the test stimulus. We found that the incorrect perception of a novel stimulus as the initial fear-evoking stimulus strongly boosted fear responses. The current findings demonstrate that a significant number of novel stimuli used to assess generalization are incorrectly identified as the initial fear-evoking stimulus, providing a perceptual account for the observed overgeneralization in panic and anxiety disorders. Accordingly, enhancing perceptual processing may be a promising treatment for targeting excessive fear generalization. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

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

PubMed

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

2016-12-01

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

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

PubMed

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

2015-05-01

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

Does a child's fear of needles decrease through a learning event with needles?

PubMed

Kajikawa, Natsuki; Maeno, Takami; Maeno, Tetsuhiro

2014-09-01

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

Stress-enhanced fear learning in rats is resistant to the effects of immediate massed extinction

PubMed Central

Long, Virginia A.; Fanselow, Michael S.

2014-01-01

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

Conditioned social dominance threat: observation of others’ social dominance biases threat learning

PubMed Central

Molapour, Tanaz; Olsson, Andreas

2016-01-01

Social groups are organized along dominance hierarchies, which determine how we respond to threats posed by dominant and subordinate others. The persuasive impact of these dominance threats on mental and physical well-being has been well described but it is unknown how dominance rank of others bias our experience and learning in the first place. We introduce a model of conditioned social dominance threat in humans, where the presence of a dominant other is paired with an aversive event. Participants first learned about the dominance rank of others by observing their dyadic confrontations. During subsequent fear learning, the dominant and subordinate others were equally predictive of an aversive consequence (mild electric shock) to the participant. In three separate experiments, we show that participants’ eye-blink startle responses and amygdala reactivity adaptively tracked dominance of others during observation of confrontation. Importantly, during fear learning dominant vs subordinate others elicited stronger and more persistent learned threat responses as measured by physiological arousal and amygdala activity. Our results characterize the neural basis of learning through observing conflicts between others, and how this affects subsequent learning through direct, personal experiences. PMID:27217107

Inhibiting corticosterone synthesis during fear memory formation exacerbates cued fear extinction memory deficits within the single prolonged stress model.

PubMed

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

2015-01-01

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

Sex differences in learned fear expression and extinction involve altered gamma oscillations in medial prefrontal cortex.

PubMed

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

2016-11-01

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

The time course of location-avoidance learning in fear of spiders.

PubMed

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

2016-01-01

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

Attentional Control and Fear Extinction in Subclinical Fear: An Exploratory Study

PubMed Central

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

2017-01-01

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

Increased anxiety but normal fear and safety learning in orexin-deficient mice.

PubMed

Khalil, Radwa; Fendt, Markus

2017-03-01

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

The prelimbic cortex directs attention toward predictive cues during fear learning.

PubMed

Sharpe, Melissa J; Killcross, Simon

2015-06-01

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

Conditioned social dominance threat: observation of others' social dominance biases threat learning.

PubMed

Haaker, Jan; Molapour, Tanaz; Olsson, Andreas

2016-10-01

Social groups are organized along dominance hierarchies, which determine how we respond to threats posed by dominant and subordinate others. The persuasive impact of these dominance threats on mental and physical well-being has been well described but it is unknown how dominance rank of others bias our experience and learning in the first place. We introduce a model of conditioned social dominance threat in humans, where the presence of a dominant other is paired with an aversive event. Participants first learned about the dominance rank of others by observing their dyadic confrontations. During subsequent fear learning, the dominant and subordinate others were equally predictive of an aversive consequence (mild electric shock) to the participant. In three separate experiments, we show that participants' eye-blink startle responses and amygdala reactivity adaptively tracked dominance of others during observation of confrontation. Importantly, during fear learning dominant vs subordinate others elicited stronger and more persistent learned threat responses as measured by physiological arousal and amygdala activity. Our results characterize the neural basis of learning through observing conflicts between others, and how this affects subsequent learning through direct, personal experiences. © The Author (2016). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

Retrieval cues that trigger reconsolidation of associative fear memory are not necessarily an exact replica of the original learning experience.

PubMed

Soeter, Marieke; Kindt, Merel

2015-01-01

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

Seeing fearful body language rapidly freezes the observer's motor cortex.

PubMed

Borgomaneri, Sara; Vitale, Francesca; Gazzola, Valeria; Avenanti, Alessio

2015-04-01

Fearful body language is a salient signal alerting the observer to the presence of a potential threat in the surrounding environment. Although detecting potential threats may trigger an immediate reduction of motor output in animals (i.e., freezing behavior), it is unclear at what point in time similar reductions occur in the human motor cortex and whether they originate from excitatory or inhibitory processes. Using single-pulse and paired-pulse transcranial magnetic stimulation (TMS), here we tested the hypothesis that the observer's motor cortex implements extremely fast suppression of motor readiness when seeing emotional bodies - and fearful body expressions in particular. Participants observed pictures of body postures and categorized them as happy, fearful or neutral while receiving TMS over the right or left motor cortex at 100-125 msec after picture onset. In three different sessions, we assessed corticospinal excitability, short intracortical inhibition (SICI) and intracortical facilitation (ICF). Independently of the stimulated hemisphere and the time of the stimulation, watching fearful bodies suppressed ICF relative to happy and neutral body expressions. Moreover, happy expressions reduced ICF relative to neutral actions. No changes in corticospinal excitability or SICI were found during the task. These findings show extremely rapid bilateral modulation of the motor cortices when seeing emotional bodies, with stronger suppression of motor readiness when seeing fearful bodies. Our results provide neurophysiological support for the evolutionary notions that emotion perception is inherently linked to action systems and that fear-related cues induce an urgent mobilization of motor reactions. Copyright © 2015 Elsevier Ltd. All rights reserved.

Contextual Influences on Concordance between Maternal Report and Laboratory Observation of Toddler Fear

PubMed Central

Kiel, Elizabeth J.; Hummel, Alexandra C.

2016-01-01

Emotion and temperament researchers have faced an enduring issue of how to best measure children’s tendencies to express specific emotions. Inconsistencies between laboratory observation and parental report have made it challenging for researchers to determine the utility of these different forms of measurement. The current study examined the effect of laboratory episode characteristics (i.e., threat-level of the episode, maternal involvement) on concordance between maternal report and laboratory observation of toddler fear. The sample included 111 mother-toddler dyads who participated in a laboratory assessment when toddlers were approximately 24-months-old. Toddler fear was assessed both via maternal report and observation from a number of laboratory episodes that varied in their level of threat and whether mothers were free or constrained in their involvement in the task. Results indicated that maternal report related to the observed fear composites for low-threat, but not high-threat episodes. On the other hand, maternal involvement in the laboratory episodes did not moderate the relation between maternal report and laboratory observation of fear. These results suggest that the threat-level of laboratory episodes designed to elicit fear, but not maternal involvement in these episodes, may be important to take into consideration when assessing their relation to maternal report of fear and fearful temperament. PMID:27606826

Sensitive periods in affective development: nonlinear maturation of fear learning.

PubMed

Hartley, Catherine A; Lee, Francis S

2015-01-01

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

Sensitive Periods in Affective Development: Nonlinear Maturation of Fear Learning

PubMed Central

Hartley, Catherine A; Lee, Francis S

2015-01-01

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

The Role of BDNF in the Development of Fear Learning.

PubMed

Dincheva, Iva; Lynch, Niccola B; Lee, Francis S

2016-10-01

Brain-derived neurotrophic factor (BDNF) is a growth factor that is dynamically expressed in the brain across postnatal development, regulating neuronal differentiation and synaptic plasticity. The neurotrophic hypothesis of psychiatric mood disorders postulates that in the adult brain, decreased BDNF levels leads to altered neural plasticity, contributing to disease. Although BDNF has been established as a key factor regulating the critical period plasticity in the developing visual system, it has recently been shown to also play a role in fear circuitry maturation, which has implications for the emergence of fear-related mood disorders. This review provides a detailed overview of developmental changes in expression of BDNF isoforms, as well as their receptors across postnatal life. In addition, recent developmental studies utilizing a genetic BDNF single nucleotide polymorphism (Val66Met) knock-in mouse highlight the impact of BDNF on fear learning during a sensitive period spanning the transition into adolescent time frame. We hypothesize that BDNF in the developing brain regulates fear circuit plasticity during a sensitive period in early adolescence, and alterations in BDNF expression (genetic or environmental) have a persistent impact on fear behavior and fear-related disorders. © 2016 Wiley Periodicals, Inc.

The role of nucleus accumbens shell in learning about neutral versus excitatory stimuli during Pavlovian fear conditioning.

PubMed

Bradfield, Laura A; McNally, Gavan P

2010-07-01

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

Fears and Phobias

MedlinePlus

... a strong swimmer might have a fear of deep water. In this case, the fear is helpful because it cautions the person to stay safe. Someone could overcome this fear by learning how to swim safely. A fear can be ...

Impaired fear extinction learning in adult heterozygous BDNF knock-out mice.

PubMed

Psotta, Laura; Lessmann, Volkmar; Endres, Thomas

2013-07-01

Brain-derived neurotrophic factor (BDNF) is a crucial regulator of neuroplasticity, which underlies learning and memory processes in different brain areas. To investigate the role of BDNF in the extinction of amygdala-dependent cued fear memories, we analyzed fear extinction learning in heterozygous BDNF knock-out mice, which possess a reduction of endogenous BDNF protein levels to ~50% of wild-type animals. Since BDNF expression has been shown to decline with aging of animals, we tested the performance in extinction learning of these mice at 2 months (young adults) and 7 months (older adults) of age. The present study shows that older adult heterozygous BDNF knock-out mice, which have a chronic 50% lack of BDNF, also possess a deficit in the acquisition of extinction memory, while extinction learning remains unaffected in young adult heterozygous BDNF knock-out mice. This deficit in extinction learning is accompanied by a reduction of BDNF protein in the hippocampus, amygdala and the prefrontal cortex. Copyright © 2013 Elsevier Inc. All rights reserved.

Do Learners Fear More than Fear Itself: The Role of Fear in Law Students Educational Experiences

ERIC Educational Resources Information Center

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

2014-01-01

While previous research has examined the various relationships between fear and learning in K-12 academic settings, the relationship is surprisingly unexplored amongst law students. Using a descriptive qualitative approach, we examine the role fear plays in law students' learning experiences. Through a series of semi-structured interviews a few…

Adolescent social defeat alters N-methyl-D-aspartic acid receptor expression and impairs fear learning in adulthood.

PubMed

Novick, Andrew M; Mears, Mackenzie; Forster, Gina L; Lei, Yanlin; Tejani-Butt, Shanaz M; Watt, Michael J

2016-05-01

Repeated social defeat of adolescent male rats results in adult mesocortical dopamine hypofunction, impaired working memory, and increased contextual anxiety-like behavior. Given the role of glutamate in dopamine regulation, cognition, and fear and anxiety, we investigated potential changes to N-methyl-D-aspartic acid (NMDA) receptors following adolescent social defeat. As both NMDA receptors and mesocortical dopamine are implicated in the expression and extinction of conditioned fear, a separate cohort of rats was challenged with a classical fear conditioning paradigm to investigate whether fear learning is altered by adolescent defeat. Quantitative autoradiography was used to measure 3H-MK-801 binding to NMDA receptors in regions of the medial prefrontal cortex, caudate putamen, nucleus accumbens, amygdala and hippocampus. Assessment of fear learning was achieved using an auditory fear conditioning paradigm, with freezing toward the auditory tone used as a measure of conditioned fear. Compared to controls, adolescent social defeat decreased adult NMDA receptor expression in the infralimbic region of the prefrontal cortex and central amygdala, while increasing expression in the CA3 region of the hippocampus. Previously defeated rats also displayed decreased conditioned freezing during the recall and first extinction periods, which may be related to the observed decreases and increases in NMDA receptors within the central amygdala and CA3, respectively. The alteration in NMDA receptors seen following adolescent social defeat suggests that dysfunction of glutamatergic systems, combined with mesocortical dopamine deficits, likely plays a role in the some of the long-term behavioral consequences of social stressors in adolescence seen in both preclinical and clinical studies. Copyright © 2016 Elsevier B.V. All rights reserved.

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

PubMed Central

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

2017-01-01

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

Biologically based neural circuit modelling for the study of fear learning and extinction

NASA Astrophysics Data System (ADS)

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

2016-11-01

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

Where There is Smoke There is Fear-Impaired Contextual Inhibition of Conditioned Fear in Smokers.

PubMed

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

2017-07-01

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

Biased Intensity Judgements of Visceral Sensations After Learning to Fear Visceral Stimuli: A Drift Diffusion Approach.

PubMed

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

2017-10-01

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

A "Fear" Studies Perspective and Critique: Analyzing English and Stengel's Progressive Study of Fear and Learning in "Education Theory." Technical Paper No. 37

ERIC Educational Resources Information Center

Fisher, R. Michael

2011-01-01

The author critiques the progressive approach of two contemporary educational philosophers (English and Stengel) on the topic of fear and learning. Using a postmodern integral approach, this article examines the tendency of reductionism, individualism, and psychologism as part of a hegemonic liberalism and modernism in discourses on fear and…

Effects of chronic stress in adolescence on learned fear, anxiety, and synaptic transmission in the rat prelimbic cortex.

PubMed

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

2014-02-01

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

Plasticity of Fear and Safety Neurons of the Amygdala in Response to Fear Extinction

PubMed Central

Sangha, Susan

2015-01-01

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

Early life programming of fear conditioning and extinction in adult male rats.

PubMed

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

2009-12-28

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

Effects of sleep on memory for conditioned fear and fear extinction

PubMed Central

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

2015-01-01

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

Effects of sleep on memory for conditioned fear and fear extinction.

PubMed

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

2015-07-01

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

Conceptual Similarity Promotes Generalization of Higher Order Fear Learning

ERIC Educational Resources Information Center

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

2011-01-01

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

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

PubMed

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

2017-04-01

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

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

PubMed Central

2014-01-01

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

Inhibition of amygdaloid dopamine D2 receptors impairs emotional learning measured with fear-potentiated startle.

PubMed

Greba, Q; Gifkins, A; Kokkinidis, L

2001-04-27

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

Fear acquisition and liking of out-group and in-group members: Learning bias or attention?

PubMed

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

2017-10-01

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

2-arachidonoylglycerol signaling impairs short-term fear extinction

PubMed Central

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

2016-01-01

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

HDAC I inhibition in the dorsal and ventral hippocampus differentially modulates predator-odor fear learning and generalization.

