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Sample records for conditioned fear memories

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

    PubMed

    Kida, Satoshi

    2014-11-01

    Pavlovian fear conditioning is a model of fear learning and memory. The mechanisms regulating fear conditioning and memory have been investigated in humans and rodents. In this paradigm, animals learn and memorize an association between a conditioned stimulus (CS), such as context, and an unconditioned stimulus (US), such as an electrical footshock that induces fear. Fear memory generated though fear conditioning is stabilized via a memory consolidation process. Moreover, recent studies have shown the existence of memory processes that control fear memory following the retrieval of consolidated memory. Indeed, when fear memory is retrieved by re-exposure to the CS, the retrieved memory is re-stabilized via the reconsolidation process. On the other hand, the retrieval of fear memory by prolonged re-exposure to the CS also leads to fear memory extinction, new inhibitory learning against the fear memory, in which animals learn that they do not need to respond to the CS. Importantly, the reinforcement of fear memory after retrieval (i.e., re-experience such as flashbacks or nightmares) has been thought to be associated with the development of emotional disorders such as post-traumatic stress disorder (PTSD). In this review, I summarize recent progress in studies on the mechanism of fear conditioning and memory consolidation, reconsolidation and extinction, and furthermore, introduce our recent establishment of a mouse PTSD model that shows enhancement of fear memory after retrieval. PMID:25536762

  2. Fear Memory.

    PubMed

    Izquierdo, Ivan; Furini, Cristiane R G; Myskiw, Jociane C

    2016-04-01

    Fear memory is the best-studied form of memory. It was thoroughly investigated in the past 60 years mostly using two classical conditioning procedures (contextual fear conditioning and fear conditioning to a tone) and one instrumental procedure (one-trial inhibitory avoidance). Fear memory is formed in the hippocampus (contextual conditioning and inhibitory avoidance), in the basolateral amygdala (inhibitory avoidance), and in the lateral amygdala (conditioning to a tone). The circuitry involves, in addition, the pre- and infralimbic ventromedial prefrontal cortex, the central amygdala subnuclei, and the dentate gyrus. Fear learning models, notably inhibitory avoidance, have also been very useful for the analysis of the biochemical mechanisms of memory consolidation as a whole. These studies have capitalized on in vitro observations on long-term potentiation and other kinds of plasticity. The effect of a very large number of drugs on fear learning has been intensively studied, often as a prelude to the investigation of effects on anxiety. The extinction of fear learning involves to an extent a reversal of the flow of information in the mentioned structures and is used in the therapy of posttraumatic stress disorder and fear memories in general. PMID:26983799

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

    ERIC Educational Resources Information Center

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

    2013-01-01

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

  4. 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

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

    PubMed

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

    2012-03-17

    Posttraumatic stress disorder (PTSD) is an anxiety disorder triggered by traumatic events. Symptoms include anxiety, depression and deficits in fear memory extinction (FE). PTSD patients show a higher prevalence of cigarette smoking than the general population. The present study investigated the effects of cotinine, a tobacco-derived compound, over anxiety and contextual fear memory after fear conditioning (FC) in mice, a model for inducing PTSD-like symptoms. Two-month-old C57BL/6J mice were separated into three experimental groups. These groups were used to investigate the effect of pretreatment with cotinine on contextual fear memory and posttreatment on extinction and stability or retrievability of the fear memory. Also, changes induced by cotinine on the expression of extracellular signal-regulated kinase (ERK)1/2 were assessed after extinction in the hippocampus. An increase in anxiety and corticosterone levels were found after fear conditioning. Cotinine did not affect corticosterone levels but enhanced the extinction of contextual fear, decreased anxiety and the stability and/or retrievability of contextual fear memory. Cotinine-treated mice showed higher levels of the active forms of ERK1/2 than vehicle-treated mice after FC. This evidence suggests that cotinine is a potential new pharmacological treatment to reduce symptoms in individuals with PTSD. PMID:22137886

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

    PubMed Central

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

    2011-01-01

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

  7. 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 PMID:25894546

  8. Brain Region-Specific Activity Patterns after Recent or Remote Memory Retrieval of Auditory Conditioned Fear

    ERIC Educational Resources Information Center

    Kwon, Jeong-Tae; Jhang, Jinho; Kim, Hyung-Su; Lee, Sujin; Han, Jin-Hee

    2012-01-01

    Memory is thought to be sparsely encoded throughout multiple brain regions forming unique memory trace. Although evidence has established that the amygdala is a key brain site for memory storage and retrieval of auditory conditioned fear memory, it remains elusive whether the auditory brain regions may be involved in fear memory storage or…

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

    PubMed

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

    2013-07-01

    It is widely assumed that learning and memory processes play an important role in the pathogenesis, expression, maintenance and therapy of anxiety disorders, such as phobias or post-traumatic stress disorder (PTSD). Memory retrieval is involved in symptom expression and maintenance of these disorders, while memory extinction is believed to be the underlying mechanism of behavioral exposure therapy of anxiety disorders. There is abundant evidence that stress and stress hormones can reduce memory retrieval of emotional information, whereas they enhance memory consolidation of extinction training. In this study we aimed at investigating if stress affects these memory processes in a fear conditioning paradigm in healthy human subjects. On day 1, fear memory was acquired through a standard differential fear conditioning procedure. On day 2 (24h after fear acquisition), participants either underwent a stressful cold pressor test (CPT) or a control condition, 20 min before memory retrieval testing and extinction training. Possible prolonged effects of the stress manipulation were investigated on day 3 (48 h after fear acquisition), when memory retrieval and extinction were tested again. On day 2, men in the stress group showed a robust cortisol response to stress and showed lower unconditioned stimulus (US) expectancy ratings than men in the control group. This reduction in fear memory retrieval was maintained on day 3. In women, who showed a significantly smaller cortisol response to stress than men, no stress effects on fear memory retrieval were observed. No group differences were observed with respect to extinction. In conclusion, the present study provides evidence that stress can reduce memory retrieval of conditioned fear in men. Our findings may contribute to the understanding of the effects of stress and glucocorticoids on fear symptoms in anxiety disorders and suggest that such effects may be sex-specific. PMID:23333200

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

    PubMed Central

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

    2014-01-01

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

  11. Brain region-specific activity patterns after recent or remote memory retrieval of auditory conditioned fear.

    PubMed

    Kwon, Jeong-Tae; Jhang, Jinho; Kim, Hyung-Su; Lee, Sujin; Han, Jin-Hee

    2012-01-01

    Memory is thought to be sparsely encoded throughout multiple brain regions forming unique memory trace. Although evidence has established that the amygdala is a key brain site for memory storage and retrieval of auditory conditioned fear memory, it remains elusive whether the auditory brain regions may be involved in fear memory storage or retrieval. To investigate this possibility, we systematically imaged the brain activity patterns in the lateral amygdala, MGm/PIN, and AuV/TeA using activity-dependent induction of immediate early gene zif268 after recent and remote memory retrieval of auditory conditioned fear. Consistent with the critical role of the amygdala in fear memory, the zif268 activity in the lateral amygdala was significantly increased after both recent and remote memory retrieval. Interesting, however, the density of zif268 (+) neurons in both MGm/PIN and AuV/TeA, particularly in layers IV and VI, was increased only after remote but not recent fear memory retrieval compared to control groups. Further analysis of zif268 signals in AuV/TeA revealed that conditioned tone induced stronger zif268 induction compared to familiar tone in each individual zif268 (+) neuron after recent memory retrieval. Taken together, our results support that the lateral amygdala is a key brain site for permanent fear memory storage and suggest that MGm/PIN and AuV/TeA might play a role for remote memory storage or retrieval of auditory conditioned fear, or, alternatively, that these auditory brain regions might have a different way of processing for familiar or conditioned tone information at recent and remote time phases. PMID:22993170

  12. Relationship between Fear Conditionability and Aversive Memories: Evidence from a Novel Conditioned-Intrusion Paradigm

    PubMed Central

    Wegerer, Melanie; Blechert, Jens; Kerschbaum, Hubert; Wilhelm, Frank H.

    2013-01-01

    Intrusive memories – a hallmark symptom of posttraumatic stress disorder (PTSD) – are often triggered by stimuli possessing similarity with cues that predicted or accompanied the traumatic event. According to learning theories, intrusive memories can be seen as a conditioned response to trauma reminders. However, direct laboratory evidence for the link between fear conditionability and intrusive memories is missing. Furthermore, fear conditioning studies have predominantly relied on standardized aversive stimuli (e.g. electric stimulation) that bear little resemblance to typical traumatic events. To investigate the general relationship between fear conditionability and aversive memories, we tested 66 mentally healthy females in a novel conditioned-intrusion paradigm designed to model real-life traumatic experiences. The paradigm included a differential fear conditioning procedure with neutral sounds as conditioned stimuli and short violent film clips as unconditioned stimuli. Subsequent aversive memories were assessed through a memory triggering task (within 30 minutes, in the laboratory) and ambulatory assessment (involuntary aversive memories in the 2 days following the experiment). Skin conductance responses and subjective ratings demonstrated successful differential conditioning indicating that naturalistic aversive film stimuli can be used in a fear conditioning experiment. Furthermore, aversive memories were elicited in response to the conditioned stimuli during the memory triggering task and also occurred in the 2 days following the experiment. Importantly, participants who displayed higher conditionability showed more aversive memories during the memory triggering task and during ambulatory assessment. This suggests that fear conditioning constitutes an important source of persistent aversive memories. Implications for PTSD and its treatment are discussed. PMID:24244407

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

    PubMed

    Feng, Tingyong; Feng, Pan; Chen, Zhencai

    2013-07-26

    Investigations of fear conditioning in rodents and humans have illuminated the neural mechanisms of fear acquisition and extinction. However, the neural mechanism of automatic memory consolidation of fear conditioning is still unclear. To address this question, we measured brain activity following fear acquisition using resting-state functional magnetic resonance imaging (rs-fMRI). In the current study, we used a marker of fMRI, amplitude of low-frequency (0.01-0.08Hz) fluctuation (ALFF) to quantify the spontaneous brain activity. Brain activity correlated to fear memory consolidation was observed in parahippocampus, insula, and thalamus in resting-state. Furthermore, after acquired fear conditioning, compared with control group some brain areas showed ALFF increased in ventromedial prefrontal cortex (vmPFC) and anterior cingulate cortex (ACC) in the experimental group, whereas some brain areas showed decreased ALFF in striatal regions (caudate, putamen). Moreover, the change of ALFF in vmPFC was positively correlated with the subjective fear ratings. These findings suggest that the parahippocampus, insula, and thalamus are the neural substrates of fear memory consolidation. The difference in activity could be attributed to a homeostatic process in which the vmPFC and ACC were involved in the fear recovery process, and change of ALFF in vmPFC predicts subjective fear ratings. PMID:23726994

  14. Inhibition of prefrontal protein synthesis following recall does not disrupt memory for trace fear conditioning

    PubMed Central

    Blum, Sonja; Runyan, Jason D; Dash, Pramod K

    2006-01-01

    Background The extent of similarity between consolidation and reconsolidation is not yet fully understood. One of the differences noted is that not every brain region involved in consolidation exhibits reconsolidation. In trace fear conditioning, the hippocampus and the medial prefrontal cortex (mPFC) are required for consolidation of long-term memory. We have previously demonstrated that trace fear memory is susceptible to infusion of the protein synthesis inhibitor anisomycin into the hippocampus following recall. In the present study, we examine whether protein synthesis inhibition in the mPFC following recall similarly results in the observation of reconsolidation of trace fear memory. Results Targeted intra-mPFC infusions of anisomycin or vehicle were performed immediately following recall of trace fear memory at 24 hours, or at 30 days, following training in a one-day or a two-day protocol. The present study demonstrates three key findings: 1) trace fear memory does not undergo protein synthesis dependent reconsolidation in the PFC, regardless of the intensity of the training, and 2) regardless of whether the memory is recent or remote, and 3) intra-mPFC inhibition of protein synthesis immediately following training impaired remote (30 days) memory. Conclusion These results suggest that not all structures that participate in memory storage are involved in reconsolidation. Alternatively, certain types of memory-related information may reconsolidate, while other components of memory may not. PMID:17026758

  15. Revealing Context-Specific Conditioned Fear Memories with Full Immersion Virtual Reality

    PubMed Central

    Huff, Nicole C.; Hernandez, Jose Alba; Fecteau, Matthew E.; Zielinski, David J.; Brady, Rachael; LaBar, Kevin S.