PubMed

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

2015-01-01

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

Preventing the return of fear using reconsolidation updating and methylene blue is differentially dependent on extinction learning

PubMed Central

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

2017-01-01

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

Neurobiology of fear and specific phobias.

PubMed

Garcia, René

2017-09-01

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

Neural circuitry of abdominal pain-related fear learning and reinstatement in irritable bowel syndrome.

PubMed

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

2015-01-01

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

Generalization of Fear to Respiratory Sensations.

PubMed

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

2015-09-01

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

Cholinergic Modulation during Acquisition of Olfactory Fear Conditioning Alters Learning and Stimulus Generalization in Mice

ERIC Educational Resources Information Center

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

2013-01-01

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

Origins of common fears in South African children.

PubMed

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

2008-12-01

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

Activation of BDNF Signaling Prevents the Return of Fear in Female Mice

ERIC Educational Resources Information Center

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

2013-01-01

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

Epigenetic Mechanisms in Learned Fear: Implications for PTSD

PubMed Central

Zovkic, Iva B; Sweatt, J David

2013-01-01

One of the most exciting discoveries in the learning and memory field in the past two decades is the observation that active regulation of gene expression is necessary for experience to trigger lasting functional and behavioral change, in a wide variety of species, including humans. Thus, as opposed to the traditional view of ‘nature' (genes) being separate from ‘nurture' (environment and experience), it is now clear that experience actively drives alterations in central nervous system (CNS) gene expression in an ongoing fashion, and that the resulting transcriptional changes are necessary for experience to trigger altered long-term behavior. In parallel over the past decade, epigenetic mechanisms, including regulation of chromatin structure and DNA methylation, have been shown to be potent regulators of gene transcription in the CNS. In this review, we describe data supporting the hypothesis that epigenetic molecular mechanisms, especially DNA methylation and demethylation, drive long-term behavioral change through active regulation of gene transcription in the CNS. Specifically, we propose that epigenetic molecular mechanisms underlie the formation and stabilization of context- and cue-triggered fear conditioning based in the hippocampus and amygdala, a conclusion reached in a wide variety of studies using laboratory animals. Given the relevance of cued and contextual fear conditioning to post-traumatic stress, by extension we propose that these mechanisms may contribute to post-traumatic stress disorder (PTSD) in humans. Moreover, we speculate that epigenetically based pharmacotherapy may provide a new avenue of drug treatment for PTSD-related cognitive and behavioral function. PMID:22692566

Pituitary adenylate cyclase-activating polypeptide (PACAP) signaling in the prefrontal cortex modulates cued fear learning, but not spatial working memory, in female rats.

PubMed

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

2018-05-01

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

Contextual Change After Fear Acquisition Affects Conditioned Responding and the Time Course of Extinction Learning-Implications for Renewal Research.

PubMed

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

2015-01-01

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

Fear inhibition in high trait anxiety.

PubMed

Kindt, Merel; Soeter, Marieke

2014-01-01

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

Hippocampal Processing of Ambiguity Enhances Fear Memory

PubMed Central

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

2016-01-01

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

Hippocampal Processing of Ambiguity Enhances Fear Memory.

PubMed

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

2017-02-01

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

Effects of chemogenetic excitation or inhibition of the ventrolateral periaqueductal gray on the acquisition and extinction of Pavlovian fear conditioning.

PubMed

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

2017-10-01

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

Disrupted Prediction Error Links Excessive Amygdala Activation to Excessive Fear.

PubMed

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

2016-01-13

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

Maternal buffering of fear-potentiated startle in children and adolescents with trauma exposure.

PubMed

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

2017-02-01

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

Cannabinoid modulation of prefrontal-limbic activation during fear extinction learning and recall in humans

PubMed Central

Rabinak, Christine A.; Angstadt, Mike; Lyons, Maryssa; Mori, Shoko; Milad, Mohammed R.; Liberzon, Israel; Phan, K. Luan

2013-01-01

Pre-extinction administration of ∆9-tetrahydrocannibinol (THC) facilitates recall of extinction in healthy humans, and evidence from animal studies suggest that this likely involves 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 hours 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. PMID:24055595

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…

Context Fear Learning Specifically Activates Distinct Populations of Neurons in Amygdala and Hypothalamus

ERIC Educational Resources Information Center

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

2011-01-01

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

The effect of ketamine on the consolidation and extinction of contextual fear memory

PubMed Central

Thomas, Kerrie L; Hall, Jeremy

2018-01-01

Ketamine, principally an antagonist of N-methyl-ᴅ-aspartate receptors, induces schizophrenia-like symptoms in adult humans, warranting its use in the investigation of psychosis-related phenotypes in animal models. Genomic studies further implicate N-methyl-ᴅ-aspartate receptor-mediated processes in schizophrenia pathology, together with more broadly-defined synaptic plasticity and associative learning processes. Strong pathophysiological links have been demonstrated between fear learning and psychiatric disorders such as schizophrenia. To further investigate the impact of ketamine on associative fear learning, we studied the effects of pre- and post-training ketamine on the consolidation and extinction of contextual fear memory in rats. Administration of 25 mg/kg ketamine prior to fear conditioning did not affect consolidation when potentially confounding effects of state dependency were controlled for. Pre-training ketamine (25 mg/kg) impaired the extinction of the conditioned fear response, which was mirrored with the use of a lower dose (8 mg/kg). Post-training ketamine (25 mg/kg) had no effect on the consolidation or extinction of conditioned fear. These observations implicate processes relating to the extinction of contextual fear memory in the manifestation of ketamine-induced phenotypes, and are consistent with existing hypotheses surrounding abnormal associative learning in schizophrenia. PMID:29338491

Using c-Jun to identify fear extinction learning-specific patterns of neural activity that are affected by single prolonged stress.

PubMed

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

2018-04-02

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

Gut vagal afferents differentially modulate innate anxiety and learned fear.

PubMed

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

2014-05-21

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

The Fear Factor: How It Affects Students Learning to Program in a Tertiary Environment

ERIC Educational Resources Information Center

Rogerson, Christine; Scott, Elsje

2010-01-01

This paper examines how students' experiences of learning to program are affected by feelings of fear, using a phenomenological approach to elicit rich descriptions of personal experiences from the narratives of final year undergraduate students. In the course of reviewing current work concerning learning or teaching programming, certain focal…

Nicotine disrupts safety learning by enhancing fear associated with a safety cue via the dorsal hippocampus.

PubMed

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

2017-07-01

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

Differential influence of social versus isolate housing on vicarious fear learning in adolescent mice.

PubMed

Panksepp, Jules B; Lahvis, Garet P

2016-04-01

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

Social transmission of Pavlovian fear: fear-conditioning by-proxy in related female rats.

PubMed

Jones, Carolyn E; Riha, Penny D; Gore, Andrea C; Monfils, Marie-H

2014-05-01

Pairing a previously neutral conditioned stimulus (CS; e.g., a tone) to an aversive unconditioned stimulus (US; e.g., a foot-shock) leads to associative learning such that the tone alone will elicit a conditioned response (e.g., freezing). Individuals can also acquire fear from a social context, such as through observing the fear expression of a conspecific. In the current study, we examined the influence of kinship/familiarity on social transmission of fear in female rats. Rats were housed in triads with either sisters or non-related females. One rat from each cage was fear conditioned to a tone CS+ shock US. On day two, the conditioned rat was returned to the chamber accompanied by one of her cage mates. Both rats were allowed to behave freely, while the tone was played in the absence of the foot-shock. The previously untrained rat is referred to as the fear-conditioned by-proxy (FCbP) animal, as she would freeze based on observations of her cage-mate's response rather than due to direct personal experience with the foot-shock. The third rat served as a cage-mate control. The third day, long-term memory tests to the CS were performed. Consistent with our previous application of this paradigm in male rats (Bruchey et al. in Behav Brain Res 214(1):80-84, 2010), our results revealed that social interactions between the fear conditioned and FCbP rats on day two contribute to freezing displayed by the FCbP rats on day three. In this experiment, prosocial behavior occurring at the termination of the cue on day two was significantly greater between sisters than their non-sister counterparts, and this behavior resulted in increased freezing on day three. Our results suggest that familiarity and/or kinship influences the social transmission of fear in female rats.

Dissociation of Learned Helplessness and Fear Conditioning in Mice: A Mouse Model of Depression

PubMed Central

Landgraf, Dominic; Long, Jaimie; Der-Avakian, Andre; Streets, Margo; Welsh, David K.

2015-01-01

The state of being helpless is regarded as a central aspect of depression, and therefore the learned helplessness paradigm in rodents is commonly used as an animal model of depression. The term ‘learned helplessness’ refers to a deficit in escaping from an aversive situation after an animal is exposed to uncontrollable stress specifically, with a control/comparison group having been exposed to an equivalent amount of controllable stress. A key feature of learned helplessness is the transferability of helplessness to different situations, a phenomenon called ‘trans-situationality’. However, most studies in mice use learned helplessness protocols in which training and testing occur in the same environment and with the same type of stressor. Consequently, failures to escape may reflect conditioned fear of a particular environment, not a general change of the helpless state of an animal. For mice, there is no established learned helplessness protocol that includes the trans-situationality feature. Here we describe a simple and reliable learned helplessness protocol for mice, in which training and testing are carried out in different environments and with different types of stressors. We show that with our protocol approximately 50% of mice develop learned helplessness that is not attributable to fear conditioning. PMID:25928892

Dissociation of learned helplessness and fear conditioning in mice: a mouse model of depression.

PubMed

Landgraf, Dominic; Long, Jaimie; Der-Avakian, Andre; Streets, Margo; Welsh, David K

2015-01-01

The state of being helpless is regarded as a central aspect of depression, and therefore the learned helplessness paradigm in rodents is commonly used as an animal model of depression. The term 'learned helplessness' refers to a deficit in escaping from an aversive situation after an animal is exposed to uncontrollable stress specifically, with a control/comparison group having been exposed to an equivalent amount of controllable stress. A key feature of learned helplessness is the transferability of helplessness to different situations, a phenomenon called 'trans-situationality'. However, most studies in mice use learned helplessness protocols in which training and testing occur in the same environment and with the same type of stressor. Consequently, failures to escape may reflect conditioned fear of a particular environment, not a general change of the helpless state of an animal. For mice, there is no established learned helplessness protocol that includes the trans-situationality feature. Here we describe a simple and reliable learned helplessness protocol for mice, in which training and testing are carried out in different environments and with different types of stressors. We show that with our protocol approximately 50% of mice develop learned helplessness that is not attributable to fear conditioning.

Potentiation of GluN2C/D NMDA receptor subtypes in the amygdala facilitates the retention of fear and extinction learning in mice.

PubMed

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

2014-02-01

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

It's time to fear! Interval timing in odor fear conditioning in rats

PubMed Central

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

2013-01-01

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

Acute and chronic effects of selective serotonin reuptake inhibitor treatment on fear conditioning: implications for underlying fear circuits.

PubMed

Burghardt, N S; Bauer, E P

2013-09-05

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

AX+, BX- Discrimination Learning in the Fear-Potentiated Startle Paradigm: Possible Relevance to Inhibitory Fear Learning in Extinction

ERIC Educational Resources Information Center

Myers, Karyn M.; Davis, Michael

2004-01-01

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

Developmental aspects of fear: Comparing the acquisition and generalization of conditioned fear in children and adults.

PubMed

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

2016-05-01

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

Impaired fear inhibition learning predicts the persistence of symptoms of posttraumatic stress disorder (PTSD).

PubMed

Sijbrandij, Marit; Engelhard, Iris M; Lommen, Miriam J J; Leer, Arne; Baas, Johanna M P

2013-12-01

Recent cross-sectional studies have shown that the inability to suppress fear under safe conditions is a key problem in people with posttraumatic stress disorder (PTSD). The current longitudinal study examined whether individual differences in fear inhibition predict the persistence of PTSD symptoms. Approximately 2 months after deployment to Afghanistan, 144 trauma-exposed Dutch soldiers were administered a conditional discrimination task (AX+/BX-). In this paradigm, A, B, and X are neutral stimuli. X combined with A is paired with a shock (AX+ trials); X combined with B is not (BX- trials). Fear inhibition was measured (AB trials). Startle electromyogram responses and shock expectancy ratings were recorded. PTSD symptoms were measured at 2 months and at 9 months after deployment. Results showed that greater startle responses during AB trials in individuals who discriminated between danger (AX+) and safety (BX-) during conditioning, predicted higher PTSD symptoms at 2 months and 9 months post-deployment. The predictive effect at 9 months remained significant after controlling for critical incidents during previous deployments and PTSD symptoms at 2 months. Responses to AX+ or BX- trials, or discrimination learning (AX+ minus BX-) did not predict PTSD symptoms. It is concluded that impaired fear inhibition learning seems to be involved in the persistence of PTSD symptoms. Copyright © 2013 Elsevier Ltd. All rights reserved.

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…

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

A dissociation between renewal and contextual fear conditioning in juvenile rats.

PubMed

Park, Chun Hui J; Ganella, Despina E; Kim, Jee Hyun

2017-05-01

We investigated whether juvenile rats do not express renewal following extinction of conditioned fear due to their inability to form a long-term contextual fear memory. In experiment 1, postnatal day (P) 18 and 25 rats received 3 white-noise and footshock pairings, followed by 60 white-noise alone presentations the next day. When tested in a different context to extinction, P25 rats displayed renewal whereas P18 rats did not. Experiments 2A and 2B surprisingly showed that P18 and P25 rats do not show differences in contextual and cued fear, regardless of the conditioning-test intervals and the number of white-noise-footshock pairings received. Finally, we observed age differences in contextual fear when P25 rats were weaned at P21 in experiment 3. These results indicate that the developmental dissociation observed in renewal of extinguished fear is not related to the widely believed late emergence of contextual fear learning. © 2017 Wiley Periodicals, Inc.

Prefrontal NMDA receptors expressed in excitatory neurons control fear discrimination and fear extinction.

PubMed

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

2015-03-01

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

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

Stress enables reinforcement-elicited serotonergic consolidation of fear memory

PubMed Central

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

2015-01-01

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

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

PubMed

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

2012-06-01

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

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

The central amygdala circuits in fear regulation

NASA Astrophysics Data System (ADS)

Li, Bo

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

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

Systemic or Intra-Amygdala Infusion of the Benzodiazepine, Midazolam, Impairs Learning, but Facilitates Re-Learning to Inhibit Fear Responses in Extinction

ERIC Educational Resources Information Center

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

2010-01-01

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

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

PubMed Central

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

2011-01-01

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

Fear conditioning and extinction in anxiety- and depression-prone persons.

PubMed

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

2015-01-01

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

The inhibition of acquired fear.

PubMed

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

2004-01-01

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

Developmental emergence of fear/threat learning: neurobiology, associations and timing.

PubMed

Tallot, L; Doyère, V; Sullivan, R M

2016-01-01

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

Developmental emergence of fear/threat learning: neurobiology, associations and timing

PubMed Central

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

2016-01-01

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

Posterior insular cortex is necessary for conditioned inhibition of fear.

PubMed

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

2016-10-01

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

Posterior insular cortex is necessary for conditioned inhibition of fear

PubMed Central

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

2016-01-01

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

How trait anxiety, interpretation bias and memory affect acquired fear in children learning about new animals.

PubMed

Field, Zoë C; Field, Andy P

2013-06-01

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

Social inference and social anxiety: evidence of a fear-congruent self-referential learning bias.

PubMed

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

2012-12-01

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

Genetic contributions of the serotonin transporter to social learning of fear and economic decision making.

PubMed

Crişan, Liviu G; Pana, Simona; Vulturar, Romana; Heilman, Renata M; Szekely, Raluca; Druğa, Bogdan; Dragoş, Nicolae; Miu, Andrei C

2009-12-01

Serotonin (5-HT) modulates emotional and cognitive functions such as fear conditioning (FC) and decision making. This study investigated the effects of a functional polymorphism in the regulatory region (5-HTTLPR) of the human 5-HT transporter (5-HTT) gene on observational FC, risk taking and susceptibility to framing in decision making under uncertainty, as well as multidimensional anxiety and autonomic control of the heart in healthy volunteers. The present results indicate that in comparison to the homozygotes for the long (l) version of 5-HTTLPR, the carriers of the short (s) version display enhanced observational FC, reduced financial risk taking and increased susceptibility to framing in economic decision making. We also found that s-carriers have increased trait anxiety due to threat in social evaluation, and ambiguous threat perception. In addition, s-carriers also show reduced autonomic control over the heart, and a pattern of reduced vagal tone and increased sympathetic activity in comparison to l-homozygotes. This is the first genetic study that identifies the association of a functional polymorphism in a key neurotransmitter-related gene with complex social-emotional and cognitive processes. The present set of results suggests an endophenotype of anxiety disorders, characterized by enhanced social learning of fear, impaired decision making and dysfunctional autonomic activity.

Genetic contributions of the serotonin transporter to social learning of fear and economic decision making

PubMed Central

Crişan, Liviu G.; Pană, Simona; Vulturar, Romana; Heilman, Renata M.; Szekely, Raluca; Drugă, Bogdan; Dragoş, Nicolae

2009-01-01

Serotonin (5-HT) modulates emotional and cognitive functions such as fear conditioning (FC) and decision making. This study investigated the effects of a functional polymorphism in the regulatory region (5-HTTLPR) of the human 5-HT transporter (5-HTT) gene on observational FC, risk taking and susceptibility to framing in decision making under uncertainty, as well as multidimensional anxiety and autonomic control of the heart in healthy volunteers. The present results indicate that in comparison to the homozygotes for the long (l) version of 5-HTTLPR, the carriers of the short (s) version display enhanced observational FC, reduced financial risk taking and increased susceptibility to framing in economic decision making. We also found that s-carriers have increased trait anxiety due to threat in social evaluation, and ambiguous threat perception. In addition, s-carriers also show reduced autonomic control over the heart, and a pattern of reduced vagal tone and increased sympathetic activity in comparison to l-homozygotes. This is the first genetic study that identifies the association of a functional polymorphism in a key neurotransmitter-related gene with complex social–emotional and cognitive processes. The present set of results suggests an endophenotype of anxiety disorders, characterized by enhanced social learning of fear, impaired decision making and dysfunctional autonomic activity. PMID:19535614

Recognizing Student Fear: The Elephant in the Classroom

ERIC Educational Resources Information Center

Bledsoe, T. Scott; Baskin, Janice J.

2014-01-01

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

Different role of the ventral medial prefrontal cortex on modulation of innate and associative learned fear.

PubMed

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

2010-12-15

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

Role of the amygdala GABA-A receptors in ACPA-induced deficits during conditioned fear learning.

PubMed

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

2017-05-01

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

The potential of epigenetics in stress-enhanced fear learning models of PTSD

PubMed Central

Blouin, Ashley M.; Sillivan, Stephanie E.; Joseph, Nadine F.

2016-01-01

Prolonged distress and dysregulated memory processes are the core features of post-traumatic stress disorder (PTSD) and represent the debilitating, persistent nature of the illness. However, the neurobiological mechanisms underlying the expression of these symptoms are challenging to study in human patients. Stress-enhanced fear learning (SEFL) paradigms, which encompass both stress and memory components in rodents, are emerging as valuable preclinical models of PTSD. Rodent models designed to study the long-term mechanisms of either stress or fear memory alone have identified a critical role for numerous epigenetic modifications to DNA and histone proteins. However, the epigenetic modifications underlying SEFL remain largely unknown. This review will provide a brief overview of the epigenetic modifications implicated in stress and fear memory independently, followed by a description of existing SEFL models and the few epigenetic mechanisms found to date to underlie SEFL. The results of the animal studies discussed here highlight neuroepigenetics as an essential area for future research in the context of PTSD through SEFL studies, because of its potential to identify novel candidates for neurotherapeutics targeting stress-induced pathogenic memories. PMID:27634148

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.

The Effect of D-Cycloserine on Immediate vs. Delayed Extinction of Learned Fear

ERIC Educational Resources Information Center

Langton, Julia M.; Richardson, Rick

2010-01-01

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

The ventromedial hypothalamus mediates predator fear memory

PubMed Central

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

2016-01-01

The amygdala has been shown to be essential for the processing of acute and learned fear across animal species. However, the downstream neural circuits that mediate these fear responses differ depending on the nature of the threat, with separate pathways identified for predator, conspecific, and physically harmful threats. In particular, the dorsomedial part of the ventromedial hypothalamus (VHMdm) is critical for the expression of defensive responses to predator. Here, we tested the hypothesis that this circuit also participates in predator fear memory by transient pharmacogenetic inhibition of VMHdm and its downstream effector, the dorsal periaqueductal grey, during predator fear learning in the mouse. Our data demonstrate that neural activity in VMHdm is required for both the acquisition and recall of predator fear memory, while that of its downstream effector, the dorsal periaqueductal grey, is required only for the acute expression of fear. These findings are consistent with a role for the medial hypothalamus in encoding an internal emotional state of fear. PMID:26991018

D-cycloserine enhances generalization of fear extinction in children.

PubMed

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

2015-06-01

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

G protein-gated K+ channel ablation in forebrain pyramidal neurons selectively impairs fear learning

PubMed Central

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

2015-01-01

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

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

Coming to terms with fear

PubMed Central

LeDoux, Joseph E.

2014-01-01

The brain mechanisms of fear have been studied extensively using Pavlovian fear conditioning, a procedure that allows exploration of how the brain learns about and later detects and responds to threats. However, mechanisms that detect and respond to threats are not the same as those that give rise to conscious fear. This is an important distinction because symptoms based on conscious and nonconscious processes may be vulnerable to different predisposing factors and may also be treatable with different approaches in people who suffer from uncontrolled fear or anxiety. A conception of so-called fear conditioning in terms of circuits that operate nonconsciously, but that indirectly contribute to conscious fear, is proposed as way forward. PMID:24501122

Animal Models of Fear Relapse

PubMed Central

Goode, Travis D.; Maren, Stephen

2014-01-01

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

Administration of riluzole to the basolateral amygdala facilitates fear extinction in rats.

PubMed

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

2018-01-15

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

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.

Experience-dependent modification of a central amygdala fear circuit

PubMed Central

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

2013-01-01

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

Flexibility in the face of fear: Hippocampal-prefrontal regulation of fear and avoidance.

PubMed

Moscarello, Justin M; Maren, Stephen

2018-02-01

Generating appropriate defensive behaviors in the face of threat is essential to survival. Although many of these behaviors are 'hard-wired', they are also flexible. For example, Pavlovian fear conditioning generates learned defensive responses, such as conditioned freezing, that can be suppressed through extinction. The expression of extinguished responses is highly context-dependent, allowing animals to engage behavioral responses appropriate to the contexts in which threats are encountered. Likewise, animals and humans will avoid noxious outcomes if given the opportunity. In instrumental avoidance learning, for example, animals overcome conditioned defensive responses, including freezing, in order to actively avoid aversive stimuli. Recent work has greatly advanced understanding of the neural basis of these phenomena and has revealed common circuits involved in the regulation of fear. Specifically, the hippocampus and medial prefrontal cortex play pivotal roles in gating fear reactions and instrumental actions, mediated by the amygdala and nucleus accumbens, respectively. Because an inability to adaptively regulate fear and defensive behavior is a central component of many anxiety disorders, the brain circuits that promote flexible responses to threat are of great clinical significance.

Social Modulation of Associative Fear Learning by Pheromone Communication

ERIC Educational Resources Information Center

Bredy, Timothy W.; Barad, Mark

2009-01-01

Mice communicate through visual, vocal, and olfactory cues that influence innate, nonassociative behavior. We here report that exposure to a recently fear-conditioned familiar mouse impairs acquisition of conditioned fear and facilitates fear extinction, effects mimicked by both an olfactory chemosignal emitted by a recently fear-conditioned…

Nicotine Modulation of Fear Memories and Anxiety: Implications for Learning and Anxiety Disorders

PubMed Central

Kutlu, Munir Gunes; Gould, Thomas J.

2015-01-01

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

Strain-dependent Effects of Acute, Chronic, and Withdrawal from Chronic Nicotine on Fear Conditioning

PubMed Central

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

2013-01-01

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

Does fear extinction in the laboratory predict outcomes of exposure therapy? A treatment analog study.

PubMed

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

2017-11-01

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

Chronic Nicotine Treatment During Adolescence Attenuates the Effects of Acute Nicotine in Adult Contextual Fear Learning.

PubMed

Holliday, Erica D; Gould, Thomas J

2017-01-01

Adolescent onset of nicotine abuse is correlated with worse chances at successful abstinence in adulthood. One reason for this may be due to enduring learning deficits resulting from nicotine use during adolescence. Previous work has indicated that chronic nicotine administration beginning in late adolescence (PND38) caused learning deficits in contextual fear when tested in adulthood. The purpose of this study was to determine if chronic nicotine treatment during adolescence would alter sensitivity to nicotine's cognitive enhancing properties in adulthood. C57BL/6J mice received saline or chronic nicotine (12.6mg/kg/day) during adolescence (postnatal day 38) or adulthood (postnatal day 54) for a period of 12 days. Following a 30-day protracted abstinence, mice received either an acute injection of saline or nicotine (0.045, 0.18, and 0.36mg/kg) prior to training and testing a mouse model of contextual fear. It was found that chronic nicotine administration in adult mice did not alter sensitivity to acute nicotine following a protracted abstinence. In adolescent mice, chronic nicotine administration disrupted adult learning and decreased sensitivity to acute nicotine in adulthood as only the highest dose tested (0.36mg/kg) was able to enhance contextual fear learning. These results suggest that adolescent nicotine exposure impairs learning in adulthood, which could increase the risk for continued nicotine use in adulthood by requiring administration of higher doses of nicotine to reverse learning impairments caused by adolescent nicotine exposure. Results from this study add to the growing body of literature suggesting chronic nicotine exposure during adolescence leads to impaired learning in adulthood and demonstrates that nicotine exposure during adolescence attenuates the cognitive enhancing effects of acute nicotine in adulthood, which suggests altered cholinergic function. © The Author 2016. Published by Oxford University Press on behalf of the Society for

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

PubMed

Sengupta, Auntora; McNally, Gavan P

2014-01-01

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

Blockade of Dopamine Activity in the Nucleus Accumbens Impairs Learning Extinction of Conditioned Fear

ERIC Educational Resources Information Center

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

2010-01-01

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

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

Object-location training elicits an overlapping but temporally distinct transcriptional profile from contextual fear conditioning.

PubMed

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

2014-12-01

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

Object-Location Training Elicits an Overlapping but Temporally Distinct Transcriptional Profile from Contextual Fear Conditioning

PubMed Central

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

2014-01-01

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

Selective early-acquired fear memories undergo temporary suppression during adolescence

PubMed Central

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

2011-01-01

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

Persistent Fear and Anxiety Can Affect Young Children's Learning and Development. Working Paper #9

ERIC Educational Resources Information Center

National Scientific Council on the Developing Child, 2010

2010-01-01

Ensuring that young children have safe, secure environments in which to grow, learn, and develop healthy brains and bodies is not only good for the children themselves but also builds a strong foundation for a thriving, prosperous society. Science shows that early exposure to circumstances that produce persistent fear and chronic anxiety can have…

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

IMPAIRED FEAR EXTINCTION ASSOCIATED WITH PTSD INCREASES WITH HOURS-SINCE-WAKING.

PubMed

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

2016-03-01

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

Dorsal periaqueductal gray-amygdala pathway conveys both innate and learned fear responses in rats

PubMed Central

Kim, Eun Joo; Horovitz, Omer; Pellman, Blake A.; Tan, Lancy Mimi; Li, Qiuling; Richter-Levin, Gal; Kim, Jeansok J.

2013-01-01

The periaqueductal gray (PAG) and amygdala are known to be important for defensive responses, and many contemporary fear-conditioning models present the PAG as downstream of the amygdala, directing the appropriate behavior (i.e., freezing or fleeing). However, empirical studies of this circuitry are inconsistent and warrant further examination. Hence, the present study investigated the functional relationship between the PAG and amygdala in two different settings, fear conditioning and naturalistic foraging, in rats. In fear conditioning, electrical stimulation of the dorsal PAG (dPAG) produced unconditional responses (URs) composed of brief activity bursts followed by freezing and 22-kHz ultrasonic vocalization. In contrast, stimulation of ventral PAG and the basolateral amygdalar complex (BLA) evoked freezing and/or ultrasonic vocalization. Whereas dPAG stimulation served as an effective unconditional stimulus for fear conditioning to tone and context conditional stimuli, neither ventral PAG nor BLA stimulation supported fear conditioning. The conditioning effect of dPAG, however, was abolished by inactivation of the BLA. In a foraging task, dPAG and BLA stimulation evoked only fleeing toward the nest. Amygdalar lesion/inactivation blocked the UR of dPAG stimulation, but dPAG lesions did not block the UR of BLA stimulation. Furthermore, in vivo recordings demonstrated that electrical priming of the dPAG can modulate plasticity of subiculum–BLA synapses, providing additional evidence that the amygdala is downstream of the dPAG. These results suggest that the dPAG conveys unconditional stimulus information to the BLA, which directs both innate and learned fear responses, and that brain stimulation-evoked behaviors are modulated by context. PMID:23959880

Testing neurophysiological markers related to fear-potentiated startle.