    2011-01-01

    The extinction of conditioned fear is known to be context-specific and is often considered more contextually bound than the fear memory itself (Bouton, 2004). Yet, recent findings in rodents have challenged the notion that contextual fear retention is initially generalized. The context-specificity of a cued fear memory to the learning context has not been addressed in the human literature largely due to limitations in methodology. Here we adapt a novel technology to test the context-specificity of cued fear conditioning using full immersion 3-D virtual reality (VR). During acquisition training, healthy participants navigated through virtual environments containing dynamic snake and spider conditioned stimuli (CSs), one of which was paired with electrical wrist stimulation. During a 24-h delayed retention test, one group returned to the same context as acquisition training whereas another group experienced the CSs in a novel context. Unconditioned stimulus expectancy ratings were assayed on-line during fear acquisition as an index of contingency awareness. Skin conductance responses time-locked to CS onset were the dependent measure of cued fear, and skin conductance levels during the interstimulus interval were an index of context fear. Findings indicate that early in acquisition training, participants express contingency awareness as well as differential contextual fear, whereas differential cued fear emerged later in acquisition. During the retention test, differential cued fear retention was enhanced in the group who returned to the same context as acquisition training relative to the context shift group. The results extend recent rodent work to illustrate differences in cued and context fear acquisition and the contextual specificity of recent fear memories. Findings support the use of full immersion VR as a novel tool in cognitive neuroscience to bridge rodent models of contextual phenomena underlying human clinical disorders. PMID:22069384

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

    PubMed

    Feng, Pan; Feng, Tingyong; Chen, Zhencai; Lei, Xu

    2014-11-01

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

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

    PubMed Central

    Feng, Pan; Chen, Zhencai; Lei, Xu

    2014-01-01

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

  18. Eye Movements Index Implicit Memory Expression in Fear Conditioning

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2015-01-01

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

  20. THE IκB KINASE REGULATES CHROMATIN STRUCTURE DURING RECONSOLIDATION OF CONDITIONED FEAR MEMORIES

    PubMed Central

    Lubin, Farah D.; Sweatt, J. David

    2007-01-01

    Summary Previously formed memories are susceptible to disruption immediately after recall due to a necessity to be reconsolidated after retrieval. Protein translation mechanisms have been widely implicated as being necessary for memory reconsolidation, but gene transcription mechanisms have been much less extensively studied in this context. We found that retrieval of contextual conditioned fear memories activates the NF-κB pathway to regulate histone H3 phosphorylation and acetylation at specific gene promoters in hippocampus, specifically via IKKα and not the NF-κB DNA-binding complex. Behaviorally, we found that inhibition of IKKα regulation of either chromatin structure or NF-κB DNA-binding complex activity leads to impairments in fear memory reconsolidation, and that elevating histone acetylation rescues this memory deficit in the face of IKK blockade. These data provide novel insights into IKK-regulated transcriptional mechanisms in hippocampus that are necessary for memory reconsolidation. PMID:17880897

  1. Low levels of estradiol are associated with elevated conditioned responding during fear extinction and with intrusive memories in daily life

    PubMed Central

    Wegerer, Melanie; Kerschbaum, Hubert; Blechert, Jens; Wilhelm, Frank H.

    2014-01-01

    Posttraumatic stress disorder (PTSD) can be conceptualized as a disorder of emotional memory showing strong (conditioned) responses to trauma reminders and intrusive memories among other symptoms. Women are at greater risk of developing PTSD than men. Recent studies have demonstrated an influence of ovarian steroid hormones in both fear conditioning and intrusive memory paradigms. However, although intrusive memories are considered non-extinguished emotional reactions to trauma reminders, none of the previous studies has investigated effects of ovarian hormones on fear conditioning mechanisms and intrusive memories in conjunction. This may have contributed to an overall inconsistent picture of the role of these hormones in emotional learning and memory. To remedy this, we exposed 37 healthy women with a natural menstrual cycle (during early follicular or luteal cycle phase) to a novel conditioned-intrusion paradigm designed to model real-life traumatic experiences. The paradigm included a differential fear conditioning procedure with short violent film clips as unconditioned stimuli. Intrusive memories about the film clips were assessed ambulatorily on subsequent days. Women with lower levels of estradiol displayed elevated differential conditioned skin conductance responding during fear extinction and showed stronger intrusive memories. The inverse relationship between estradiol and intrusive memories was at least partially accounted for by the conditioned responding observed during fear extinction. Progesterone levels were not associated with either fear acquisition/extinction or with intrusive memories. This suggests that lower levels of estradiol might promote stronger symptoms of PTSD through associative processes. PMID:25463649

  2. Low levels of estradiol are associated with elevated conditioned responding during fear extinction and with intrusive memories in daily life.

    PubMed

    Wegerer, Melanie; Kerschbaum, Hubert; Blechert, Jens; Wilhelm, Frank H

    2014-12-01

    Posttraumatic stress disorder (PTSD) can be conceptualized as a disorder of emotional memory showing strong (conditioned) responses to trauma reminders and intrusive memories among other symptoms. Women are at greater risk of developing PTSD than men. Recent studies have demonstrated an influence of ovarian steroid hormones in both fear conditioning and intrusive memory paradigms. However, although intrusive memories are considered non-extinguished emotional reactions to trauma reminders, none of the previous studies has investigated effects of ovarian hormones on fear conditioning mechanisms and intrusive memories in conjunction. This may have contributed to an overall inconsistent picture of the role of these hormones in emotional learning and memory. To remedy this, we exposed 37 healthy women with a natural menstrual cycle (during early follicular or luteal cycle phase) to a novel conditioned-intrusion paradigm designed to model real-life traumatic experiences. The paradigm included a differential fear conditioning procedure with short violent film clips as unconditioned stimuli. Intrusive memories about the film clips were assessed ambulatorily on subsequent days. Women with lower levels of estradiol displayed elevated differential conditioned skin conductance responding during fear extinction and showed stronger intrusive memories. The inverse relationship between estradiol and intrusive memories was at least partially accounted for by the conditioned responding observed during fear extinction. Progesterone levels were not associated with either fear acquisition/extinction or with intrusive memories. This suggests that lower levels of estradiol might promote stronger symptoms of PTSD through associative processes. PMID:25463649

  3. Effects of enhanced zinc and copper in drinking water on spatial memory and fear conditioning

    USGS Publications Warehouse

    Chrosniak, L.D.; Smith, L.N.; McDonald, C.G.; Jones, B.F.; Flinn, J.M.

    2006-01-01

    Ingestion of enhanced zinc can cause memory impairments and copper deficiencies. This study examined the effect of zinc supplementation, with and without copper, on two types of memory. Rats raised pre- and post-natally on 10 mg/kg ZnCO3 or ZnSO4 in the drinking water were tested in a fear-conditioning experiment at 11 months of age. Both zinc groups showed a maladaptive retention of fearful memories compared to controls raised on tap water. Rats raised on 10 mg/kg ZnCO3, 10 mg/kg ZnCO3 + 0.25 mg/kg CuCl2, or tap water, were tested for spatial memory ability at 3 months of age. Significant improvements in performance were found in the ZnCO3 + CuCl2 group compared to the ZnCO3 group, suggesting that some of the cognitive deficits associated with zinc supplementation may be remediated by addition of copper. ?? 2005 Elsevier B.V. All rights reserved.

  4. Retrieving fear memories, as time goes by….

    PubMed

    Do Monte, F H; Quirk, G J; Li, B; Penzo, M A

    2016-08-01

    Research in fear conditioning has provided a comprehensive picture of the neuronal circuit underlying the formation of fear memories. In contrast, our understanding of the retrieval of fear memories is much more limited. This disparity may stem from the fact that fear memories are not rigid, but reorganize over time. To bring some clarity and raise awareness about the time-dependent dynamics of retrieval circuits, we review current evidence on the neuronal circuitry participating in fear memory retrieval at both early and late time points following auditory fear conditioning. We focus on the temporal recruitment of the paraventricular nucleus of the thalamus (PVT) for the retrieval and maintenance of fear memories. Finally, we speculate as to why retrieval circuits change with time, and consider the functional strategy of recruiting structures not previously considered as part of the retrieval circuit. PMID:27217148

  5. Pre-test metyrapone impairs memory recall in fear conditioning tasks: lack of interaction with β-adrenergic activity

    PubMed Central

    Careaga, Mariella B. L.; Tiba, Paula A.; Ota, Simone M.; Suchecki, Deborah

    2015-01-01

    Cognitive processes, such as learning and memory, are essential for our adaptation to environmental changes and consequently for survival. Numerous studies indicate that hormones secreted during stressful situations, such as glucocorticoids (GCs), adrenaline and noradrenaline, regulate memory functions, modulating aversive memory consolidation and retrieval, in an interactive and complementary way. Thus, the facilitatory effects of GCs on memory consolidation as well as their suppressive effects on retrieval are substantially explained by this interaction. On the other hand, low levels of GCs are also associated with negative effects on memory consolidation and retrieval and the mechanisms involved are not well understood. The present study sought to investigate the consequences of blocking the rise of GCs on fear memory retrieval in multiple tests, assessing the participation of β-adrenergic signaling on this effect. Metyrapone (GCs synthesis inhibitor; 75 mg/kg), administered 90 min before the first test of contextual or tone fear conditioning (TFC), negatively affected animals’ performances, but this effect did not persist on a subsequent test, when the conditioned response was again expressed. This result suggested that the treatment impaired fear memory retrieval during the first evaluation. The administration immediately after the first test did not affect the animals’ performances in contextual fear conditioning (CFC), suggesting that the drug did not interfere with processes triggered by memory reactivation. Moreover, metyrapone effects were independent of β-adrenergic signaling, since concurrent administration with propranolol (2 mg/kg), a β-adrenergic antagonist, did not modify the effects induced by metyrapone alone. These results demonstrate that pre-test metyrapone administration led to negative effects on fear memory retrieval and this action was independent of a β-adrenergic signaling. PMID:25784866

  6. Facilitation of contextual fear memory extinction and anti-anxiogenic effects of AM404 and cannabidiol in conditioned rats.