PubMed

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

2018-06-11

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

Pharmacogenetic excitation of dorsomedial prefrontal cortex restores fear prediction error.

PubMed

Yau, Joanna Oi-Yue; McNally, Gavan P

2015-01-07

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

Impaired contextual fear-conditioning in MAM rodent model of schizophrenia.

PubMed

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

2018-05-01

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

Behavioral interventions to eliminate fear responses.

PubMed

Yue, Jingli; Shi, Le; Lin, Xiao; Khan, Muhammad Zahid; Shi, Jie; Lu, Lin

2018-05-07

Fear memory underlies anxiety-related disorders, including posttraumatic stress disorder (PTSD). PTSD is a fear-based disorder, characterized by difficulties in extinguishing the learned fear response and maintaining extinction. Currently, the first-line treatment for PTSD is exposure therapy, which forms an extinction memory to compete with the original fear memory. However, the extinguished fear often returns under numerous circumstances, suggesting that novel methods are needed to eliminate fear memory or facilitate extinction memory. This review discusses research that targeted extinction and reconsolidation to manipulate fear memory. Recent studies indicate that sleep is an active state that can regulate memory processes. We also discuss the influence of sleep on fear memory. For each manipulation, we briefly summarize the neural mechanisms that have been identified in human studies. Finally, we highlight potential limitations and future directions in the field to better translate existing interventions to clinical settings.

Animal models of fear relapse.

PubMed

Goode, Travis D; Maren, Stephen

2014-01-01

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

Differential splicing and glycosylation of Apoer2 alters synaptic plasticity and fear learning

PubMed Central

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

2015-01-01

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

Prefrontal Cortical GABA Transmission Modulates Discrimination and Latent Inhibition of Conditioned Fear: Relevance for Schizophrenia

PubMed Central

Piantadosi, Patrick T; Floresco, Stan B

2014-01-01

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

Prefrontal cortical GABA transmission modulates discrimination and latent inhibition of conditioned fear: relevance for schizophrenia.

PubMed

Piantadosi, Patrick T; Floresco, Stan B

2014-09-01

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

Neural correlates of appetitive-aversive interactions in Pavlovian fear conditioning.

PubMed

Nasser, Helen M; McNally, Gavan P

2013-03-19

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

Arc expression identifies the lateral amygdala fear memory trace

PubMed Central

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

2016-01-01

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

Amygdala kindling-resistant (SLOW) or -prone (FAST) rat strains show differential fear responses.

PubMed

Mohapel, P; McIntyre, D C

1998-12-01

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

A reinforcement learning model of joy, distress, hope and fear

NASA Astrophysics Data System (ADS)

Broekens, Joost; Jacobs, Elmer; Jonker, Catholijn M.

2015-07-01

In this paper we computationally study the relation between adaptive behaviour and emotion. Using the reinforcement learning framework, we propose that learned state utility, ?, models fear (negative) and hope (positive) based on the fact that both signals are about anticipation of loss or gain. Further, we propose that joy/distress is a signal similar to the error signal. We present agent-based simulation experiments that show that this model replicates psychological and behavioural dynamics of emotion. This work distinguishes itself by assessing the dynamics of emotion in an adaptive agent framework - coupling it to the literature on habituation, development, extinction and hope theory. Our results support the idea that the function of emotion is to provide a complex feedback signal for an organism to adapt its behaviour. Our work is relevant for understanding the relation between emotion and adaptation in animals, as well as for human-robot interaction, in particular how emotional signals can be used to communicate between adaptive agents and humans.

N-butyldeoxynojirimycin treatment restores the innate fear response and improves learning in mucopolysaccharidosis IIIA mice.

PubMed

Kaidonis, Xenia; Byers, Sharon; Ranieri, Enzo; Sharp, Peter; Fletcher, Janice; Derrick-Roberts, Ainslie

2016-06-01

Mucopolysaccharidosis IIIA is a heritable neurodegenerative disorder resulting from the dysfunction of the lysosomal hydrolase sulphamidase. This leads to the primary accumulation of the complex carbohydrate heparan sulphate in a wide range of tissues and the secondary neuronal storage of gangliosides GM2 and GM3 in the brain. GM2 storage is associated with CNS deterioration in the GM2 gangliosidosis group of lysosomal storage disorders and may also contribute to MPS CNS disease. N-butyldeoxynojirimycin, an inhibitor of ceramide glucosyltransferase activity and therefore of ganglioside synthesis, was administered to MPS IIIA mice both prior to maximal GM2 and GM3 accumulation (early treatment) and after the maximum level of ganglioside had accumulated in the brain (late treatment) to determine if behaviour was altered by ganglioside level. Ceramide glucosyltransferase activity was decreased in both treatment groups; however, brain ganglioside levels were only decreased in the late treatment group. Learning in the water cross maze was improved in both groups and the innate fear response was also restored in both groups. A reduction in the expression of inflammatory gene Ccl3 was observed in the early treatment group, while IL1β expression was reduced in both treatment groups. Thus, it appears that NB-DNJ elicits a transient decrease in brain ganglioside levels, some modulation of inflammatory cytokines and a functional improvement in behaviour that can be elicited both before and after overt neurological changes manifest. NB-DNJ improves learning and restores the innate fear response in MPS IIIA mice by decreasing ceramide glucosyltransferase activity and transiently reducing ganglioside storage and/or modulating inflammatory signals. Copyright © 2016 Elsevier Inc. All rights reserved.

Generalization of Pain-Related Fear Based on Conceptual Knowledge.

PubMed

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

2017-05-01

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

Sleep Deprivation Disrupts Recall of Conditioned Fear Extinction.

PubMed

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

2017-03-01

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

The paraventricular thalamus controls a central amygdala fear circuit.

PubMed

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

2015-03-26

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

Cortisol effects on fear memory reconsolidation in women.

PubMed

Meir Drexler, Shira; Merz, Christian J; Hamacher-Dang, Tanja C; Wolf, Oliver T

2016-07-01

Previous work from our group has shown that cortisol enhances fear reconsolidation in men. Whether similar effects can be observed in women remains an open question. The effects of cortisol on the reconsolidation of fear memories were investigated in women. Based on results in men, we expected a specific enhancing effect of cortisol administration on the reactivated fear memory. In addition, possible interactions with oral contraceptive use were tested. We incorporated a differential fear conditioning paradigm in a 3-day reconsolidation design. A fear memory, which was created on the first day, was reactivated on the second day following cortisol administration in the target group. One control group was given cortisol without reactivation, and the other participated in the reactivation session following placebo intake. On the third day, the return of fear for all stimuli following reinstatement was tested. Skin conductance response served as measure of conditioned response. In contrast to the hypothesis, cortisol in combination with reactivation did not enhance fear reconsolidation. No differences between the three experimental groups were apparent. In addition, hormonal contraceptive use had no effect on any of the learning phases and did not interact with the cortisol manipulation. The lack of an effect in women might be the result of alternating concentrations of sex hormones during different phases of the menstrual cycle or following oral contraceptive use. Considering the higher vulnerability of women to stress-related mental disorders, further investigations in women are of great importance for both theory and treatment.

The hypocretin/orexin system mediates the extinction of fear memories.

PubMed

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

2014-11-01

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

The Hypocretin/Orexin System Mediates the Extinction of Fear Memories

PubMed Central

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

2014-01-01

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

Declarative virtual water maze learning and emotional fear conditioning in primary insomnia.

PubMed

Kuhn, Marion; Hertenstein, Elisabeth; Feige, Bernd; Landmann, Nina; Spiegelhalder, Kai; Baglioni, Chiara; Hemmerling, Johanna; Durand, Diana; Frase, Lukas; Klöppel, Stefan; Riemann, Dieter; Nissen, Christoph

2018-05-02

Healthy sleep restores the brain's ability to adapt to novel input through memory formation based on activity-dependent refinements of the strength of neural transmission across synapses (synaptic plasticity). In line with this framework, patients with primary insomnia often report subjective memory impairment. However, investigations of memory performance did not produce conclusive results. The aim of this study was to further investigate memory performance in patients with primary insomnia in comparison to healthy controls, using two well-characterized learning tasks, a declarative virtual water maze task and emotional fear conditioning. Twenty patients with primary insomnia according to DSM-IV criteria (17 females, three males, 43.5 ± 13.0 years) and 20 good sleeper controls (17 females, three males, 41.7 ± 12.8 years) were investigated in a parallel-group study. All participants completed a hippocampus-dependent virtual Morris water maze task and amygdala-dependent classical fear conditioning. Patients with insomnia showed significantly delayed memory acquisition in the virtual water maze task, but no significant difference in fear acquisition compared with controls. These findings are consistent with the notion that memory processes that emerge from synaptic refinements in a hippocampal-neocortical network are particularly sensitive to chronic disruptions of sleep, while those in a basic emotional amygdala-dependent network may be more resilient. © 2018 European Sleep Research Society.

What Predicts Fear of School Violence among U.S. Adolescents?

ERIC Educational Resources Information Center

Akiba, Motoko

2010-01-01

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

Differential splicing and glycosylation of Apoer2 alters synaptic plasticity and fear learning.

PubMed

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

2014-11-25

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

Temporal-difference prediction errors and Pavlovian fear conditioning: role of NMDA and opioid receptors.

PubMed

Cole, Sindy; McNally, Gavan P

2007-10-01

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

Fear Generalization and Anxiety: Behavioral and Neural Mechanisms.

PubMed

Dunsmoor, Joseph E; Paz, Rony

2015-09-01

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

Anorexia nervosa as a motivated behavior: Relevance of anxiety, stress, fear and learning.

PubMed

Guarda, Angela S; Schreyer, Colleen C; Boersma, Gretha J; Tamashiro, Kellie L; Moran, Timothy H

2015-12-01

The high comorbidity between anorexia nervosa (AN) and anxiety disorders is well recognized. AN is a motivated behavioral disorder in which habit formation is likely to contribute to the persistence of abnormal eating and exercise behaviors. Secondary alterations in brain circuitry underlying the reward value of food and exercise, along with disturbances in neuroendocrine hunger and satiety signaling arising from starvation and excessive exercise, are likely contributors to the maintenance of anorectic behaviors in genetically vulnerable individuals. The potential role of fear conditioning in facilitating onset of AN, or of impaired fear extinction in contributing to the high relapse rates observed following weight restoration, is of interest. Evidence from animal models of anxiety and human laboratory studies indicate that low estrogen impairs fear extinction. Low estradiol levels in AN may therefore play a role in perpetuating fear of food and fat in recently weight restored patients. Translational models including the activity based anorexia (ABA) rodent model of AN, and neuroimaging studies of fear extinction and conditioning, could help clarify the underlying molecular mechanisms and neurocircuitry involved in food avoidance behaviors in AN. Moreover, the adaptation of novel treatment interventions with efficacy in anxiety disorders may contribute to the development of new treatments for this impairing disorder. Copyright © 2015. Published by Elsevier Inc.

Cortisol modifies extinction learning of recently acquired fear in men

PubMed Central

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

2014-01-01

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

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

PubMed

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

2014-01-01

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

Rats with ventral hippocampal damage are impaired at various forms of learning including conditioned inhibition, spatial navigation, and discriminative fear conditioning to similar contexts.

PubMed

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

2018-10-01

The ventral hippocampus (vHPC) has been implicated in learning and memory functions that seem to differ from its dorsal counterpart. The goal of this series of experiments was to provide further insight into the functional contributions of the vHPC. Our previous work implicated the vHPC in spatial learning, inhibitory learning, and fear conditioning to context. However, the specific role of vHPC on these different forms of learning are not clear. Accordingly, we assessed the effects of neurotoxic lesions of the ventral hippocampus on retention of a conditioned inhibitory association, early versus late spatial navigation in the water task, and discriminative fear conditioning to context under high ambiguity conditions. The results showed that the vHPC was necessary for the expression of conditioned inhibition, early spatial learning, and discriminative fear conditioning to context when the paired and unpaired contexts have high cue overlap. We argue that this pattern of effects, combined with previous work, suggests a key role for vHPC in the utilization of broad contextual representations for inhibition and discriminative memory in high ambiguity conditions. Copyright © 2018 Elsevier B.V. All rights reserved.

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.

Hippocampal interleukin-1 mediates stress-enhanced fear learning: A potential role for astrocyte-derived interleukin-1β.

PubMed

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

2018-01-01

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

Evidence for recovery of fear following immediate extinction in rats and humans

PubMed Central

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

2008-01-01

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

Erasing fear for an imagined threat event.

PubMed

Soeter, Marieke; Kindt, Merel

2012-11-01

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

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

PubMed Central

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

2017-01-01

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

Effects of 7-nitroindazole, a selective neural nitric oxide synthase inhibitor, on context-shock associative learning in a two-process contextual fear conditioning paradigm.

PubMed

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

2016-10-01

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

Pharmacogenetic reactivation of the original engram evokes an extinguished fear memory.

PubMed

Yoshii, Takahiro; Hosokawa, Hiroshi; Matsuo, Naoki

2017-02-01

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

Encoding of Discriminative Fear Memory by Input-Specific LTP in the Amygdala.

PubMed

Kim, Woong Bin; Cho, Jun-Hyeong

2017-08-30

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

Stress exposure prior to fear acquisition interacts with estradiol status to alter recall of fear extinction in humans.