    PubMed

    Bitencourt, Rafael M; Pamplona, Fabrício A; Takahashi, Reinaldo N

    2008-12-01

    The present study investigated the central effects of the eCB uptake/metabolism inhibitor AM404 and the phytocannabinoid cannabidiol (CBD) on the extinction of contextual fear memories in rats. Rats were conditioned and 24 h later subjected to three consecutive 9-min non-reinforced exposures to the conditioning context (extinction sessions, 24 h intervals). AM404 or CBD was injected i.c.v. 5 min before each extinction session and a 3-min drug-free test of contextual memory was performed 24 h after the last extinction session. AM404 (1.0 microg/microl, i.c.v.) and CBD (2.0 microg/microl, i.c.v.) facilitated extinction of contextual fear memory, with persistent effects. These responses were antagonized by the CB1-selective antagonist SR141716A (0.2 mg/kg, i.p.), but not by the TRPV1-selective antagonist capsazepine (5.0 microg/microl, i.c.v.). The effect of the anxiolytic drug Diazepam (DZP) on the extinction of contextual fear memory was also investigated. In contrast with the CBD and AM404 results, DZP induced a general reduction in the expression of conditioned freezing. Both AM404 and CBD induced anti-anxiogenic effect in the fear-potentiated plus-maze test, whereas DZP was anxiolytic in conditioned and unconditioned rats. In conclusion, CBD, a non-psychoactive phytocannabinoid could be an interesting pharmacological approach to reduce the anxiogenic effects of stress and promote the extinction of fear memories. PMID:18706790

  7. Effects of sleep deprivation on different phases of memory in the rat: dissociation between contextual and tone fear conditioning tasks

    PubMed Central

    Rossi, Vanessa Contatto; Tiba, Paula Ayako; Moreira, Karin Di Monteiro; Ferreira, Tatiana Lima; Oliveira, Maria Gabriela Menezes; Suchecki, Deborah

    2014-01-01

    Numerous studies show that sleep deprivation (SD) impacts negatively on cognitive processes, including learning and memory. Memory formation encompasses distinct phases of which acquisition, consolidation and retrieval are better known. Previous studies with pre-training SD induced by the platform method have shown impairment in fear conditioning tasks. Nonetheless, pre-training manipulations do not allow the distinction between effects on acquisition and/or consolidation, interfering, ultimately, on recall of/performance in the task. In the present study, animals were first trained in contextual and tone fear conditioning (TFC) tasks and then submitted to SD with the purpose to evaluate the effect of this manipulation on different stages of the learning process, e.g., in the uptake of (new) information during learning, its encoding and stabilization, and the recall of stored memories. Besides, we also investigated the effect of SD in the extinction of fear memory and a possible state-dependent learning induced by this manipulation. For each task (contextual or TFC), animals were trained and then distributed into control, not sleep-deprived (CTL) and SD groups, the latter being submitted to the modified multiple platform paradigm for 96 h. Subsets of eight rats in each group/experiment were submitted to the test of the tasks, either immediately or at different time intervals after SD. The results indicated that (a) pre- but not post-training SD impaired recall in the contextual and TFC; (b) this impairment was not state-dependent; and (c) in the contextual fear conditioning (CFC), pre-test SD prevented extinction of the learned task. Overall, these results suggest that SD interferes with acquisition, recall and extinction, but not necessarily with consolidation of emotional memory. PMID:25426040

  8. Prefrontal neuronal circuits of contextual fear conditioning.

    PubMed

    Rozeske, R R; Valerio, S; Chaudun, F; Herry, C

    2015-01-01

    Over the past years, numerous studies have provided a clear understanding of the neuronal circuits and mechanisms involved in the formation, expression and extinction phases of conditioned cued fear memories. Yet, despite a strong clinical interest, a detailed understanding of these memory phases for contextual fear memories is still missing. Besides the well-known role of the hippocampus in encoding contextual fear behavior, growing evidence indicates that specific regions of the medial prefrontal cortex differentially regulate contextual fear acquisition and storage in both animals and humans that ultimately leads to expression of contextual fear memories. In this review, we provide a detailed description of the recent literature on the role of distinct prefrontal subregions in contextual fear behavior and provide a working model of the neuronal circuits involved in the acquisition, expression and generalization of contextual fear memories. PMID:25287656

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

    PubMed

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

    2016-06-15

    Patients with Alzheimer's disease (AD) experience a wide array of cognitive deficits, which typically include the impairment of explicit memory. In previous studies, the authors reported that a flavonoid, quercetin, reduces the expression of ATF4 and delays memory deterioration in an early-stage AD mouse model. In the present study, the effects of long-term quercetin intake on memory recall were assessed using contextual fear conditioning in aged wild-type mice. In addition, the present study examined whether memory recall was affected by the intake of quercetin-rich onion (a new cultivar of hybrid onion 'Quergold') powder in early-stage AD patients. In-vivo analysis indicated that memory recall was enhanced in aged mice fed a quercetin-containing diet. Memory recall in early-stage AD patients, determined using the Revised Hasegawa Dementia Scale, was significantly improved by the intake of quercetin-rich onion (Quergold) powder for 4 weeks compared with the intake of control onion ('Mashiro' white onion) powder. These results indicate that quercetin might influence memory recall. PMID:27145228

  10. Differences in memory development among C57BL/6NCrl, 129S2/SvPasCrl, and FVB/NCrl mice after delay and trace fear conditioning.

    PubMed

    March, Amelia; Borchelt, David; Golde, Todd; Janus, Christopher

    2014-02-01

    Fear-conditioning testing paradigms have been used to study differences in memory formation between inbred mouse strains, including numerous mouse models of human diseases. In this study, we characterized the conditioned fear memory of 3 inbred strains: C57BL/6NCrl, 129S2/SvPasCrl, and FVB/NCrl, obtained from Charles River Laboratories. We used 2 training paradigms: delay conditioning, in which an unconditional stimulus coterminates with the presentation of a conditional stimulus, and trace conditioning, in which the conditional and unconditional stimuli are separated by a trace interval. In each paradigm, we evaluated the recent (3 d) and remote (25 d) memory of the mice by using a longitudinal design. Our results showed that both C57BL/6NCrl and 129S2/SvPasCrl mice developed strong and long-lasting context and tone memories in both paradigms, but FVB/NCrl mice showed a weaker but nevertheless consistent tone memory after delay training. Tone memory in the FVB strain was stronger in male than female mice. The remote tone memory of 129S2/SvPasCrl mice diminished after delay training but was stable and stronger than that of C57BL/6NCrl mice after trace training. In conclusion, both C57BL/6NCrl and 129S2/SvPasCrl mice showed reliable and long-lasting fear memory after delay or trace training, with 129 mice showing particularly strong tone memory after trace conditioning. The FVB/NCrl strain, especially male mice, showed reliable tone fear memory after delay training. Our findings confirm that both C57BL/6NCrl and 129S2/SvPasCrl mice develop strong context and tone memory in delay and trace fear-conditioning paradigms. PMID:24672832

  11. Differences in Memory Development among C57BL/6NCrl, 129S2/SvPasCrl, and FVB/NCrl Mice after Delay and Trace Fear Conditioning

    PubMed Central

    March, Amelia; Borchelt, David; Golde, Todd; Janus, Christopher

    2014-01-01

    Fear-conditioning testing paradigms have been used to study differences in memory formation between inbred mouse strains, including numerous mouse models of human diseases. In this study, we characterized the conditioned fear memory of 3 inbred strains: C57BL/6NCrl, 129S2/SvPasCrl, and FVB/NCrl, obtained from Charles River Laboratories. We used 2 training paradigms: delay conditioning, in which an unconditional stimulus coterminates with the presentation of a conditional stimulus, and trace conditioning, in which the conditional and unconditional stimuli are separated by a trace interval. In each paradigm, we evaluated the recent (3 d) and remote (25 d) memory of the mice by using a longitudinal design. Our results showed that both C57BL/6NCrl and 129S2/SvPasCrl mice developed strong and long-lasting context and tone memories in both paradigms, but FVB/NCrl mice showed a weaker but nevertheless consistent tone memory after delay training. Tone memory in the FVB strain was stronger in male than female mice. The remote tone memory of 129S2/SvPasCrl mice diminished after delay training but was stable and stronger than that of C57BL/6NCrl mice after trace training. In conclusion, both C57BL/6NCrl and 129S2/SvPasCrl mice showed reliable and long-lasting fear memory after delay or trace training, with 129 mice showing particularly strong tone memory after trace conditioning. The FVB/NCrl strain, especially male mice, showed reliable tone fear memory after delay training. Our findings confirm that both C57BL/6NCrl and 129S2/SvPasCrl mice develop strong context and tone memory in delay and trace fear-conditioning paradigms. PMID:24672832

  12. Memory suppression trades prolonged fear and sleep-dependent fear plasticity for the avoidance of current fear

    NASA Astrophysics Data System (ADS)

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

    2013-07-01

    Sleep deprivation immediately following an aversive event reduces fear by preventing memory consolidation during homeostatic sleep. This suggests that acute insomnia might act prophylactically against the development of posttraumatic stress disorder (PTSD) even though it is also a possible risk factor for PTSD. We examined total sleep deprivation and memory suppression to evaluate the effects of these interventions on subsequent aversive memory formation and fear conditioning. Active suppression of aversive memory impaired retention of event memory. However, although the remembered fear was more reduced in sleep-deprived than sleep-control subjects, suppressed fear increased, and seemed to abandon the sleep-dependent plasticity of fear. Active memory suppression, which provides a psychological model for Freud's ego defense mechanism, enhances fear and casts doubt on the potential of acute insomnia as a prophylactic measure against PTSD. Our findings bring into question the role of sleep in aversive-memory consolidation in clinical PTSD pathophysiology.

  13. Involvement of dopaminergic and cholinergic systems in social isolation-induced deficits in social affiliation and conditional fear memory in mice.

    PubMed

    Okada, R; Fujiwara, H; Mizuki, D; Araki, R; Yabe, T; Matsumoto, K

    2015-07-23

    Post-weaning social isolation rearing (SI) in rodents elicits various behavioral abnormalities including attention deficit hyperactivity disorder-like behaviors. In order to obtain a better understanding of SI-induced behavioral abnormalities, we herein investigated the effects of SI on social affiliation and conditioned fear memory as well as the neuronal mechanism(s) underlying these effects. Four-week-old male mice were group-housed (GH) or socially isolated for 2-4 weeks before the experiments. The social affiliation test and fear memory conditioning were conducted at the age of 6 and 7 weeks, respectively. SI mice were systemically administered saline or test drugs 30 min before the social affiliation test and fear memory conditioning. Contextual and auditory fear memories were elucidated 1 and 4 days after fear conditioning. Social affiliation and contextual and auditory fear memories were weaker in SI mice than in GH mice. Methylphenidate (MPH), an inhibitor for dopamine transporters, ameliorated the SI-induced social affiliation deficit and the effect was attenuated by SCH23390, a D1 receptor antagonist, but not by sulpiride, a D2 receptor antagonist. On the other hand, tacrine, an acetylcholinesterase inhibitor, had no effect on this deficit. In contrast, tacrine improved SI-induced deficits in fear memories in a manner that was reversed by the muscarinic receptor antagonist scopolamine, while MPH had no effect on memory deficits. Neurochemical studies revealed that SI down-regulated the expression levels of the phosphorylated forms of neuro-signaling proteins, calmodulin-dependent kinase II (p-CaMKII), and cyclic AMP-responsive element binding protein (p-CREB), as well as early growth response protein-1 (Egr-1) in the hippocampus. The administration of MPH or tacrine before fear conditioning had no effect on the levels of the phosphorylated forms of the neuro-signaling proteins elucidated following completion of the auditory fear memory test; however

  14. Deletion of Glutamate Delta-1 Receptor in Mouse Leads to Enhanced Working Memory and Deficit in Fear Conditioning

    PubMed Central

    Yadav, Roopali; Hillman, Brandon G.; Gupta, Subhash C.; Suryavanshi, Pratyush; Bhatt, Jay M.; Pavuluri, Ratnamala; Stairs, Dustin J.; Dravid, Shashank M.