PubMed

Antov, Martin I; Stockhorst, Ursula

2014-11-01

Classical fear acquisition and extinction are important models for the etiology and treatment of anxiety disorders such as posttraumatic stress disorder (PTSD). Women are at a higher risk for PTSD than men. Levels of circulating 17-β estradiol (E2) in women have been linked to deficits in fear extinction and extinction recall. In PTSD, fear learning coincides with acute traumatic stress. However, little is known about the possible interaction between stress exposure and hormone status on fear acquisition and extinction learning. In a 2-day, 2×3 between-subjects design with healthy participants, we examined the effects of stress (psychosocial stressor vs. control, placed 45 min prior to conditioning) and natural E2-status on differential fear conditioning, covering fear acquisition, immediate extinction (Day 1), and 24h-delayed extinction recall (Day 2). To operationalize E2-status, we compared women in the early follicular phase (EF) of their menstrual cycle (low E2, low progesterone plasma levels), women in the midcycle phase (MC, high E2, low progesterone), and men. Conditioning was indicated by differential skin conductance responses. We found an interaction between stress exposure and natural E2-status in women only: In MC-women, extinction recall on Day 2 (24h after initial extinction training) was better when fear acquisition had been preceded by stress. In EF-women, the inverse was true. We show that extinction recall of conditioned fear acquired after stress depends on estrogen status in women. Therefore, extinction-based exposure therapy in free-cycling female anxiety patients should take cycle status into account. Copyright © 2014 Elsevier Ltd. All rights reserved.

How Administration of the Beta-Blocker Propranolol Before Extinction can Prevent the Return of Fear

PubMed Central

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

2016-01-01

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

A Bayesian context fear learning algorithm/automaton

PubMed Central

Krasne, Franklin B.; Cushman, Jesse D.; Fanselow, Michael S.

2015-01-01

Contextual fear conditioning is thought to involve the synaptic plasticity-dependent establishment in hippocampus of representations of to-be-conditioned contexts which can then become associated with USs in the amygdala. A conceptual and computational model of this process is proposed in which contextual attributes are assumed to be sampled serially and randomly during contextual exposures. Given this assumption, moment-to-moment information about such attributes will often be quite different from one exposure to another and, in particular, between exposures during which representations are created, exposures during which conditioning occurs, and during recall sessions. This presents challenges to current conceptual models of hippocampal function. In order to meet these challenges, our model's hippocampus was made to operate in different modes during representation creation and recall, and non-hippocampal machinery was constructed that controlled these hippocampal modes. This machinery uses a comparison between contextual information currently observed and information associated with existing hippocampal representations of familiar contexts to compute the Bayesian Weight of Evidence that the current context is (or is not) a known one, and it uses this value to assess the appropriateness of creation or recall modes. The model predicts a number of known phenomena such as the immediate shock deficit, spurious fear conditioning to contexts that are absent but similar to actually present ones, and modulation of conditioning by pre-familiarization with contexts. It also predicts a number of as yet unknown phenomena. PMID:26074792

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

Childhood Fears: What Children Are Afraid of and Why.

ERIC Educational Resources Information Center

Crosser, Sandra

1995-01-01

It is important for early childhood professionals to learn about childhood fears so that they can help children cope with them. Children's fears are normal, the nature of preschoolers' fears is related to their cognitive development, and a child's temperament and sense of autonomy may influence the extent of and manner of reaction to a fearful…

Deep brain stimulation of the ventral striatum enhances extinction of conditioned fear

PubMed Central

Rodriguez-Romaguera, Jose; Do Monte, Fabricio H. M.; Quirk, Gregory J.

2012-01-01

Deep brain stimulation (DBS) of the ventral capsule/ventral striatum (VC/VS) reduces symptoms of intractable obsessive-compulsive disorder (OCD), but the mechanism of action is unknown. OCD is characterized by avoidance behaviors that fail to extinguish, and DBS could act, in part, by facilitating extinction of fear. We investigated this possibility by using auditory fear conditioning in rats, for which the circuits of fear extinction are well characterized. We found that DBS of the VS (the VC/VS homolog in rats) during extinction training reduced fear expression and strengthened extinction memory. Facilitation of extinction was observed for a specific zone of dorsomedial VS, just above the anterior commissure; stimulation of more ventrolateral sites in VS impaired extinction. DBS effects could not be obtained with pharmacological inactivation of either dorsomedial VS or ventrolateral VS, suggesting an extrastriatal mechanism. Accordingly, DBS of dorsomedial VS (but not ventrolateral VS) increased expression of a plasticity marker in the prelimbic and infralimbic prefrontal cortices, the orbitofrontal cortex, the amygdala central nucleus (lateral division), and intercalated cells, areas known to learn and express extinction. Facilitation of fear extinction suggests that, in accord with clinical observations, DBS could augment the effectiveness of cognitive behavioral therapies for OCD. PMID:22586125

Elevated Arc/Arg 3.1 protein expression in the basolateral amygdala following auditory trace-cued fear conditioning.

PubMed

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

2013-11-01

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

Tracking the fear memory engram: discrete populations of neurons within amygdala, hypothalamus, and lateral septum are specifically activated by auditory fear conditioning

PubMed Central

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

2015-01-01

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

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

Fear Conditioning Selectively Disrupts Noradrenergic Facilitation of GABAergic Inhibition in the Basolateral Amygdala

PubMed Central

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

2016-01-01

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

Optogenetic stimulation of a hippocampal engram activates fear memory recall.

PubMed

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

2012-03-22

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

Optogenetic stimulation of a hippocampal engram activates fear memory recall

PubMed Central

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

2012-01-01

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

Oxytocin receptor neurotransmission in the dorsolateral bed nucleus of the stria terminalis facilitates the acquisition of cued fear in the fear-potentiated startle paradigm in rats.

PubMed

Moaddab, Mahsa; Dabrowska, Joanna

2017-07-15

Oxytocin (OT) is a hypothalamic neuropeptide that modulates fear and anxiety-like behaviors. Dorsolateral bed nucleus of the stria terminalis (BNST dl ) plays a critical role in the regulation of fear and anxiety, and expresses high levels of OT receptor (OTR). However, the role of OTR neurotransmission within the BNST dl in mediating these behaviors is unknown. Here, we used adult male Sprague-Dawley rats to investigate the role of OTR neurotransmission in the BNST dl in the modulation of the acoustic startle response, as well as in the acquisition and consolidation of conditioned fear using fear potentiated startle (FPS) paradigm. Bilateral intra-BNST dl administration of OT (100 ng) did not affect the acquisition of conditioned fear response. However, intra-BNST dl administration of specific OTR antagonist (OTA), (d(CH 2 ) 5 1 , Tyr(Me) 2 , Thr 4 , Orn 8 , des-Gly-NH 2 9 )-vasotocin, (200 ng), prior to the fear conditioning session, impaired the acquisition of cued fear, without affecting a non-cued fear component of FPS. Neither OTA, nor OT affected baseline startle or shock reactivity during fear conditioning. Therefore, the observed impairment of cued fear after OTA infusion resulted from the specific effect on the formation of cued fear. In contrast to the acquisition, neither OTA nor OT affected the consolidation of FPS, when administered after the completion of fear conditioning session. Taken together, these results reveal the important role of OTR neurotransmission in the BNST dl in the formation of conditioned fear to a discrete cue. This study also highlights the role of the BNST dl in learning to discriminate between threatening and safe stimuli. Copyright © 2017 Elsevier Ltd. All rights reserved.

More than just noise: Inter-individual differences in fear acquisition, extinction and return of fear in humans - Biological, experiential, temperamental factors, and methodological pitfalls.

PubMed

Lonsdorf, Tina B; Merz, Christian J

2017-09-01

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

Behavioral Mechanisms of Context Fear Generalization in Mice

ERIC Educational Resources Information Center

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

2016-01-01

There is growing interest in generalization of learned contextual fear, driven in part by the hypothesis that mood and anxiety disorders stem from impaired hippocampal mechanisms of fear generalization and discrimination. However, there has been relatively little investigation of the behavioral and procedural mechanisms that might control…

Activation of D1/5 Dopamine Receptors: A Common Mechanism for Enhancing Extinction of Fear and Reward-Seeking Behaviors.

PubMed

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

2016-07-01

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

Age and adolescent social stress effects on fear extinction in female rats.

PubMed

McCormick, C M; Mongillo, D L; Simone, J J

2013-11-01

We previously observed that social instability stress (SS: daily 1 h isolation and change of cage partners for 16 days) in adolescence, but not in adulthood, decreased context and cue memory after fear conditioning in male rats. Effects of stress are typically sex-specific, and so here we investigated adolescent and adult SS effects in females on the strength of acquired contextual and cued fear conditioning, as well as extinction learning, beginning either the day after the stress procedure or four weeks later. For SS in adolescence, SS females spent more time freezing (fear measure) during extinction than did controls, whereas SS in adulthood had no effect on any measure of fear conditioning. The results also indicated an effect of age: females in late adolescence show more rapid extinction of cue and better memory of extinction of context compared to adult females, which may indicate resilience to acute footshock in adolescence. Thus fear circuitry continues to mature into late adolescence, which may underlie the heightened plasticity in response to chronic stressors of adolescents compared to adults.

Enhancing dopaminergic signaling and histone acetylation promotes long-term rescue of deficient fear extinction.

PubMed

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

2016-12-06

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

Enhancing dopaminergic signaling and histone acetylation promotes long-term rescue of deficient fear extinction

PubMed Central

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

2016-01-01

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

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

PubMed

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

2016-10-01

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

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

Central Ghrelin Resistance Permits the Overconsolidation of Fear Memory.

PubMed

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

2017-06-15

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

Bilateral Alternating Auditory Stimulations Facilitate Fear Extinction and Retrieval.

PubMed

Boukezzi, Sarah; Silva, Catarina; Nazarian, Bruno; Rousseau, Pierre-François; Guedj, Eric; Valenzuela-Moguillansky, Camila; Khalfa, Stéphanie

2017-01-01

Disruption of fear conditioning, its extinction and its retrieval are at the core of posttraumatic stress disorder (PTSD). Such deficits, especially fear extinction delay, disappear after alternating bilateral stimulations (BLS) during eye movement desensitization and reprocessing (EMDR) therapy. An animal model of fear recovery, based on auditory cued fear conditioning and extinction learning, recently showed that BLS facilitate fear extinction and fear extinction retrieval. Our goal was to determine if these previous results found in animals can be reproduced in humans. Twenty-two healthy participants took part in a classical fear conditioning, extinction, and extinction recall paradigm. Behavioral responses (fear expectations) as well as psychophysiological measures (skin conductance responses, SCRs) were recorded. The results showed a significant fear expectation decrease during fear extinction with BLS. Additionally, SCR for fear extinction retrieval were significantly lower with BLS. Our results demonstrate the importance of BLS to reduce negative emotions, and provide a successful model to further explore the neural mechanisms underlying the sole BLS effect in the EMDR.

Tracking the fear memory engram: discrete populations of neurons within amygdala, hypothalamus, and lateral septum are specifically activated by auditory fear conditioning.

PubMed

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

2015-08-01

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

Acute exercise enhances the consolidation of fear extinction memory and reduces conditioned fear relapse in a sex-dependent manner.

PubMed

Bouchet, Courtney A; Lloyd, Brian A; Loetz, Esteban C; Farmer, Caroline E; Ostrovskyy, Mykola; Haddad, Natalie; Foright, Rebecca M; Greenwood, Benjamin N

2017-08-01

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 enhance the acquisition and consolidation of fear extinction in male rats, but the effects of exercise on relapse of fear after extinction are not well understood. Here, we characterized the effects of 2 h of voluntary exercise during the consolidation phase of contextual or auditory fear extinction learning on long-term fear extinction memory and renewal in adult, male and female, Long-Evans rats. Results indicate that exercise enhances consolidation of fear extinction memory and reduces fear relapse after extinction in a sex-dependent manner. These data suggest that brief bouts of exercise could be used as an augmentation strategy for exposure therapy, even in previously sedentary subjects. Fear memories of discrete cues, rather than of contextual ones, may be most susceptible to exercise-augmented extinction, especially in males. Additionally, exercise seems to have the biggest impact on fear relapse phenomena, even if fear extinction memories themselves are only minimally enhanced. © 2017 Bouchet et al.; Published by Cold Spring Harbor Laboratory Press.

Sleep supports cued fear extinction memory consolidation independent of circadian phase.

PubMed

Melo, Irene; Ehrlich, Ingrid

2016-07-01

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

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

Developmental Effects of Acute, Chronic, and Withdrawal from Chronic Nicotine on Fear Conditioning

PubMed Central

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

2012-01-01

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

Fear conditioning leads to alteration in specific genes expression in cortical and thalamic neurons that project to the lateral amygdala.

PubMed

Katz, Ira K; Lamprecht, Raphael

2015-02-01

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

Agency in the Darkness: 'Fear of the Unknown', Learning Disability and Teacher Education for Inclusion

ERIC Educational Resources Information Center

Robinson, Deborah; Goodey, Chris

2018-01-01

This paper proposes inclusion phobia as a sharper and more operative definition of the 'fear of the unknown' often cited as an explanation for resistance to inclusive education. Using 'severe and profound learning disability' as the paradigm case, we situate the phobia surrounding this label in its social and historical context. Our hypothesis is…

Opposite effects of fear conditioning and extinction on dendritic spine remodelling.

PubMed

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

2012-02-19

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

Fearing shades of grey: individual differences in fear responding towards generalisation stimuli.

PubMed

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

2017-09-01

Individual differences in fear generalisation have been proposed to play a role in the aetiology and/or maintenance of anxiety disorders, but few data are available to directly support that claim. The research that is available has focused mostly on generalisation of peripheral and central physiological fear responses. Far less is known about the generalisation of avoidance, the behavioural component of fear. In two experiments, we evaluated how neuroticism, a known vulnerability factor for anxiety, modulates an array of fear responses, including avoidance tendencies, towards generalisation stimuli (GS). Participants underwent differential fear conditioning, in which one conditioned stimulus (CS+) was repeatedly paired with an aversive outcome (shock; unconditioned stimulus, US), whereas another was not (CS-). Fear generalisation was observed across measures in Experiment 1 (US expectancy and evaluative ratings) and Experiment 2 (US expectancy, evaluative ratings, skin conductance, startle responses, safety behaviours), with overall highest responding to the CS+, lowest to the CS- and intermediate responding to the GSs. Neuroticism had very little impact on fear generalisation (but did affect GS recognition rates in Experiment 1), in line with the idea that fear generalisation is largely an adaptive process.

Absence of verbal recall or memory for symptom acquisition in fear and trauma exposure: a conceptual case for fear conditioning and learned nonuse in assessment and treatment.

PubMed

Seifert, A Ronald

2012-01-01

Absence of memory or verbal recall for symptom acquisition in fear and trauma exposure, as well as absence of successful coping behavior for life events, is associated with a number of diagnoses, including traumatic brain injury, posttraumatic stress disorder, pain, and anxiety. The difficulty with diagnosis and treatment planning based on the absence of recall, memory, and successful coping behavior is threefold: (1) these assessments do not distinguish between disruption of behavior and lack of capacity, (2) the absence of verbal recall and memory complicates cognitive-based treatment, and (3) a confounding issue is the same absent behavior can be observed at different times and contexts. While memory of the specific details of the initial traumatic event(s) may not be available to verbal report, the existence of time- and context-dependent relationships for the initial as well as subsequent experiences is arguable. The absence of memory or lack of verbal recall does not rule out measurable physiological bodily responses for the initial trauma(s), nor does it help to establish the effects of subsequent experiences for symptom expression. Also, the absence of memory must include the prospect of fear-based learning that does not require or involve the cortex. It is posited that the literatures of fear conditioning and learned nonuse provide complementary illustrations of how the time and context of the initial trauma(s) and subsequent experiences affect behavior, which is not dependent on the effected individual being able to provide a memory-based verbal report. The replicated clinical application demonstrates that, without scientific demonstration, neither neuroanatomy nor verbal report can be assumed sufficient to predict overt behavior or physiologic responses. For example, while commonly assumed to be predictively so, autonomic nervous system innervation is insufficient to define the unique stimulus- and context-dependent physiological responses of an

Computerized Dental Injection Fear Treatment

PubMed Central

Heaton, L.J.; Leroux, B.G.; Ruff, P.A.; Coldwell, S.E.

2013-01-01

One in four adults reports a clinically significant fear of dental injections, leading many to avoid dental care. While systematic desensitization is the most common therapeutic method for treating specific phobias such as fear of dental injections, lack of access to trained therapists, as well as dentists’ lack of training and time in providing such a therapy, means that most fearful individuals are not able to receive the therapy needed to be able to receive necessary dental treatment. Computer Assisted Relaxation Learning (CARL) is a self-paced computerized treatment based on systematic desensitization for dental injection fear. This multicenter, block-randomized, dentist-blind, parallel-group study conducted in 8 sites in the United States compared CARL with an informational pamphlet in reducing fear of dental injections. Participants completing CARL reported significantly greater reduction in self-reported general and injection-specific dental anxiety measures compared with control individuals (p < .001). Twice as many CARL participants (35.3%) as controls (17.6%) opted to receive a dental injection after the intervention, although this was not statistically significant. CARL, therefore, led to significant changes in self-reported fear in study participants, but no significant differences in the proportion of participants having a dental injection (ClinicalTrials.gov, NCT00609648). PMID:23690352

Monetary effects on fear conditioning.

PubMed

Qu, Chen; Zhang, Aiyi; Chen, Qishan

2013-04-01

Previous research has found that the loss of money as a negative secondary reinforcer was as effective as a primary reinforcer during fear conditioning. The purpose of the present study was to explore the effect of monetary gain as a positive secondary reinforcer in fear conditioning. Participants were assigned to a high-reward group or low-reward group. Three kinds of squares prompting non-compensation shock, compensation shock, and no shock were presented. Skin conductance responses (SCRs) and self-ratings were recorded. The results revealed that (a) both SCRs and self-ratings in the compensation shock condition were lower than in the non-compensation shock condition, suggesting that money might block the learning stage of fear conditioning; and (b) a higher ratio of fear reduction was present in self-rating when compared to SCRs, suggesting that people might overstate the utility of money, subjectively. Monetary effects, the effects of different amounts of money, and the differences between subjective and physiological levels are discussed.

Bilateral Alternating Auditory Stimulations Facilitate Fear Extinction and Retrieval

PubMed Central

Boukezzi, Sarah; Silva, Catarina; Nazarian, Bruno; Rousseau, Pierre-François; Guedj, Eric; Valenzuela-Moguillansky, Camila; Khalfa, Stéphanie

2017-01-01

Disruption of fear conditioning, its extinction and its retrieval are at the core of posttraumatic stress disorder (PTSD). Such deficits, especially fear extinction delay, disappear after alternating bilateral stimulations (BLS) during eye movement desensitization and reprocessing (EMDR) therapy. An animal model of fear recovery, based on auditory cued fear conditioning and extinction learning, recently showed that BLS facilitate fear extinction and fear extinction retrieval. Our goal was to determine if these previous results found in animals can be reproduced in humans. Twenty-two healthy participants took part in a classical fear conditioning, extinction, and extinction recall paradigm. Behavioral responses (fear expectations) as well as psychophysiological measures (skin conductance responses, SCRs) were recorded. The results showed a significant fear expectation decrease during fear extinction with BLS. Additionally, SCR for fear extinction retrieval were significantly lower with BLS. Our results demonstrate the importance of BLS to reduce negative emotions, and provide a successful model to further explore the neural mechanisms underlying the sole BLS effect in the EMDR. PMID:28659851

Toward an account of clinical anxiety predicated on basic, neurally mapped mechanisms of Pavlovian fear-learning: the case for conditioned overgeneralization.

PubMed

Lissek, Shmuel

2012-04-01

The past two decades have brought dramatic progress in the neuroscience of anxiety due, in no small part, to animal findings specifying the neurobiology of Pavlovian fear-conditioning. Fortuitously, this neurally mapped process of fear learning is widely expressed in humans, and has been centrally implicated in the etiology of clinical anxiety. Fear-conditioning experiments in anxiety patients thus represent a unique opportunity to bring recent advances in animal neuroscience to bear on working, brain-based models of clinical anxiety. The current presentation details the neural basis and clinical relevance of fear conditioning, and highlights generalization of conditioned fear to stimuli resembling the conditioned danger cue as one of the more robust conditioning markers of clinical anxiety. Studies testing such generalization across a variety of anxiety disorders (panic, generalized anxiety disorder, and social anxiety disorder) with systematic methods developed in animals will next be presented. Finally, neural accounts of overgeneralization deriving from animal and human data will be described with emphasis given to implications for the neurobiology and treatment of clinical anxiety. © 2012 Wiley Periodicals, Inc.

5-HT2C receptors in the BNST are necessary for the enhancement of fear learning by selective serotonin reuptake inhibitors.

PubMed

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

2016-12-01

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

In Search for Boundary Conditions of Reconsolidation: A Failure of Fear Memory Interference

PubMed Central

Schroyens, Natalie; Beckers, Tom; Kindt, Merel

2017-01-01

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

Cholinergic signaling controls conditioned-fear behaviors and enhances plasticity of cortical-amygdala circuits

PubMed Central

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

2016-01-01

Summary We examined the contribution of endogenous cholinergic signaling to the acquisition and extinction of fear- related memory by optogenetic regulation of cholinergic input to the basal lateral amygdala (BLA). Stimulation of cholinergic terminal fields within the BLA in awake-behaving mice during training in a cued fear-conditioning paradigm slowed the extinction of learned fear as assayed by multi-day retention of extinction learning. Inhibition of cholinergic activity during training reduced the acquisition of learned fear behaviors. Circuit mechanisms underlying the behavioral effects of cholinergic signaling in the BLA were assessed by in vivo and ex vivo electrophysiological recording. Photo-stimulation of endogenous cholinergic input: (1) enhances firing of putative BLA principal neurons through activation of acetylcholine receptors (AChRs); (2) enhances glutamatergic synaptic transmission in the BLA and (3) induces LTP of cortical-amygdala circuits. These studies support an essential role of cholinergic modulation of BLA circuits in the inscription and retention of fear memories. PMID:27161525

Effects of alcoholic beverage treatment on spatial learning and fear memory in mice.

PubMed

Hashikawa-Hobara, Narumi; Mishima, Shuta; Nagase, Shotaro; Morita, Keishi; Otsuka, Ami; Hashikawa, Naoya

2018-04-24

Although chronic ethanol treatment is known to impair learning and memory, humans commonly consume a range of alcoholic beverages. However, the specific effects of some alcoholic beverages on behavioral performance are largely unknown. The present study compared the effects of a range of alcoholic beverages (plain ethanol solution, red wine, sake and whiskey; with a matched alcohol concentration of 10%) on learning and memory. 6-week-old C57BL6J mice were orally administered alcohol for 7 weeks. The results revealed that red wine treatment exhibited a trend toward improvement of spatial memory and advanced extinction of fear memory. Additionally, red wine treatment significantly increased mRNA levels of brain-derived neurotrophic factor (BDNF) and N-methyl-D-aspartate (NMDA) receptors in mice hippocampus. These results support previous reports that red wine has beneficial effects.

Noradrenergic blockade stabilizes prefrontal activity and enables fear extinction under stress

PubMed Central

Fitzgerald, Paul J.; Giustino, Thomas F.; Seemann, Jocelyn R.; Maren, Stephen

2015-01-01

Stress-induced impairments in extinction learning are believed to sustain posttraumatic stress disorder (PTSD). Noradrenergic signaling may contribute to extinction impairments by modulating medial prefrontal cortex (mPFC) circuits involved in fear regulation. Here we demonstrate that aversive fear conditioning rapidly and persistently alters spontaneous single-unit activity in the prelimbic and infralimbic subdivisions of the mPFC in behaving rats. These conditioning-induced changes in mPFC firing were mitigated by systemic administration of propranolol (10 mg/kg, i.p.), a β-noradrenergic receptor antagonist. Moreover, propranolol administration dampened the stress-induced impairment in extinction observed when extinction training is delivered shortly after fear conditioning. These findings suggest that β-adrenoceptors mediate stress-induced changes in mPFC spike firing that contribute to extinction impairments. Propranolol may be a helpful adjunct to behavioral therapy for PTSD, particularly in patients who have recently experienced trauma. PMID:26124100

Bridging the Gap: Towards a Cell-Type Specific Understanding of Neural Circuits Underlying Fear Behaviors

PubMed Central

McCullough, KM; Morrison, FG; Ressler, KJ

2016-01-01

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

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…

Fear in the Palestinian Classroom: Pedagogy, Authoritarianism and Transformation

ERIC Educational Resources Information Center

Affouneh, Saida; Hargreaves, Eleanore

2015-01-01

Drawing on pictures, written sentences and interview contributions, this article explores some Palestinian children's perspectives in order to gain insights into some children's classroom fear in the light of its potential influence on learning. After presenting some existing research indicating a negative relationship between fear and young…

Modification of Fear Memory by Pharmacological and Behavioural Interventions during Reconsolidation.

PubMed

Thome, Janine; Koppe, Georgia; Hauschild, Sophie; Liebke, Lisa; Schmahl, Christian; Lis, Stefanie; Bohus, Martin

2016-01-01

Dysfunctional fear responses play a central role in many mental disorders. New insights in learning and memory suggest that pharmacological and behavioural interventions during the reconsolidation of reactivated fear memories may increase the efficacy of therapeutic interventions. It has been proposed that interventions applied during reconsolidation may modify the original fear memory, and thus prevent the spontaneous recovery and reinstatement of the fear response. We investigated whether pharmacological (propranolol) and behavioural (reappraisal, multisensory stimulation) interventions reduce fear memory, and prevent reinstatement of fear in comparison to a placebo control group. Eighty healthy female subjects underwent a differential fear conditioning procedure with three stimuli (CS). Two of these (CS+) were paired with an electric shock on day 1. On day 2, 20 subjects were pseudo-randomly assigned to either the propranolol or placebo condition, or underwent one of the two behavioural interventions after one of the two CS+ was reactivated. On day 3, all subjects underwent an extinction phase, followed by a reinstatement test. Dependent variables were US expectancy ratings, fear-potentiated startle, and skin conductance response. Differential fear responses to the reactivated and non-reactivated CS+ were observed only in the propranolol condition. Here, the non-reactivated CS+ evoked stronger fear-potentiated startle-responses compared to the placebo group. None of the interventions prevented the return of the extinguished fear response after re-exposure to the unconditioned stimulus. Our data are in line with an increasing body of research stating that the occurrence of reconsolidation may be constrained by boundary conditions such as subtle differences in experimental manipulations and instructions. In conclusion, our findings do not support a beneficial effect in using reconsolidation processes to enhance effects of psychotherapeutic interventions. This

Modification of Fear Memory by Pharmacological and Behavioural Interventions during Reconsolidation

PubMed Central

Thome, Janine; Koppe, Georgia; Hauschild, Sophie; Liebke, Lisa; Schmahl, Christian; Lis, Stefanie; Bohus, Martin

2016-01-01

Background Dysfunctional fear responses play a central role in many mental disorders. New insights in learning and memory suggest that pharmacological and behavioural interventions during the reconsolidation of reactivated fear memories may increase the efficacy of therapeutic interventions. It has been proposed that interventions applied during reconsolidation may modify the original fear memory, and thus prevent the spontaneous recovery and reinstatement of the fear response. Methods We investigated whether pharmacological (propranolol) and behavioural (reappraisal, multisensory stimulation) interventions reduce fear memory, and prevent reinstatement of fear in comparison to a placebo control group. Eighty healthy female subjects underwent a differential fear conditioning procedure with three stimuli (CS). Two of these (CS+) were paired with an electric shock on day 1. On day 2, 20 subjects were pseudo-randomly assigned to either the propranolol or placebo condition, or underwent one of the two behavioural interventions after one of the two CS+ was reactivated. On day 3, all subjects underwent an extinction phase, followed by a reinstatement test. Dependent variables were US expectancy ratings, fear-potentiated startle, and skin conductance response. Results Differential fear responses to the reactivated and non-reactivated CS+ were observed only in the propranolol condition. Here, the non-reactivated CS+ evoked stronger fear-potentiated startle-responses compared to the placebo group. None of the interventions prevented the return of the extinguished fear response after re-exposure to the unconditioned stimulus. Conclusions Our data are in line with an increasing body of research stating that the occurrence of reconsolidation may be constrained by boundary conditions such as subtle differences in experimental manipulations and instructions. In conclusion, our findings do not support a beneficial effect in using reconsolidation processes to enhance effects of

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…

Dispositional cognitive reappraisal modulates the neural correlates of fear acquisition and extinction.

PubMed

Hermann, Andrea; Keck, Tanja; Stark, Rudolf

2014-09-01

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

Behavioral mechanisms of context fear generalization in mice

PubMed Central

Huckleberry, Kylie A.; Ferguson, Laura B.