    2013-01-01

    Glutamate delta-1 (GluD1) receptors are expressed throughout the forebrain during development with high levels in the hippocampus during adulthood. We have recently shown that deletion of GluD1 receptor results in aberrant emotional and social behaviors such as hyperaggression and depression-like behaviors and social interaction deficits. Additionally, abnormal expression of synaptic proteins was observed in amygdala and prefrontal cortex of GluD1 knockout mice (GluD1 KO). However the role of GluD1 in learning and memory paradigms remains unknown. In the present study we evaluated GluD1 KO in learning and memory tests. In the eight-arm radial maze GluD1 KO mice committed fewer working memory errors compared to wildtype mice but had normal reference memory. Enhanced working memory in GluD1 KO was also evident by greater percent alternation in the spontaneous Y-maze test. No difference was observed in object recognition memory in the GluD1 KO mice. In the Morris water maze test GluD1 KO mice showed no difference in acquisition but had longer latency to find the platform in the reversal learning task. GluD1 KO mice showed a deficit in contextual and cue fear conditioning but had normal latent inhibition. The deficit in contextual fear conditioning was reversed by D-Cycloserine (DCS) treatment. GluD1 KO mice were also found to be more sensitive to foot-shock compared to wildtype. We further studied molecular changes in the hippocampus, where we found lower levels of GluA1, GluA2 and GluK2 subunits while a contrasting higher level of GluN2B in GluD1 KO. Additionally, we found higher postsynaptic density protein 95 (PSD95) and lower glutamate decarboxylase 67 (GAD67) expression in GluD1 KO. We propose that GluD1 is crucial for normal functioning of synapses and absence of GluD1 leads to specific abnormalities in learning and memory. These findings provide novel insights into the role of GluD1 receptors in the central nervous system. PMID:23560106

  15. Encoding of fear learning and memory in distributed neuronal circuits.

    PubMed

    Herry, Cyril; Johansen, Joshua P

    2014-12-01

    How sensory information is transformed by learning into adaptive behaviors is a fundamental question in neuroscience. Studies of auditory fear conditioning have revealed much about the formation and expression of emotional memories and have provided important insights into this question. Classical work focused on the amygdala as a central structure for fear conditioning. Recent advances, however, have identified new circuits and neural coding strategies mediating fear learning and the expression of fear behaviors. One area of research has identified key brain regions and neuronal coding mechanisms that regulate the formation, specificity and strength of fear memories. Other work has discovered critical circuits and neuronal dynamics by which fear memories are expressed through a medial prefrontal cortex pathway and coordinated activity across interconnected brain regions. Here we review these recent advances alongside prior work to provide a working model of the extended circuits and neuronal coding mechanisms mediating fear learning and memory. PMID:25413091

  16. Post-training re-exposure to fear conditioned stimuli enhances memory consolidation and biases rats toward the use of dorsolateral striatum-dependent response learning.

    PubMed

    Leong, Kah-Chung; Goodman, Jarid; Packard, Mark G

    2015-09-15

    In a dual-solution task that can be acquired using either hippocampus-dependent "place" or dorsolateral striatum-dependent "response" learning, emotional arousal induced by unconditioned stimuli (e.g. anxiogenic drug injections or predator odor exposure) biases rats toward response learning. In the present experiments emotionally-arousing conditioned stimuli were used to modulate the relative use of multiple memory systems. In Experiment 1, adult male Long-Evans rats initially received three standard fear-conditioning trials in which a tone (2 kHz, 75 dB) was paired with a brief electrical shock (1 mA, 2s). On day 2, the rats were trained in a dual-solution plus-maze task to swim from the same start arm (South) to a hidden escape platform always located in the same goal arm (East). Immediately following training, rats received post-training re-exposure to the fear-conditioned stimuli (i.e. tone and context) without shock. On day 3, the relative use of place or response learning was assessed on a probe trial in which rats were started from the opposite start arm (North). Post-training re-exposure to fear-conditioned stimuli produced preferential use of a response strategy. In Experiment 2, different rats received fear conditioning and were then trained in a single-solution task that required the use of response learning. Immediately following training, rats received post-training re-exposure to the fear-conditioned stimuli without shock. Re-exposure to fear-conditioned stimuli enhanced memory consolidation in the response learning task. Thus, re-exposure to fear-conditioned stimuli biases rats toward the use of dorsolateral striatum-dependent response learning and enhances memory consolidation of response learning. PMID:26005126

  17. Modeling fear-conditioned bradycardia in humans.

    PubMed

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

    2016-06-01

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

  18. Age-related increase in amyloid plaque burden is associated with impairment in conditioned fear memory in CRND8 mouse model of amyloidosis

    PubMed Central

    2012-01-01

    Introduction The current pathological confirmation of the diagnosis of Alzheimer's disease (AD) is still based on postmortem identification of parenchymal amyloid beta (Aβ) plaques, intra-neuronal neurofibrillary tangles, and neuronal loss. The memory deficits that are present in the early stages of AD are linked to the dysfunction of structures in the entorhinal cortex and limbic system, especially the hippocampus and amygdala. Using the CRND8 transgenic mouse model of amyloidosis, which over-expresses a mutant human amyloid precursor protein (APP) gene, we evaluated hippocampus-dependent contextual and amygdala-dependent tone fear conditioned (FC) memory, and investigated the relationship between the fear memory indices and Aβ plaque burden. Methods Mice were tested at three, six, and 12 months of age, which corresponds to early, mild, and severe Aβ plaque deposition, following a cross-sectional experimental design. We used a delay version of the fear conditioning paradigm in which tone stimulus was co-terminated with foot-shocks during exploration of the training chamber. The Aβ plaque burden was evaluated at each age after the completion of the behavioral tests. Results CRDN8 mice showed context fear memory comparable to control mice at three and six months, but were significantly impaired at 12 months of age. In contrast, the tone fear memory was significantly impaired in the model at each age of testing. The Aβ plaque burden significantly increased with age, and was correlated with the overall impairment in context and tone fear memory in the CRND8 mice within the studied age. Conclusions Our data extend previous studies showing that other APP mouse models exhibit impairment in fear conditioned memory, by demonstrating that this impairment is progressive and correlates well with an overall increase in Aβ burden. Also, the demonstrated greater sensitivity of the tone conditioning test in the identification of age dependent differences between CRND8 and

  19. Paradoxical mineralocorticoid receptor-mediated effect in fear memory encoding and expression of rats submitted to an olfactory fear conditioning task.

    PubMed

    Souza, Rimenez R; Dal Bó, Silvia; de Kloet, E Ronald; Oitzl, Melly S; Carobrez, Antonio P

    2014-04-01

    There is general agreement that the substantial modification in memory and motivational states exerted by corticosteroids after a traumatic experience is mediated in complementary manner by the mineralocorticoid (MR) and glucocorticoid (GR) receptors. Here we tested the hypothesis that pharmacological manipulation of MR activity would affect behavioral strategy and information storage in an olfactory fear conditioning (OFC) task. Male Wistar rats were submitted to the OFC with different training intensities. We observed that following high intensity OFC acquisition, a set of defensive coping strategies, which includes avoidance and risk assessment behaviors, was elicited when subjects were exposed to the conditioned stimulus (CS) 48 h later. In addition, following either OFC acquisition or retrieval (CS-I test) a profound corticosterone secretion was also detected. Systemic administration of the MR antagonist spironolactone altered the behavioral coping style irrespective the antagonist was administered 60 min prior to the acquisition or before the retrieval session. Surprisingly, the MR agonist fludrocortisone given 60 min prior to acquisition or retrieval of OFC had similar effects as the antagonist. In addition, post-training administration of fludrocortisone, following a weak training procedure, facilitated the consolidation of OFC. Fludrocortisone rather than spironolactone reduced serum corticosterone levels, suggesting that, at least in part, the effects of the MR agonist may derive from additional GR-mediated HPA-axis suppression. In conclusion, the present study suggests the involvement of the MR in the fine-tuning of behavioral adaptation necessary for optimal information storage and expression, as revealed by the marked alterations in the risk assessment behavior. PMID:24296155

  20. Durable fear memories require PSD-95.

    PubMed

    Fitzgerald, P J; Pinard, C R; Camp, M C; Feyder, M; Sah, A; Bergstrom, H C; Graybeal, C; Liu, Y; Schlüter, O M; Grant, S G; Singewald, N; Xu, W; Holmes, A

    2015-07-01

    Traumatic fear memories are highly durable but also dynamic, undergoing repeated reactivation and rehearsal over time. Although overly persistent fear memories underlie anxiety disorders, such as posttraumatic stress disorder, the key neural and molecular mechanisms underlying fear memory durability remain unclear. Postsynaptic density 95 (PSD-95) is a synaptic protein regulating glutamate receptor anchoring, synaptic stability and certain types of memory. Using a loss-of-function mutant mouse lacking the guanylate kinase domain of PSD-95 (PSD-95(GK)), we analyzed the contribution of PSD-95 to fear memory formation and retrieval, and sought to identify the neural basis of PSD-95-mediated memory maintenance using ex vivo immediate-early gene mapping, in vivo neuronal recordings and viral-mediated knockdown (KD) approaches. We show that PSD-95 is dispensable for the formation and expression of recent fear memories, but essential for the formation of precise and flexible fear memories and for the maintenance of memories at remote time points. The failure of PSD-95(GK) mice to retrieve remote cued fear memory was associated with hypoactivation of the infralimbic (IL) cortex (but not the anterior cingulate cortex (ACC) or prelimbic cortex), reduced IL single-unit firing and bursting, and attenuated IL gamma and theta oscillations. Adeno-associated virus-mediated PSD-95 KD in the IL, but not the ACC, was sufficient to impair recent fear extinction and remote fear memory, and remodel IL dendritic spines. Collectively, these data identify PSD-95 in the IL as a critical mechanism supporting the durability of fear memories over time. These preclinical findings have implications for developing novel approaches to treating trauma-based anxiety disorders that target the weakening of overly persistent fear memories. PMID:25510511

  1. 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

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

    ERIC Educational Resources Information Center

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

    2014-01-01

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

  3. Surface expression of hippocampal NMDA GluN2B receptors regulated by fear conditioning determines its contribution to memory consolidation in adult rats.

    PubMed

    Sun, Yan-Yan; Cai, Wei; Yu, Jie; Liu, Shu-Su; Zhuo, Min; Li, Bao-Ming; Zhang, Xue-Han

    2016-01-01

    The number and subtype composition of N-methyl-d-aspartate receptor (NMDAR) at synapses determines their functional properties and role in learning and memory. Genetically increased or decreased amount of GluN2B affects hippocampus-dependent memory in the adult brain. But in some experimental conditions (e.g., memory elicited by a single conditioning trial (1 CS-US)), GluN2B is not a necessary factor, which indicates that the precise role of GluN2B in memory formation requires further exploration. Here, we examined the role of GluN2B in the consolidation of fear memory using two training paradigms. We found that GluN2B was only required for the consolidation of memory elicited by five conditioning trials (5 CS-US), not by 1 CS-US. Strikingly, the expression of membrane GluN2B in CA1was training-strength-dependently increased after conditioning, and that the amount of membrane GluN2B determined its involvement in memory consolidation. Additionally, we demonstrated the increases in the activities of cAMP, ERK, and CREB in the CA1 after conditioning, as well as the enhanced intrinsic excitability and synaptic efficacy in CA1 neurons. Up-regulation of membrane GluN2B contributed to these enhancements. These studies uncover a novel mechanism for the involvement of GluN2B in memory consolidation by its accumulation at the cell surface in response to behavioral training. PMID:27487820

  4. Surface expression of hippocampal NMDA GluN2B receptors regulated by fear conditioning determines its contribution to memory consolidation in adult rats

    PubMed Central

    Sun, Yan-Yan; Cai, Wei; Yu, Jie; Liu, Shu-Su; Zhuo, Min; Li, Bao-Ming; Zhang, Xue-Han

    2016-01-01

    The number and subtype composition of N-methyl-d-aspartate receptor (NMDAR) at synapses determines their functional properties and role in learning and memory. Genetically increased or decreased amount of GluN2B affects hippocampus-dependent memory in the adult brain. But in some experimental conditions (e.g., memory elicited by a single conditioning trial (1 CS-US)), GluN2B is not a necessary factor, which indicates that the precise role of GluN2B in memory formation requires further exploration. Here, we examined the role of GluN2B in the consolidation of fear memory using two training paradigms. We found that GluN2B was only required for the consolidation of memory elicited by five conditioning trials (5 CS-US), not by 1 CS-US. Strikingly, the expression of membrane GluN2B in CA1was training-strength-dependently increased after conditioning, and that the amount of membrane GluN2B determined its involvement in memory consolidation. Additionally, we demonstrated the increases in the activities of cAMP, ERK, and CREB in the CA1 after conditioning, as well as the enhanced intrinsic excitability and synaptic efficacy in CA1 neurons. Up-regulation of membrane GluN2B contributed to these enhancements. These studies uncover a novel mechanism for the involvement of GluN2B in memory consolidation by its accumulation at the cell surface in response to behavioral training. PMID:27487820

  5. The formation and extinction of fear memory in tree shrews

    PubMed Central

    Shang, Shujiang; Wang, Cong; Guo, Chengbing; Huang, Xu; Wang, Liecheng; Zhang, Chen

    2015-01-01

    Fear is an emotion that is well-studied due to its importance for animal survival. Experimental animals, such as rats and mice, have been widely used to model fear. However, higher animals such as nonhuman primates have rarely been used to study fear due to ethical issues and high costs. Tree shrews are small mammals that are closely related to primates; they have been used to model human-related psychosocial conditions such as stress and alcohol tolerance. Here, we describe an experimental paradigm to study the formation and extinction of fear memory in tree shrews. We designed an experimental apparatus of a light/dark box with a voltage foot shock. We found that tree shrews preferred staying in the dark box in the daytime without stimulation and showed avoidance to voltage shocks applied to the footplate in a voltage-dependent manner. Foot shocks applied to the dark box for 5 days (10 min per day) effectively reversed the light–dark preference of the tree shrews, and this memory lasted for more than 50 days without any sign of memory decay (extinction) in the absence of further stimulation. However, this fear memory was reversed with 4 days of reverse training by applying the same stimulus to the light box. When reducing the stimulus intensity during the training period, a memory extinction and subsequently reinstatement effects were observed. Thus, our results describe an efficient method of monitoring fear memory formation and extinction in tree shrews. PMID:26283941

  6. Predator odor fear conditioning: Current perspectives and new directions

    PubMed Central

    Takahashi, Lorey K.; Chan, Megan M.; Pilar, Mark L.

    2008-01-01

    Predator odor fear conditioning involves the use of a natural unconditioned stimulus, as opposed to aversive electric foot-shock, to obtain novel information on the neural circuitry associated with emotional learning and memory. Researchers are beginning to identify brain sites associated with conditioned contextual fear such as the ventral anterior olfactory nucleus, dorsal premammillary nucleus, ventrolateral periaqueductal gray, cuneiform nucleus, and locus coeruleus. In addition, a few studies have reported an involvement of the basolateral and medial nucleus of the amygdala and hippocampus in fear conditioning. However, several important issues concerning the effectiveness of different predator odor unconditioned stimuli to produce fear conditioning, the precise role of brain nuclei in fear conditioning, and the general relation between the current predator odor and the traditional electric foot-shock fear conditioning procedures remain to be satisfactorily addressed. This review discusses the major behavioral results in the current predator odor fear conditioning literature and introduces two novel contextual and auditory fear conditioning models using cat odor. The new models provide critical information on the acquisition of conditioned fear behavior during training and the expression of conditioned responses in the retention test. Future studies adopting fear conditioning procedures that incorporate measures of both unconditioned and conditioned responses during training may lead to broad insights into predator odor fear conditioning and identify specific brain nuclei mediating conditioned stimulus – predator odor unconditioned stimulus associations. PMID:18577397

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

    PubMed

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

    2012-01-18

    A variety of studies have implicated the anterior cingulate cortex (ACC) in fear, including permanent storage of fear memory. Recent pharmacological and genetic studies indicate that early synaptic plasticity in the ACC may also contribute to certain forms of fear memory at early time points. However, no study has directly examined the possible changes in neuronal activity of ACC neurons in freely behaving mice during early learning. In the present study, we examined the neural responses of the ACC during trace fear conditioning. We found that ACC putative pyramidal and nonpyramidal neurons were involved in the termination of fear behavior ("un-freezing"), and the spike activity of these neurons was reduced during freezing. Some of the neurons were also found to acquire un-freezing locked activity and change their tuning. The results implicate the ACC neurons in fear learning and controlling the abolition of fear behavior. We also show that the ACC is important for making cue-related fear memory associations in the trace fear paradigm as measured with tone-evoked potentials and single-unit activity. Collectively, our findings indicate that the ACC is involved in predicting future aversive events and terminating fear during trace fear. PMID:22262906

  8. False context fear memory in rats.

    PubMed

    Bae, Sarah E; Holmes, Nathan M; Westbrook, R Frederick

    2015-10-01

    Four experiments used rats to study false context fear memories. In Experiment 1, rats were pre-exposed to a distinctive chamber (context A) or to a control environment (context C), shocked after a delay in a second chamber (context B) and tested either in B or A. Rats pre-exposed to A froze just as much as control rats in B but more than control rats in A. In Experiment 2, rats were pre-exposed to A or C, subjected to an immediate shock in B and tested in B or A. Rats pre-exposed to A froze when tested in A but did not freeze when tested in B and control rats did not freeze in either A or B. The false fear memory to the pre-exposed A was contingent on its similarity with the shocked B. In Experiment 3, rats pre-exposed to A and subjected to immediate shock in B froze when tested in A but did not freeze when tested in C and rats pre-exposed to C did not freeze when tested either in A or C. In Experiment 4, rats pre-exposed to A and subjected to immediate shock in B froze more when tested in A than rats whose pre-exposure to A began with an immediate shock. The results were discussed in terms of a dual systems explanation of context fear conditioning: a hippocampal-dependent process that forms a unitary representation of context and an amygdala-based process which associates this representation with shock. PMID:26373831

  9. Long-term memory of visually cued fear conditioning: roles of the neuronal nitric oxide synthase gene and cyclic AMP response element-binding protein.

    PubMed

    Kelley, J B; Anderson, K L; Altmann, S L; Itzhak, Y

    2011-02-01

    Nitric oxide (NO) produced by neuronal nitric oxide synthase (nNOS) has a role in late-phase long-term potentiation (LTP) and long-term memory (LTM) formation. Our recent studies implicated NO signaling in contextual and auditory cued fear conditioning. The present study investigated the role of NO signaling in visually cued fear conditioning. First, visually cued fear conditioning was investigated in wild-type (WT) and nNOS knockout (KO) mice. Second, the effects of pharmacological modulators of NO signaling on the acquisition of visually cued fear conditioning were investigated. Third, plasma levels of corticosterone were measured to determine a relationship between physiological and behavioral responses to fear conditioning. Fourth, levels of extracellular signal-related kinase (ERK1/2) and cyclic AMP response element binding protein (CREB) phosphorylation, downstream of NO signaling, were determined in the amygdala as potential correlates of fear learning. Mice underwent single or multiple (4) spaced trainings that consisted of a visual cue (blinking light) paired with footshock. WT mice acquired cued and contextual LTM following single and multiple trainings. nNOS KO mice acquired neither cued nor contextual LTM following a single training; however, multiple trainings improved contextual but not cued LTM. The selective nNOS inhibitor S-methyl-thiocitrulline (SMTC) impaired cued and contextual LTM in WT mice. The NO donor molsidomine recovered contextual LTM but had no effect on cued LTM in nNOS KO mice. Re-exposure to the visual cue 24 h posttraining elicited freezing response and a marked increase in plasma corticosterone levels in WT but not nNOS KO mice. The expression of CREB phosphorylation (Ser-133) was significantly higher in naive nNOS KO mice than in WT counterparts, and pharmacological modulators of NO had significant effects on levels of CREB phosphorylation and expression. These findings suggest that visual cue-dependent LTM is impaired in nNOS KO

  10. [GABA-Receptors in Modulation of Fear Memory Extinction].

    PubMed

    Dubrovina, N I

    2016-01-01

    GABA is the major inhibitory neurotransmitter in the central nervous system determining the efficacy of neuronal interaction. GABA-receptors play a key role in different aspects of fear memory--acquisition and consolidation, retention, reconsolidation and extinction. Extinction is an important behavioural phenomenon which allows organism to adapt its behavior to a changing environment. Extinction of fear memory is a form of new inhibitory learning which interferes with expression of the initial acquired fear conditioning. Resistance to extinction is symptom of depression and posttraumatic stress disorder. The aim of the present review was to summarize own and literary data about GABAergic modulation of fear extinction and pharmacological correction of extinction impairment at influences on GABA(A)- and GABA(B)- receptors. PMID:27538279

  11. Disruption of Memory Reconsolidation Erases a Fear Memory Trace in the Human Amygdala: An 18-Month Follow-Up

    PubMed Central

    Björkstrand, Johannes; Agren, Thomas; Frick, Andreas; Engman, Jonas; Larsson, Elna-Marie; Furmark, Tomas; Fredrikson, Mats

    2015-01-01

    Fear memories can be attenuated by reactivation followed by disrupted reconsolidation. Using functional magnetic resonance imaging we recently showed that reactivation and reconsolidation of a conditioned fear memory trace in the basolateral amygdala predicts subsequent fear expression over two days, while reactivation followed by disrupted reconsolidation abolishes the memory trace and suppresses fear. In this follow-up study we demonstrate that the behavioral effect persists over 18 months reflected in superior reacquisition after undisrupted, as compared to disrupted reconsolidation, and that neural activity in the basolateral amygdala representing the initial fear memory predicts return of fear. We conclude that disrupting reconsolidation have long lasting behavioral effects and may permanently erase the fear component of an amygdala-dependent memory. PMID:26132145