2016-01-01

There is growing interest in generalization of learned contextual fear, driven in part by the hypothesis that mood and anxiety disorders stem from impaired hippocampal mechanisms of fear generalization and discrimination. However, there has been relatively little investigation of the behavioral and procedural mechanisms that might control generalization of contextual fear. We assessed the relative contribution of different contextual features to context fear generalization and characterized how two common conditioning protocols—foreground (uncued) and background (cued) contextual fear conditioning—affected context fear generalization. In one experiment, mice were fear conditioned in context A, and then tested for contextual fear both in A and in an alternate context created by changing a subset of A's elements. The results suggest that floor configuration and odor are more salient features than chamber shape. A second experiment compared context fear generalization in background and foreground context conditioning. Although foreground conditioning produced more context fear than background conditioning, the two procedures produced equal amounts of generalized fear. Finally, results indicated that the order of context tests (original first versus alternate first) significantly modulates context fear generalization, perhaps because the original and alternate contexts are differentially sensitive to extinction. Overall, results demonstrate that context fear generalization is sensitive to procedural variations and likely reflects the operation of multiple interacting psychological and neural mechanisms. PMID:27918275

Contribution of estradiol levels and hormonal contraceptives to sex differences within the fear network during fear conditioning and extinction.

PubMed

Hwang, Moon Jung; Zsido, Rachel G; Song, Huijin; Pace-Schott, Edward F; Miller, Karen Klahr; Lebron-Milad, Kelimer; Marin, Marie-France; Milad, Mohammed R

2015-11-18

Findings about sex differences in the field of fear conditioning and fear extinction have been mixed. At the psychophysiological level, sex differences emerge only when taking estradiol levels of women into consideration. This suggests that this hormone may also influence sex differences with regards to activations of brain regions involved in fear conditioning and its extinction. Importantly, the neurobiological correlates associated with the use of hormonal oral contraceptives in women have not been fully contrasted against men and against naturally cycling women with different levels of estradiol. In this study, we begin to fill these scientific gaps. We recruited 37 healthy men and 48 healthy women. Of these women, 16 were using oral contraceptives (OC) and 32 were naturally cycling. For these naturally cycling women, a median split was performed on their serum estradiol levels to create a high estradiol (HE) group (n = 16) and a low estradiol (LE) group (n = 16). All participants underwent a 2-day fear conditioning and extinction paradigm in a 3 T MR scanner. Using the 4 groups (men, HE women, LE women, and OC users) and controlling for age and coil type, one-way ANCOVAs were performed to look at significant activations within the nodes of the fear circuit. Using post-hoc analyses, beta-weights were extracted in brain regions showing significant effects in order to unveil the differences based on hormonal status (men, HE, LE, OC). Significant main effect of hormonal status group was found across the different phases of the experiment and in different sub-regions of the insular and cingulate cortices, amygdala, hippocampus, and hypothalamus. During conditioning, extinction and recall, most of the observed differences suggested higher activations among HE women relative to men. During the unconditioned response, however, a different pattern was observed with men showing significantly higher brain activations. Our data further support the important contribution

The neural circuits of innate fear: detection, integration, action, and memorization

PubMed Central

Silva, Bianca A.; Gross, Cornelius T.

2016-01-01

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

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. Copyright © 2014. Published by Elsevier Ltd.

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

Amygdala-ventral striatum circuit activation decreases long-term fear

PubMed Central

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

2016-01-01

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

Easy to remember, difficult to forget: the development of fear regulation

PubMed Central

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

2014-01-01

Fear extinction learning is a highly adaptive process that involves the integrity of frontolimbic circuitry. Its disruption has been associated with emotional dysregulation in stress and anxiety disorders. In this article we consider how age, genetics and experiences shape our capacity to regulate fear in cross-species studies. Evidence for adolescent-specific diminished fear extinction learning is presented in the context of immature frontolimbic circuitry. We also present evidence for less neural plasticity in fear regulation as a function of early life stress and by genotype, focusing on the common brain derived neurotrophin factor (BDNF) Val66Met polymorphism. Finally, we discuss this work in the context of exposure-based behavioral therapies for the treatment of anxiety and stress disorders that are based on principles of fear extinction. We conclude by speculating on how such therapies may be optimized for the individual based on the patient’s age, genetic profile and personal history to move from standard treatment of care to personalized and precision medicine. PMID:25238998

The role of sleep and sleep deprivation in consolidating fear memories.

PubMed

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

2013-07-15

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

Neuronal Nitric-Oxide Synthase Deficiency Impairs the Long-Term Memory of Olfactory Fear Learning and Increases Odor Generalization

ERIC Educational Resources Information Center

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

2013-01-01

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

Does Fear Reactivity during Exposure Predict Panic Symptom Reduction?

ERIC Educational Resources Information Center

Meuret, Alicia E.; Seidel, Anke; Rosenfield, Benjamin; Hofmann, Stefan G.; Rosenfield, David

2012-01-01

Objective: Fear reactivity during exposure is a commonly used indicator of learning and overall therapy outcome. The objective of this study was to assess the predictive value of fear reactivity during exposure using multimodal indicators and an advanced analytical design. We also investigated the degree to which treatment condition (cognitive…

Inactivation of the Infralimbic but Not the Prelimbic Cortex Impairs Consolidation and Retrieval of Fear Extinction

ERIC Educational Resources Information Center

Laurent, Vincent; Westbrook, R. Frederick

2009-01-01

Rats were subjected to one or two cycles of context fear conditioning and extinction to study the roles of the prelimbic cortex (PL) and infralimbic cortex (IL) in learning and relearning to inhibit fear responses. Inactivation of the PL depressed fear responses across the first or second extinction but did not impair learning or relearning fear…

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.

Fear of death.

PubMed

Penson, Richard T; Partridge, Rosamund A; Shah, Muhammad A; Giansiracusa, David; Chabner, Bruce A; Lynch, Thomas J

2005-02-01

Shortly before his death in 1995, Kenneth B. Schwartz, a cancer patient at Massachusetts General Hospital (MGH) founded The Kenneth B. Schwartz Center at MGH. The Schwartz Center is a nonprofit organization dedicated to supporting and advancing compassionate health care delivery, which provides hope to the patient and support to caregivers and encourages the healing process. The center sponsors the Schwartz Center Rounds, a monthly multidisciplinary forum where caregivers reflect on important psychosocial issues faced by patients, their families, and their caregivers, and gain insight and support from fellow staff members. For many, cancer is synonymous with death. Fearing death is a rational response. For too long, medicine has ignored this primeval fear. Increasingly, clinicians recognize and address end-of-life issues, facing patients' and our own emotional vulnerabilities in order to connect and explore problems and fears. Listening and learning from the patient guides us as we acknowledge much of the mystery that still surrounds the dying process. Rarely is there a simple or right answer. An empathetic response to suffering patients is the best support. Support is vital in fostering the adjustment of patients. A silent presence may prove more helpful than well-meant counsel for many patients. Through an examination of eight caregiver narratives of their patients' experiences, the role of the health care provider in the dying process, particularly in regard to challenging fear, is reviewed.

Hunger Promotes Fear Extinction by Activation of an Amygdala Microcircuit

PubMed Central

Verma, Dilip; Wood, James; Lach, Gilliard; Herzog, Herbert; Sperk, Guenther; Tasan, Ramon

2016-01-01

Emotions control evolutionarily-conserved behavior that is central to survival in a natural environment. Imbalance within emotional circuitries, however, may result in malfunction and manifestation of anxiety disorders. Thus, a better understanding of emotional processes and, in particular, the interaction of the networks involved is of considerable clinical relevance. Although neurobiological substrates of emotionally controlled circuitries are increasingly evident, their mutual influences are not. To investigate interactions between hunger and fear, we performed Pavlovian fear conditioning in fasted wild-type mice and in mice with genetic modification of a feeding-related gene. Furthermore, we analyzed in these mice the electrophysiological microcircuits underlying fear extinction. Short-term fasting before fear acquisition specifically impaired long-term fear memory, whereas fasting before fear extinction facilitated extinction learning. Furthermore, genetic deletion of the Y4 receptor reduced appetite and completely impaired fear extinction, a phenomenon that was rescued by fasting. A marked increase in feed-forward inhibition between the basolateral and central amygdala has been proposed as a synaptic correlate of fear extinction and involves activation of the medial intercalated cells. This form of plasticity was lost in Y4KO mice. Fasting before extinction learning, however, resulted in specific activation of the medial intercalated neurons and re-established the enhancement of feed-forward inhibition in this amygdala microcircuit of Y4KO mice. Hence, consolidation of fear and extinction memories is differentially regulated by hunger, suggesting that fasting and modification of feeding-related genes could augment the effectiveness of exposure therapy and provide novel drug targets for treatment of anxiety disorders. PMID:26062787

Hunger Promotes Fear Extinction by Activation of an Amygdala Microcircuit.

PubMed

Verma, Dilip; Wood, James; Lach, Gilliard; Herzog, Herbert; Sperk, Guenther; Tasan, Ramon

2016-01-01

Emotions control evolutionarily-conserved behavior that is central to survival in a natural environment. Imbalance within emotional circuitries, however, may result in malfunction and manifestation of anxiety disorders. Thus, a better understanding of emotional processes and, in particular, the interaction of the networks involved is of considerable clinical relevance. Although neurobiological substrates of emotionally controlled circuitries are increasingly evident, their mutual influences are not. To investigate interactions between hunger and fear, we performed Pavlovian fear conditioning in fasted wild-type mice and in mice with genetic modification of a feeding-related gene. Furthermore, we analyzed in these mice the electrophysiological microcircuits underlying fear extinction. Short-term fasting before fear acquisition specifically impaired long-term fear memory, whereas fasting before fear extinction facilitated extinction learning. Furthermore, genetic deletion of the Y4 receptor reduced appetite and completely impaired fear extinction, a phenomenon that was rescued by fasting. A marked increase in feed-forward inhibition between the basolateral and central amygdala has been proposed as a synaptic correlate of fear extinction and involves activation of the medial intercalated cells. This form of plasticity was lost in Y4KO mice. Fasting before extinction learning, however, resulted in specific activation of the medial intercalated neurons and re-established the enhancement of feed-forward inhibition in this amygdala microcircuit of Y4KO mice. Hence, consolidation of fear and extinction memories is differentially regulated by hunger, suggesting that fasting and modification of feeding-related genes could augment the effectiveness of exposure therapy and provide novel drug targets for treatment of anxiety disorders.

Can experimentally induced positive affect attenuate generalization of fear of movement-related pain?

PubMed

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

2015-03-01

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

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

Nicotinic Receptors in the Dorsal and Ventral Hippocampus Differentially Modulate Contextual Fear Conditioning

PubMed Central

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

2012-01-01

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

Using facial expressions as CSs and fearsome and disgusting pictures as UCSs: affective responding and evaluative learning of fear and disgust in blood-injection-injury phobia.

PubMed

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

2005-01-01

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

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

Effective and ineffective use of fear in health promotion campaigns.

PubMed Central

Soames Job, R F

1988-01-01

Health promotion campaigns are typically designed to elicit fear, yet the use of fear is often ineffective in achieving the desired behavior change. Campaigns which attempt to use fear as part of a punishment procedure are unlikely to succeed. Consistent with established principles of learning, fear is most likely to be effective if the campaign allows for the desired behavior to be reinforced by a reduction in the level of fear. This entails five requirements: 1) fear onset should occur before the desired behavior is offered; 2) the event upon which the fear is based should appear to be likely; 3) a specific desired behavior should be offered as part of the campaign; 4) the level of fear elicited should only be such that the desired behavior offered is sufficient to substantially reduce the fear; 5) fear offset should occur as a reinforcer for the desired behavior, confirming its effectiveness. Under some circumstances it may be difficult to ensure that these requirements are met. In general, a positive reinforcement approach may prove to be more effective than the use of fear. PMID:3276236

Dissociating response systems: erasing fear from memory.

PubMed

Soeter, Marieke; Kindt, Merel

2010-07-01

In addition to the extensive evidence in animals, we previously showed that disrupting reconsolidation by noradrenergic blockade produced amnesia for the original fear response in humans. Interestingly, the declarative memory for the fear association remained intact. These results asked for a solid replication. Moreover, given the constructive nature of memories, the intact recollection of the fear association could eventually 'rebuild' the fear memory, resulting in the spontaneous recovery of the fear response. Yet, perseverance of the amnesic effects would have substantial clinical implications, as even the most effective treatments for psychiatric disorders display high percentages of relapse. Using a differential fear conditioning procedure in humans, we replicated our previous findings by showing that administering propranolol (40mg) prior to memory reactivation eliminated the startle fear response 24h later. But most importantly, this effect persisted at one month follow-up. Notably, the propranolol manipulation not only left the declarative memory for the acquired contingency untouched, but also skin conductance discrimination. In addition, a close association between declarative knowledge and skin conductance responses was found. These findings are in line with the supposed double dissociation of fear conditioning and declarative knowledge relative to the amygdala and hippocampus in humans. They support the view that skin conductance conditioning primarily reflects contingency learning, whereas the startle response is a rather specific measure of fear. Furthermore, the results indicate the absence of a causal link between the actual knowledge of a fear association and its fear response, even though they often operate in parallel. Interventions targeting the amygdalar fear memory may be essential in specifically and persistently dampening the emotional impact of fear. From a clinical and ethical perspective, disrupting reconsolidation points to promising

An Investigation on the Language Anxiety and Fear of Negative Evaluation among Turkish EFL Learners

ERIC Educational Resources Information Center

Aydin, Selami

2008-01-01

Teachers' observations, students' experiences, and the review of related literature indicate that language anxiety is a significant factor adversely affecting the language learning process. Thus, this study aims to investigate the sources and levels of fear of negative evaluation as well as language anxiety among Turkish students as EFL learners,…

Urban Youth, Fear of Crime, and Resulting Defensive Actions.

ERIC Educational Resources Information Center

Williams, J. Sherwood; And Others

1994-01-01

Used data from 1,775 urban youth collected in 1986 to examine fear of crime and defensive actions taken by youth. Results revealed that only 11% reported having taken no defensive actions as result of fear of crime. Nearly three-fifths took precaution of having escort at night. Learning self-defense techniques was reported by 19%; 10% indicated…

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

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.

A safety mechanism for observational learning.

PubMed

Badets, Arnaud; Boutin, Arnaud; Michelet, Thomas

2018-04-01

This empirical article presents the first evidence of a "safety mechanism" based on an observational-learning paradigm. It is accepted that during observational learning, a person can use different strategies to learn a motor skill, but it is unknown whether the learner is able to circumvent the encoding of an uncompleted observed skill. In this study, participants were tested in a dyadic protocol in which an observer watched a participant practicing two different motor sequences during a learning phase. During this phase, one of the two motor sequences was interrupted by a stop signal that precluded motor learning. The results of the subsequent retention test revealed that both groups learned the two motor sequences, but only the physical practice group showed worse performance for the interrupted sequence. The observers were consequently able to use a safety strategy to learn both sequences equally. Our findings are discussed in light of the implications of the action observation network for sequence learning and the cognitive mechanisms of error-based observation.