  12. Neural and cellular mechanisms of fear and extinction memory formation.

    PubMed

    Orsini, Caitlin A; Maren, Stephen

    2012-08-01

    Over the course of natural history, countless animal species have evolved adaptive behavioral systems to cope with dangerous situations and promote survival. Emotional memories are central to these defense systems because they are rapidly acquired and prepare organisms for future threat. Unfortunately, the persistence and intrusion of memories of fearful experiences are quite common and can lead to pathogenic conditions, such as anxiety and phobias. Over the course of the last 30 years, neuroscientists and psychologists alike have attempted to understand the mechanisms by which the brain encodes and maintains these aversive memories. Of equal interest, though, is the neurobiology of extinction memory formation as this may shape current therapeutic techniques. Here we review the extant literature on the neurobiology of fear and extinction memory formation, with a strong focus on the cellular and molecular mechanisms underlying these processes. PMID:22230704

  13. Neural and Cellular Mechanisms of Fear and Extinction Memory Formation

    PubMed Central

    Orsini, Caitlin A.; Maren, Stephen

    2012-01-01

    Over the course of natural history, countless animal species have evolved adaptive behavioral systems to cope with dangerous situations and promote survival. Emotional memories are central to these defense systems because they are rapidly acquired and prepare organisms for future threat. Unfortunately, the persistence and intrusion of memories of fearful experiences are quite common and can lead to pathogenic conditions, such as anxiety and phobias. Over the course of the last thirty years, neuroscientists and psychologists alike have attempted to understand the mechanisms by which the brain encodes and maintains these aversive memories. Of equal interest, though, is the neurobiology of extinction memory formation as this may shape current therapeutic techniques. Here we review the extant literature on the neurobiology of fear and extinction memory formation, with a strong focus on the cellular and molecular mechanisms underlying these processes. PMID:22230704

  14. Tracking the Fear Memory Engram: Discrete Populations of Neurons within Amygdala, Hypothalamus, and Lateral Septum Are Specifically Activated by Auditory Fear Conditioning

    ERIC Educational Resources Information Center

    Butler, Christopher W.; 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…

  15. Identification and Characterization of the V(D)J Recombination Activating Gene 1 in Long-Term Memory of Context Fear Conditioning

    PubMed Central

    Castro-Pérez, Edgardo; Soto-Soto, Emilio; Pérez-Carambot, Marizabeth; Dionisio-Santos, Dawling; Saied-Santiago, Kristian; Ortiz-Zuazaga, Humberto G.; Peña de Ortiz, Sandra

    2016-01-01

    An increasing body of evidence suggests that mechanisms related to the introduction and repair of DNA double strand breaks (DSBs) may be associated with long-term memory (LTM) processes. Previous studies from our group suggested that factors known to function in DNA recombination/repair machineries, such as DNA ligases, polymerases, and DNA endonucleases, play a role in LTM. Here we report data using C57BL/6 mice showing that the V(D)J recombination-activating gene 1 (RAG1), which encodes a factor that introduces DSBs in immunoglobulin and T-cell receptor genes, is induced in the amygdala, but not in the hippocampus, after context fear conditioning. Amygdalar induction of RAG1 mRNA, measured by real-time PCR, was not observed in context-only or shock-only controls, suggesting that the context fear conditioning response is related to associative learning processes. Furthermore, double immunofluorescence studies demonstrated the neuronal localization of RAG1 protein in amygdalar sections prepared after perfusion and fixation. In functional studies, intra-amygdalar injections of RAG1 gapmer antisense oligonucleotides, given 1 h prior to conditioning, resulted in amygdalar knockdown of RAG1 mRNA and a significant impairment in LTM, tested 24 h after training. Overall, these findings suggest that the V(D)J recombination-activating gene 1, RAG1, may play a role in LTM consolidation. PMID:26843989

  16. 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

  17. 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

  18. Effect of ablated hippocampal neurogenesis on the formation and extinction of contextual fear memory

    PubMed Central

    Ko, Hyoung-Gon; Jang, Deok-Jin; Son, Junehee; Kwak, Chuljung; Choi, Jun-Hyeok; Ji, Young-Hoon; Lee, Yun-Sil; Son, Hyeon; Kaang, Bong-Kiun

    2009-01-01

    Newborn neurons in the subgranular zone (SGZ) of the hippocampus incorporate into the dentate gyrus and mature. Numerous studies have focused on hippocampal neurogenesis because of its importance in learning and memory. However, it is largely unknown whether hippocampal neurogenesis is involved in memory extinction per se. Here, we sought to examine the possibility that hippocampal neurogenesis may play a critical role in the formation and extinction of hippocampus-dependent contextual fear memory. By methylazoxymethanol acetate (MAM) or gamma-ray irradiation, hippocampal neurogenesis was impaired in adult mice. Under our experimental conditions, only a severe impairment of hippocampal neurogenesis inhibited the formation of contextual fear memory. However, the extinction of contextual fear memory was not affected. These results suggest that although adult newborn neurons contribute to contextual fear memory, they may not be involved in the extinction or erasure of hippocampus-dependent contextual fear memory. PMID:19138433

  19. Electrolytic Lesions of the Medial Prefrontal Cortex Do Not Interfere with Long-Term Memory of Extinction of Conditioned Fear

    ERIC Educational Resources Information Center

    Garcia, Rene; Chang, Chun-hui; Maren, Stephen

    2006-01-01

    Lesion studies indicate that rats without the medial prefrontal cortex (mPFC) have difficulty recalling fear extinction acquired the previous day. Several electrophysiological studies have also supported this observation by demonstrating that extinction-related increases in neuronal activity in the mPFC participate in expression of fear…

  20. False Context Fear Memory in Rats

    ERIC Educational Resources Information Center

    Bae, Sarah; Holmes, Nathan M.; Westbrook, R. Frederick

    2015-01-01

    Four experiments used rats to study false context fear memories. In Experiment 1, rats were pre-exposed to a distinctive chamber (context A) or to a control environment (context C), shocked after a delay in a second chamber (context B) and tested either in B or A. Rats pre-exposed to A froze just as much as control rats in B but more than control…

  1. Novelty-Induced Arousal Enhances Memory for Cued Classical Fear Conditioning: Interactions between Peripheral Adrenergic and Brainstem Glutamatergic Systems

    ERIC Educational Resources Information Center

    King, Stanley O., II; Williams, Cedric L.

    2009-01-01

    Exposure to novel contexts produce heightened states of arousal and biochemical changes in the brain to consolidate memory. However, processes permitting simple exposure to unfamiliar contexts to elevate sympathetic output and to improve memory are poorly understood. This shortcoming was addressed by examining how novelty-induced changes in…

  2. The Roles of the Actin Cytoskeleton in Fear Memory Formation

    PubMed Central

    Lamprecht, Raphael

    2011-01-01

    The formation and storage of fear memory is needed to adapt behavior and avoid danger during subsequent fearful events. However, fear memory may also play a significant role in stress and anxiety disorders. When fear becomes disproportionate to that necessary to cope with a given stimulus, or begins to occur in inappropriate situations, a fear or anxiety disorder exists. Thus, the study of cellular and molecular mechanisms underpinning fear memory may shed light on the formation of memory and on anxiety and stress related disorders. Evidence indicates that fear learning leads to changes in neuronal synaptic transmission and morphology in brain areas underlying fear memory formation including the amygdala and hippocampus. The actin cytoskeleton has been shown to participate in these key neuronal processes. Recent findings show that the actin cytoskeleton is needed for fear memory formation and extinction. Moreover, the actin cytoskeleton is involved in synaptic plasticity and in neuronal morphogenesis in brain areas that mediate fear memory. The actin cytoskeleton may therefore mediate between synaptic transmission during fear learning and long-term cellular alterations mandatory for fear memory formation. PMID:21808614

  3. The role of basal forebrain cholinergic neurons in fear and extinction memory.

    PubMed

    Knox, Dayan

    2016-09-01

    Cholinergic input to the neocortex, dorsal hippocampus (dHipp), and basolateral amygdala (BLA) is critical for neural function and synaptic plasticity in these brain regions. Synaptic plasticity in the neocortex, dHipp, ventral Hipp (vHipp), and BLA has also been implicated in fear and extinction memory. This finding raises the possibility that basal forebrain (BF) cholinergic neurons, the predominant source of acetylcholine in these brain regions, have an important role in mediating fear and extinction memory. While empirical studies support this hypothesis, there are interesting inconsistencies among these studies that raise questions about how best to define the role of BF cholinergic neurons in fear and extinction memory. Nucleus basalis magnocellularis (NBM) cholinergic neurons that project to the BLA are critical for fear memory and contextual fear extinction memory. NBM cholinergic neurons that project to the neocortex are critical for cued and contextual fear conditioned suppression, but are not critical for fear memory in other behavioral paradigms and in the inhibitory avoidance paradigm may even inhibit contextual fear memory formation. Medial septum and diagonal band of Broca cholinergic neurons are critical for contextual fear memory and acquisition of cued fear extinction. Thus, even though the results of previous studies suggest BF cholinergic neurons modulate fear and extinction memory, inconsistent findings among these studies necessitates more research to better define the neural circuits and molecular processes through which BF cholinergic neurons modulate fear and extinction memory. Furthermore, studies determining if BF cholinergic neurons can be manipulated in such a manner so as to treat excessive fear in anxiety disorders are needed. PMID:27264248

  4. Memory-emotional interactions as revealed by fear generalization in animal-fearful individuals.

    PubMed

    Kopp, Bruno; Schlimm, Mike; Hermann, Christiane

    2005-06-01

    Discriminative fear learning and fear generalization were examined in animal-fearful individuals and in control participants. Electrical shocks were administered contingent upon discriminative pictures of spiders or snakes, respectively, in a generalization-after-discrimination paradigm. Neither discriminative fear learning nor extinction was affected by the individual fear status of the animal categories. Novel feared stimuli, which resembled discriminative stimuli, were treated as more shock predictive than novel non-feared stimuli during generalization testing. Neither preparedness theory nor selective sensitization theory was capable to account for these observations. The findings are commensurable with the hypothesis that phobic fear interferes with the retrieval of memory traces. PMID:15814082

  5. Conditioned fear modulates visual selection.

    PubMed

    Mulckhuyse, Manon; Crombez, Geert; Van der Stigchel, Stefan

    2013-06-01

    Eye movements reflect the dynamic interplay between top-down- and bottom-up-driven processes. For example, when we voluntarily move our eyes across the visual field, salient visual stimuli in the environment may capture our attention, our eyes, or modulate the trajectory of an eye movement. Previous research has shown that the behavioral relevance of a salient stimulus modulates these processes. This study investigated whether a stimulus signaling an aversive event modulates saccadic behavior. Using a differential fear-conditioning procedure, we presented a threatening (conditional stimulus: CS+) and a nonthreatening stimulus distractor (CS-) during an oculomotor selection task. The results show that short-latency saccades deviated more strongly toward the CS+ than toward the CS- distractor, whereas long-latency saccades deviated more strongly away from the CS+ than from the CS- distractor. Moreover, the CS+ distractor captured the eyes more often than the CS- distractor. Together, these results demonstrate that conditioned fear has a direct and immediate influence on visual selection. The findings are interpreted in terms of a neurobiological model of emotional visual processing. PMID:23356561

  6. 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. PMID:25198514

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

    PubMed Central

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

    2015-01-01

    Brain-derived neurotrophic factor (BDNF), the most abundant neutrophin in the mammalian central nervous system, is critically involved in synaptic plasticity. In both rodents and humans, BDNF has been implicated in hippocampus- and amygdala-dependent learning and memory and has more recently been linked to fear extinction processes. Fifty-nine healthy participants, genotyped for the functional BDNFval66met polymorphism, underwent a fear conditioning and 24h-delayed extinction protocol while skin conductance and blood oxygenation level dependent (BOLD) responses (functional magnetic resonance imaging) were acquired. We present the first report of neural activation pattern during fear acquisition ‘and’ extinction for the BDNFval66met polymorphism using a differential conditioned stimulus (CS)+ > CS− comparison. During conditioning, we observed heightened allele dose-dependent responses in the amygdala and reduced responses in the subgenual anterior cingulate cortex in BDNFval66met met-carriers. During early extinction, 24h later, we again observed heightened responses in several regions ascribed to the fear network in met-carriers as opposed to val-carriers (insula, amygdala, hippocampus), which likely reflects fear memory recall. No differences were observed during late extinction, which likely reflects learned extinction. Our data thus support previous associations of the BDNFval66met polymorphism with neural activation in the fear and extinction network, but speak against a specific association with fear extinction processes. PMID:25103087

  8. Sound tuning of amygdala plasticity in auditory fear conditioning

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2016-01-01

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

  10. Stability of Recent and Remote Contextual Fear Memory

    ERIC Educational Resources Information Center

    Frankland, Paul W.; Ding, Hoi-Ki; Takahashi, Eiki; Suzuki, Akinobu; Kida, Satoshi; Silva, Alcino J.