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

PubMed Central

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

2011-01-01

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

Generalization of fear inhibition by disrupting hippocampal protein synthesis-dependent reconsolidation process.

PubMed

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

2011-09-01

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

Remembering the object you fear: brain potentials during recognition of spiders in spider-fearful individuals.

PubMed

Michalowski, Jaroslaw M; Weymar, Mathias; Hamm, Alfons O

2014-01-01

In the present study we investigated long-term memory for unpleasant, neutral and spider pictures in 15 spider-fearful and 15 non-fearful control individuals using behavioral and electrophysiological measures. During the initial (incidental) encoding, pictures were passively viewed in three separate blocks and were subsequently rated for valence and arousal. A recognition memory task was performed one week later in which old and new unpleasant, neutral and spider pictures were presented. Replicating previous results, we found enhanced memory performance and higher confidence ratings for unpleasant when compared to neutral materials in both animal fearful individuals and controls. When compared to controls high animal fearful individuals also showed a tendency towards better memory accuracy and significantly higher confidence during recognition of spider pictures, suggesting that memory of objects prompting specific fear is also facilitated in fearful individuals. In line, spider-fearful but not control participants responded with larger ERP positivity for correctly recognized old when compared to correctly rejected new spider pictures, thus showing the same effects in the neural signature of emotional memory for feared objects that were already discovered for other emotional materials. The increased fear memory for phobic materials observed in the present study in spider-fearful individuals might result in an enhanced fear response and reinforce negative beliefs aggravating anxiety symptomatology and hindering recovery.

Implications of memory modulation for post-traumatic stress and fear disorders

PubMed Central

Parsons, Ryan G; Ressler, Kerry J

2013-01-01

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

Fear of water in children and adults: etiology and familial effects.

PubMed

Graham, J; Gaffan, E A

1997-02-01

Water-fearful children (non-swimmers. 5-8 yrs and adults (non-swimmers or late learners, 23-73 yr) were compared with non-fearful controls of similar swimming ability. Parallel assessments were carried out with children and adults to investigate water-related experiences, water fear and competence in parents and siblings, and the relationship of water fear to other fear dimensions. Children were assessed behaviorally and by self and mother's report, adults by self-report. In neither children nor adults was there clear evidence that fearful and non-fearful groups differed in incidence of aversive water-related experience before fear onset. Parents usually believed that children's fear was present at first contact. In both samples, we found parent-offspring and sibling resemblances in fear. Analysis of details of children's contact with parents suggested that social learning within the family decreased water fear rather than increasing it; when both child and parent showed fear, that was as likely to reflect genetic influences as modeling. Young children's water fear forms part of a generic cluster, fear of the Unknown or Danger, while in adults it becomes independent of generic fears.

What Can Ethobehavioral Studies Tell Us About The Brain’s Fear System?

PubMed Central

Pellman, Blake A.; Kim, Jeansok J.

2016-01-01

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

A role of nucleus accumbens dopamine receptors in the nucleus accumbens core, but not shell, in fear prediction error.

PubMed

Li, Susan S Y; McNally, Gavan P

2015-08-01

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

Activation of the Infralimbic Cortex in a Fear Context Enhances Extinction Learning

ERIC Educational Resources Information Center

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

2010-01-01

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

Adult-Onset Hypothyroidism Enhances Fear Memory and Upregulates Mineralocorticoid and Glucocorticoid Receptors in the Amygdala

PubMed Central

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

2011-01-01

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

Adult-onset hypothyroidism enhances fear memory and upregulates mineralocorticoid and glucocorticoid receptors in the amygdala.

PubMed

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

2011-01-01

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

Fear expression and return of fear following threat instruction with or without direct contingency experience.

PubMed

Mertens, Gaëtan; Kuhn, Manuel; Raes, An K; Kalisch, Raffael; De Houwer, Jan; Lonsdorf, Tina B

2016-08-01

Prior research showed that mere instructions about the contingency between a conditioned stimulus (CS) and an unconditioned stimulus (US) can generate fear reactions to the CS. Little is known, however, about the extent to which actual CS-US contingency experience adds anything beyond the effect of contingency instructions. Our results extend previous studies on this topic in that it included fear potentiated startle as an additional dependent variable and examined return of fear (ROF) following reinstatement. We observed that CS-US pairings can enhance fear reactions beyond the effect of contingency instructions. Moreover, for all measures of fear, instructions elicited immediate fear reactions that could not be completely overridden by subsequent situational safety information. Finally, ROF following reinstatement for instructed CS+s was unaffected by actual experience. In summary, our results demonstrate the power of contingency instructions and reveal the additional impact of actual experience of CS-US pairings.

The role of the medial prefrontal cortex in trace fear extinction

PubMed Central

Kwapis, Janine L.; Jarome, Timothy J.

2015-01-01

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

Infralimbic EphB2 Modulates Fear Extinction in Adolescent Rats

PubMed Central

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

2015-01-01

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

Infralimbic EphB2 Modulates Fear Extinction in Adolescent Rats.

PubMed

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

2015-09-09

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

Stress and Fear Extinction

PubMed Central

Maren, Stephen; Holmes, Andrew

2016-01-01

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

Fear memory consolidation in sleep requires protein kinase A.

PubMed

Cho, Jiyeon; Sypniewski, Krzysztof A; Arai, Shoko; Yamada, Kazuo; Ogawa, Sonoko; Pavlides, Constantine

2018-05-01

It is well established that protein kinase A (PKA) is involved in hippocampal dependent memory consolidation. Sleep is also known to play an important role in this process. However, whether sleep-dependent memory consolidation involves PKA activation has not been clearly determined. Using behavioral observation, animals were categorized into sleep and awake groups. We show that intrahippocampal injections of the PKA inhibitor Rp-cAMPs in post-contextual fear conditioning sleep produced a suppression of long-term fear memory, while injections of Rp-cAMPs during an awake state, at a similar time point, had no effect. In contrast, injections of the PKA activator Sp-cAMPs in awake state, rescued sleep deprivation-induced memory impairments. These results suggest that following learning, PKA activation specifically in sleep is required for the consolidation of long-term memory. © 2018 Cho et al.; Published by Cold Spring Harbor Laboratory Press.

Distinct Contributions of the Basolateral Amygdala and the Medial Prefrontal Cortex to Learning and Relearning Extinction of Context Conditioned Fear

ERIC Educational Resources Information Center

Laurent, Vincent; Westbrook, R. Frederick

2008-01-01

We studied the roles of the basolateral amygdala (BLA) and the medial prefrontal cortex (mPFC) in learning and relearning to inhibit context conditioned fear (freezing) in extinction. In Experiment 1, pre-extinction BLA infusion of the NMDA receptor (NMDAr) antagonist, ifenprodil, impaired the development and retention of inhibition but…

Extinction training during the reconsolidation window prevents recovery of fear.

PubMed

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

2012-08-24

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

Observational Learning in the Music Masterclass

ERIC Educational Resources Information Center

Haddon, Elizabeth

2014-01-01

This article contributes to research on music masterclasses through examining learning through observation. It investigates how students are learning as observers in this context; whether and how they will transfer their masterclass learning to their own instrumental/vocal development, and whether they have discussed learning through observation.…

Intra-amygdala microinfusion of IL-6 impairs the auditory fear conditioning of rats via JAK/STAT activation.

PubMed

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

2014-12-15

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

Learning enhances intrinsic excitability in a subset of lateral amygdala neurons

PubMed Central

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

2014-01-01

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

Toddlers’ dysregulated fear predicts delta-beta coupling during preschool

PubMed Central

Phelps, Randi A.; Brooker, Rebecca J.; Buss, Kristin A.

2015-01-01

Dysregulated fear, or the persistence of high levels of fear in low-threat contexts, is an early risk factor for the development of anxiety symptoms. Previous work has suggested both propensities for over-control and under-control of fearfulness as risk factors for anxiety problems, each of which may be relevant to observations of dysregulated fear. Given difficulty disentangling over-control and under-control through traditional behavioral measures, we used delta-beta coupling to begin to understand the degree to which dysregulated fear may reflect propensities for over- or under-control. We found that toddlers who showed high levels of dysregulated fear evidenced greater delta-beta coupling at frontal and central electrode sites as preschoolers relative to children who were low in dysregulated fear. Importantly, these differences were not observed when comparisons were made based on fear levels in high threat contexts. Results suggest dysregulated fear may involve tendencies toward over-control at the neural level. PMID:26624221

Shining Light on Social Learning Circuits.

PubMed

Chang, Steve W C; Dal Monte, Olga

2018-05-28

Learning from others powerfully shapes our lives, yet the circuit-specific mechanisms underlying social learning in the brain remain unclear. A recent study in mice provides evidence that direct neuronal projections from the anterior cingulate cortex (ACC) to the basolateral amygdala (BLA) play a critical role in observational fear learning. Copyright © 2018 Elsevier Ltd. All rights reserved.

Fear of missing a lesion: use of simulated breast models to decrease student anxiety when learning clinical breast examinations.

PubMed

Pugh, Carla M; Salud, Lawrence H

2007-06-01

Medical students experience a considerable amount of discomfort during their training. The purpose of the current study was to identify sources of student anxiety when learning clinical breast examinations (CBEs) and to evaluate the effects of simulated breast models on student comfort. Simulated breast models were introduced into the curriculum for 175 second-year medical students. Using surveys, students identified sources of anxiety and rated their comfort levels when learning CBE skills. "Fear of missing a lesion" and the "Intimate/personal nature of the exam" accounted for 73.8% of student anxiety when learning CBEs. In addition, there were significant improvements (P < .05) in student comfort levels when using simulated breast models to learn CBE skills. We have identified 2 of the top causes of anxiety for second-year medical students learning CBE. In addition, we found simulated breast models to be effective in increasing student comfort levels when learning CBEs.

Influence of contingency awareness on neural, electrodermal and evaluative responses during fear conditioning

PubMed Central

Merz, Christian J.; Klucken, Tim; Schweckendiek, Jan; Vaitl, Dieter; Wolf, Oliver T.; Stark, Rudolf

2011-01-01

In an fMRI study, effects of contingency awareness on conditioned responses were assessed in three groups comprising 118 subjects. A differential fear-conditioning paradigm with visual conditioned stimuli, an electrical unconditioned stimulus and two distractors was applied. The instructed aware group was informed about the contingencies, whereas the distractors prevented contingency detection in the unaware group. The third group (learned aware) was not informed about the contingencies, but learned them despite the distractors. Main effects of contingency awareness on conditioned responses emerged in several brain structures. Post hoc tests revealed differential dorsal anterior cingulate, insula and ventral striatum responses in aware conditioning only, whereas the amygdala was activated independent of contingency awareness. Differential responses of the hippocampus were specifically observed in learned aware subjects, indicating a role in the development of contingency awareness. The orbitofrontal cortex showed varying response patterns: lateral structures showed higher responses in instructed aware than unaware subjects, the opposite was true for medial parts. Conditioned subjective and electrodermal responses emerged only in the two aware groups. These results confirm the independence of conditioned amygdala responses from contingency awareness and indicate specific neural circuits for different aspects of fear acquisition in unaware, learned aware and instructed aware subjects. PMID:20693389

Fear of negative evaluation biases social evaluation inference: evidence from a probabilistic learning task.

PubMed

Button, Katherine S; Kounali, Daphne; Stapinski, Lexine; Rapee, Ronald M; Lewis, Glyn; Munafò, Marcus R

2015-01-01

Fear of negative evaluation (FNE) defines social anxiety yet the process of inferring social evaluation, and its potential role in maintaining social anxiety, is poorly understood. We developed an instrumental learning task to model social evaluation learning, predicting that FNE would specifically bias learning about the self but not others. During six test blocks (3 self-referential, 3 other-referential), participants (n = 100) met six personas and selected a word from a positive/negative pair to finish their social evaluation sentences "I think [you are / George is]…". Feedback contingencies corresponded to 3 rules, liked, neutral and disliked, with P[positive word correct] = 0.8, 0.5 and 0.2, respectively. As FNE increased participants selected fewer positive words (β = -0.4, 95% CI -0.7, -0.2, p = 0.001), which was strongest in the self-referential condition (FNE × condition 0.28, 95% CI 0.01, 0.54, p = 0.04), and the neutral and dislike rules (FNE × condition × rule, p = 0.07). At low FNE the proportion of positive words selected for self-neutral and self-disliked greatly exceeded the feedback contingency, indicating poor learning, which improved as FNE increased. FNE is associated with differences in processing social-evaluative information specifically about the self. At low FNE this manifests as insensitivity to learning negative self-referential evaluation. High FNE individuals are equally sensitive to learning positive or negative evaluation, which although objectively more accurate, may have detrimental effects on mental health.

Individual differences in recovery from traumatic fear

PubMed Central

Holmes, Andrew; Singewald, Nicolas

2013-01-01

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

Early-life inflammation with LPS delays fear extinction in adult rodents.

PubMed

Doenni, V M; Song, C M; Hill, M N; Pittman, Q J

2017-07-01

A large body of evidence has been brought forward connecting developmental immune activation to abnormal fear and anxiety levels. Anxiety disorders have extremely high lifetime prevalence, yet susceptibility factors that contribute to their emergence are poorly understood. In this research we investigated whether an inflammatory insult early in life can alter the response to fear conditioning in adulthood. Fear learning and extinction are important and adaptive behaviors, mediated largely by the amygdala and its interconnectivity with cortico-limbic circuits. Male and female rat pups were given LPS (100μg/kg i.p.) or saline at postnatal day 14; LPS activated cFos expression in the central amygdala 2.5h after exposure, but not the basal or lateral nuclei. When tested in adulthood, acquisition of an auditory cued or contextual learned fear memory was largely unaffected as was the extinction of fear to a conditioned context. However, we detected a deficit in auditory fear extinction in male and female rats that experienced early-life inflammation, such that there is a significant delay in fear extinction processes resulting in more sustained fear behaviors in response to a conditioned cue. This response was specific to extinction training and did not persist into extinction recall. The effect could not be explained by differences in pain threshold (unaltered) or in baseline anxiety, which was elevated in adolescent females only and unaltered in adolescent males and adult males and females. This research provides further evidence for the involvement of the immune system during development in the shaping of fear and anxiety related behaviors. Copyright © 2016 Elsevier Inc. All rights reserved.

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.