    2006-01-01

    Following initial encoding, memories undergo a prolonged period of reorganization. While such reorganization may occur in many different memory systems, its purpose is not clear. Previously, we have shown that recall of recent contextual fear memories engages the dorsal hippocampus (dHPC). In contrast, recall of remote contextual fear memories…

  11. Fear extinction memory consolidation requires potentiation of pontine-wave activity during REM sleep.

    PubMed

    Datta, Subimal; O'Malley, Matthew W

    2013-03-01

    Sleep plays an important role in memory consolidation within multiple memory systems including contextual fear extinction memory, but little is known about the mechanisms that underlie this process. Here, we show that fear extinction training in rats, which extinguished conditioned fear, increased both slow-wave sleep and rapid-eye movement (REM) sleep. Surprisingly, 24 h later, during memory testing, only 57% of the fear-extinguished animals retained fear extinction memory. We found that these animals exhibited an increase in phasic pontine-wave (P-wave) activity during post-training REM sleep, which was absent in the 43% of animals that failed to retain fear extinction memory. The results of this study provide evidence that brainstem activation, specifically potentiation of phasic P-wave activity, during post-training REM sleep is critical for consolidation of fear extinction memory. The results of this study also suggest that, contrary to the popular hypothesis of sleep and memory, increased sleep after training alone does not guarantee consolidation and/or retention of fear extinction memory. Rather, the potentiation of specific sleep-dependent physiological events may be a more accurate predictor for successful consolidation of fear extinction memory. Identification of this unique mechanism will significantly improve our present understanding of the cellular and molecular mechanisms that underlie the sleep-dependent regulation of emotional memory. Additionally, this discovery may also initiate development of a new, more targeted treatment method for clinical disorders of fear and anxiety in humans that is more efficacious than existing methods such as exposure therapy that incorporate only fear extinction. PMID:23467372

  12. Fear Extinction Memory Consolidation Requires Potentiation of Pontine-Wave Activity during REM Sleep

    PubMed Central

    Datta, Subimal; O'Malley, Matthew W .

    2013-01-01

    Sleep plays an important role in memory consolidation within multiple memory systems including contextual fear extinction memory, but little is known about the mechanisms that underlie this process. Here, we show that fear extinction training in rats, which extinguished conditioned fear, increased both slow-wave sleep and rapid-eye movement (REM) sleep. Surprisingly, 24 h later, during memory testing, only 57% of the fear-extinguished animals retained fear extinction memory. We found that these animals exhibited an increase in phasic pontine-wave (P-wave) activity during post-training REM sleep, which was absent in the 43% of animals that failed to retain fear extinction memory. The results of this study provide evidence that brainstem activation, specifically potentiation of phasic P-wave activity, during post-training REM sleep is critical for consolidation of fear extinction memory. The results of this study also suggest that, contrary to the popular hypothesis of sleep and memory, increased sleep after training alone does not guarantee consolidation and/or retention of fear extinction memory. Rather, the potentiation of specific sleep-dependent physiological events may be a more accurate predictor for successful consolidation of fear extinction memory. Identification of this unique mechanism will significantly improve our present understanding of the cellular and molecular mechanisms that underlie the sleep-dependent regulation of emotional memory. Additionally, this discovery may also initiate development of a new, more targeted treatment method for clinical disorders of fear and anxiety in humans that is more efficacious than existing methods such as exposure therapy that incorporate only fear extinction. PMID:23467372

  13. Inhibition of Rac1 Activity in the Hippocampus Impairs the Forgetting of Contextual Fear Memory.

    PubMed

    Jiang, Lizhu; Mao, Rongrong; Zhou, Qixin; Yang, Yuexiong; Cao, Jun; Ding, Yuqiang; Yang, Yuan; Zhang, Xia; Li, Lingjiang; Xu, Lin

    2016-03-01

    Fear is crucial for survival, whereas hypermnesia of fear can be detrimental. Inhibition of the Rac GTPase is recently reported to impair the forgetting of initially acquired memory in Drosophila. Here, we investigated whether inhibition of Rac1 activity in rat hippocampus could contribute to the hypermnesia of contextual fear. We found that spaced but not massed training of contextual fear conditioning caused inhibition of Rac1 activity in the hippocampus and heightened contextual fear. Furthermore, intrahippocampal injection of the Rac1 inhibitor NSC23766 heightened contextual fear in massed training, while Rac1 activator CN04-A weakened contextual fear in spaced training rats. Our study firstly demonstrates that contextual fear memory in rats is actively regulated by Rac1 activity in the hippocampus, which suggests that the forgetting impairment of traumatic events in posttraumatic stress disorder may be contributed to the pathological inhibition of Rac1 activity in the hippocampus. PMID:25613020

  14. Updating versus Exposure to Prevent Consolidation of Conditioned Fear

    PubMed Central

    Pile, Victoria; Barnhofer, Thorsten; Wild, Jennifer

    2015-01-01

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

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

    PubMed

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

    2016-07-01

    A prominent feature of fear memories and anxiety disorders is that they endure across extended periods of time. Here, we examine how the severity of the initial fear experience influences incubation, generalization, and sensitization of contextual fear memories across time. Adult rats were presented with either five, two, one, or zero shocks (1.2 mA, 2 sec) during contextual fear conditioning. Following a recent (1 d) or remote (28 d) retention interval all subjects were returned to the original training context to measure fear memory and/or to a novel context to measure the specificity of fear conditioning. Our results indicate rats that received two or five shocks show an "incubation"-like enhancement of fear between recent and remote retention intervals, while single-shocked animals show stable levels of context fear memory. Moreover, when fear was tested in a novel context, 1 and 2 shocked groups failed to freeze, whereas five shocked rats showed a time-dependent generalization of context memory. Stress enhancement of fear learning to a second round of conditioning was evident in all previously shocked animals. Based on these results, we conclude that the severity or number of foot shocks determines not only the level of fear memory, but also the time-dependent incubation of fear and its generalization across distinct contexts. PMID:27317198

  16. Adrenergic Transmission Facilitates Extinction of Conditional Fear in Mice

    ERIC Educational Resources Information Center

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

    2004-01-01

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

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

    PubMed

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

    2013-01-01

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

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

    PubMed

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

    2015-05-01

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

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

    PubMed Central

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

    2015-01-01

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

  20. Impairment of fear memory consolidation and expression by antihistamines.

    PubMed

    Nonaka, Ayako; Masuda, Fumitaka; Nomura, Hiroshi; Matsuki, Norio

    2013-02-01

    Antihistamines are widely used to treat allergy symptoms. First-generation antihistamines have adverse effects on the central nervous system (CNS), such as hypnotic and amnesic effects, whereas second-generation antihistamines have poor brain penetration, and therefore, have fewer CNS-related adverse effects. Memory consists of several phases, including acquisition, consolidation, expression, and extinction. It remains unclear whether these phases are affected by antihistamines. We investigated the effects of diphenhydramine, a first-generation antihistamine, and levocetirizine and olopatadine, second-generation antihistamines, on memory phases. Mice were subjected to fear conditioning on day 1 and tested on day 2. Antihistamines were administered before conditioning, immediately after conditioning, or before the test session. Diphenhydramine (30mg/kg) decreased freezing time when administered immediately after conditioning or before the test session. These effects were not attributable to a change in locomotor activity. Levocetirizine (0.1, 1, 10mg/kg) and olopatadine (1, 10, 20mg/kg) had no effects on conditioned fear. We also examined the effect of diphenhydramine and levocetirizine on the expression of an activity-dependent gene associated with the test session. Diphenhydramine, but not levocetirizine, increased Arc transcription in the central nucleus of the amygdala. These data indicate that diphenhydramine, but not levocetirizine or olopatadine, impairs the consolidation and expression of conditioned fear. PMID:23178698

  1. The effects of transcutaneous vagus nerve stimulation on conditioned fear extinction in humans.

    PubMed

    Burger, Andreas M; Verkuil, Bart; Van Diest, Ilse; Van der Does, Willem; Thayer, Julian F; Brosschot, Jos F

    2016-07-01

    A critical component of the treatment for anxiety disorders is the extinction of fear via repeated exposure to the feared stimulus. This process is strongly dependent on successful memory formation and consolidation. Stimulation of the vagus nerve enhances memory formation in both animals and humans. The objective of this study was to assess whether transcutaneous stimulation of the vagus nerve (tVNS) can accelerate extinction memory formation and retention in fear conditioned humans. To assess fear conditioning and subsequent fear extinction, we assessed US expectancy ratings, fear potentiated startle responses and phasic heart rate responses. We conducted a randomized controlled trial in thirty-one healthy participants. After fear conditioning participants were randomly assigned to receive tVNS or sham stimulation during the extinction phase. Retention of extinction memory was tested 24h later. tVNS accelerated explicit fear extinction learning (US expectancy ratings), but did not lead to better retention of extinction memory 24h later. We did not find a differential physiological conditioning response during the acquisition of fear and thus were unable to assess potential effects of tVNS on the extinction of physiological indices of fear. These findings complement recent studies that suggest vagus nerve stimulation could be a promising tool to improve memory consolidation and fear extinction. PMID:27222436

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

    PubMed Central

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

    2015-01-01

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

  3. Competition between engrams influences fear memory formation and recall.

    PubMed

    Rashid, Asim J; Yan, Chen; Mercaldo, Valentina; Hsiang, Hwa-Lin Liz; Park, Sungmo; Cole, Christina J; De Cristofaro, Antonietta; Yu, Julia; Ramakrishnan, Charu; Lee, Soo Yeun; Deisseroth, Karl; Frankland, Paul W; Josselyn, Sheena A

    2016-07-22

    Collections of cells called engrams are thought to represent memories. Although there has been progress in identifying and manipulating single engrams, little is known about how multiple engrams interact to influence memory. In lateral amygdala (LA), neurons with increased excitability during training outcompete their neighbors for allocation to an engram. We examined whether competition based on neuronal excitability also governs the interaction between engrams. Mice received two distinct fear conditioning events separated by different intervals. LA neuron excitability was optogenetically manipulated and revealed a transient competitive process that integrates memories for events occurring closely in time (coallocating overlapping populations of neurons to both engrams) and separates memories for events occurring at distal times (disallocating nonoverlapping populations to each engram). PMID:27463673

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

    PubMed Central

    Kindt, Merel; Soeter, Marieke; Sevenster, Dieuwke

    2014-01-01

    The basic design used in our human fear-conditioning studies on disrupting reconsolidation includes testing over different phases across three consecutive days. On day 1 - the fear acquisition phase, healthy participants are exposed to a series of picture presentations. One picture stimulus (CS1+) is repeatedly paired with an aversive electric stimulus (US), resulting in the acquisition of a fear association, whereas another picture stimulus (CS2-) is never followed by an US. On day 2 - the memory reactivation phase, the participants are re-exposed to the conditioned stimulus without the US (CS1-), which typically triggers a conditioned fear response. After the memory reactivation we administer an oral dose of 40 mg of propranolol HCl, a β-adrenergic receptor antagonist that indirectly targets the protein synthesis required for reconsolidation by inhibiting the noradrenaline-stimulated CREB phosphorylation. On day 3 - the test phase, the participants are again exposed to the unreinforced conditioned stimuli (CS1- and CS2-) in order to measure the fear-reducing effect of the manipulation. This retention test is followed by an extinction procedure and the presentation of situational triggers to test for the return of fear. Potentiation of the eye blink startle reflex is measured as an index for conditioned fear responding. Declarative knowledge of the fear association is measured through online US expectancy ratings during each CS presentation. In contrast to extinction learning, disrupting reconsolidation targets the original fear memory thereby preventing the return of fear. Although the clinical applications are still in their infancy, disrupting reconsolidation of fear memory seems to be a promising new technique with the prospect to persistently dampen the expression of fear memory in patients suffering from anxiety disorders and other psychiatric disorders. PMID:25549103

  5. Role of conceptual knowledge in learning and retention of conditioned fear

    PubMed Central

    Dunsmoor, Joseph E.; Martin, Alex; LaBar, Kevin S.

    2011-01-01

    Associating sensory cues with aversive outcomes is a relatively basic process shared across species. Yet higher-order cognitive processes likely contribute to associative fear learning in many circumstances, especially in humans. Here we ask whether fears can be acquired based on conceptual knowledge of object categories, and whether such concept-based fear conditioning leads to enhanced memory representations for conditioned objects. Participants were presented with a heterogeneous collection of images of animals and tools. Objects from one category were reinforced by an electrical shock, whereas the other category was never reinforced. Results confirmed concept-based fear learning through subjective report of shock expectancy, heightened skin conductance responses, and enhanced 24 hour recognition memory for items from the conditioned category. These results provide novel evidence that conditioned fear can generalize through knowledge of object concepts, and sheds light on the persistent nature of fear memories and category-based fear responses symptomatic of some anxiety disorders. PMID:22118937

  6. Extract of Ginkgo biloba EGb 761 facilitates fear conditioning measured by fear-potentiated startle.

    PubMed

    Yang, Yi-Ling; Su, Ya-Wen; Ng, Ming-Chong; Chang, Chai-Lun; Lu, Kwok-Tung

    Extract of Ginkgo biloba EGb 761 has been used in the treatment of various common geriatric complaints including vertigo, short-term memory loss, hearing loss, lack of attention, vigilance and cerebral vascular disorder. Recent results suggest that it can serve as a cognitive enhancer and anti-stress buffer. It raises a possibility that EGb 761 may be involved in the fear conditioning. In this study, we used fear-potentiated startle (FPS) to evaluate the possible effects of EGb 761 on the acquisition stage of fear conditioning. Our results showed that administration of EGb 761 30 min prior to the conditioning facilitated acquisition of conditioned fear in a dose dependent manner. No significant differences had been observed in either basal startle response or shock activity. These results indicated that the facilitation effect of EGb 761 was not the result of impaired basal startle response or enhanced pain perception. Subsequent control experiment results indicated that the facilitation effect of EGb 761 on the acquisition was not due to anxiogenic effect or non-specific effect. Our data present the first evidence that EGb 761 can enhance fear memory formation rather than serve as an anti-stress buffer. PMID:15936528

  7. Chronic Cannabinoid Administration in Vivo Compromises Extinction of Fear Memory

    ERIC Educational Resources Information Center

    Lin, Hui-Ching; Mao, Sheng-Chun; Chen, Po-See; Gean, Po-Wu

    2008-01-01

    Endocannabinoids are critically involved in the extinction of fear memory. Here we examined the effects of repeated cannabinoid administration on the extinction of fear memory in rats and on inhibitory synaptic transmission in medial prefrontal cortex (mPFC) slices. Rats were treated with the CB1 receptor agonist WIN55212-2 (WIN 10 mg/kg, i.p.)…

  8. Optogenetic Activation of Presynaptic Inputs in Lateral Amygdala Forms Associative Fear Memory

    ERIC Educational Resources Information Center

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

    2014-01-01

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

  9. Angiotensin-(1-7)/Mas axis modulates fear memory and extinction in mice.

    PubMed

    Lazaroni, Thiago Luiz do Nascimento; Bastos, Cristiane Perácio; Moraes, Márcio Flávio Dutra; Santos, Robson Souza; Pereira, Grace Schenatto

    2016-01-01

    Inappropriate defense-alerting reaction to fear is a common feature of neuropsychiatric diseases. Therefore, impairments in brain circuits, as well as in molecular pathways underlying the neurovegetative adjustments to fear may play an essential role on developing neuropsychiatric disorders. Here we tested the hypothesis that interfering with angiotensin-(1-7) [Ang-(1-7)]/Mas receptor axis homeostasis, which appears to be essential to arterial pressure control, would affect fear memory and extinction. Mas knockout (MasKO) mice, in FVB/N background, showed normal cued fear memory and extinction, but increased freezing in response to context. Next, as FVB/N has poor performance in contextual fear memory, we tested MasKO in mixed 129xC57BL/6 background. MasKO mice behaved similarly to wild-type (WT), but memory extinction was slower in contextual fear conditioning to a weak protocol (1CS/US). In addition, delayed extinction in MasKO mice was even more pronounced after a stronger protocol (3CS/US). We showed previously that Angiotensin II receptor AT1 antagonist, losantan, rescued object recognition memory deficit in MasKO mice. Here, losartan was also effective. Memory extinction was accelerated in MasKO mice after treatment with losartan. In conclusion, we showed for the first time that Ang-(1-7)/Mas axis may modulate fear memory extinction. Furthermore, we suggest MasKO mice as an animal model to study post-traumatic stress disorder (PTSD). PMID:26642920

  10. Factors Regulating the Effects of Hippocampal Inactivation on Renewal of Conditional Fear after Extinction

    ERIC Educational Resources Information Center

    Corcoran, Kevin A.; Maren, Stephen

    2004-01-01

    After extinction of fear to a Pavlovian conditional stimulus (CS), contextual stimuli come to regulate the expression of fear to that CS. There is growing evidence that the context dependence of memory retrieval after extinction involves the hippocampus. In the present experiment, we examine whether hippocampal involvement in memory retrieval…

  11. Optogenetic activation of presynaptic inputs in lateral amygdala forms associative fear memory

    PubMed Central

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

    2014-01-01

    In Pavlovian fear conditioning, the lateral amygdala (LA) has been highlighted as a key brain site for association between sensory cues and aversive stimuli. However, learning-related changes are also found in upstream sensory regions such as thalamus and cortex. To isolate the essential neural circuit components for fear memory association, we tested whether direct activation of presynaptic sensory inputs in LA, without the participation of upstream activity, is sufficient to form fear memory in mice. Photostimulation of axonal projections from the two main auditory brain regions, the medial geniculate nucleus of the thalamus and the secondary auditory cortex, was paired with aversive footshock. Twenty-four hours later the same photostimulation induced robust conditioned freezing and this fear memory formation was disrupted when glutamatergic synaptic transmission was locally blocked in the LA. Therefore, our results prove for the first time that synapses between sensory input areas and the LA, previously implicated as a crucial brain site for fear memory formation, actually are sufficient to serve as a conditioned stimulus. Our results strongly support the idea that the LA may be sufficient to encode and store associations between neutral cue and aversive stimuli during natural fear conditioning as a critical part of a broad fear memory engram. PMID:25322798

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

    PubMed

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

    2016-09-01

    Behavioral studies have suggested a key role for the cannabinoid system in the modulation of conditioned fear memory. Likewise, much of the literature has revealed that the serotonergic system affects Pavlovian fear conditioning and extinction. A high level of functional overlap between the serotonin and cannabinoid systems has also been reported. To clarify the interaction between the hippocampal serotonin (5-HT4) receptor and the cannabinoid CB1 receptor in the acquisition of fear memory, the effects of 5-HT4 agents, arachidonylcyclopropylamide (ACPA; CB1 receptor agonist), and the combined use of these drugs on fear learning were studied in a fear conditioning task in adult male NMRI mice. Pre-training intraperitoneal administration of ACPA (0.1 mg/kg) decreased the percentage of freezing time in both context- and tone-dependent fear conditions, suggesting impairment of the acquisition of fear memory. Pre-training, intra-hippocampal (CA1) microinjection of RS67333, a 5-HT4 receptor agonist, at doses of 0.1 and 0.2 or 0.2 µg/mouse impaired contextual and tone fear memory, respectively. A subthreshold dose of RS67333 (0.005 µg/mouse) did not alter the ACPA response in either condition. Moreover, intra-CA1 microinjection of RS23597 as a 5-HT4 receptor antagonist did not alter context-dependent fear memory acquisition, but it did impair tone-dependent fear memory acquisition. However, a subthreshold dose of the RS23597 (0.01 µg/mouse) potentiated ACPA-induced fear memory impairment in both conditions. Therefore, we suggest that the blockade of hippocampal 5-HT4 serotonergic system modulates cannabinoid signaling induced by the activation of CB1 receptors in conditioned fear. PMID:27296273

  13. Effects of unconscious processing on implicit memory for fearful faces.

    PubMed

    Yang, Jiongjiong; Xu, Xiaohong; Du, Xiaoya; Shi, Cuntong; Fang, Fang

    2011-01-01

    Emotional stimuli can be processed even when participants perceive them without conscious awareness, but the extent to which unconsciously processed emotional stimuli influence implicit memory after short and long delays is not fully understood. We addressed this issue by measuring a subliminal affective priming effect in Experiment 1 and a long-term priming effect in Experiment 2. In Experiment 1, a flashed fearful or neutral face masked by a scrambled face was presented three times, then a target face (either fearful or neutral) was presented and participants were asked to make a fearful/neutral judgment. We found that, relative to a neutral prime face (neutral-fear face), a fearful prime face speeded up participants' reaction to a fearful target (fear-fear face), when they were not aware of the masked prime face. But this response pattern did not apply to the neutral target. In Experiment 2, participants were first presented with a masked faces six times during encoding. Three minutes later, they were asked to make a fearful/neutral judgment for the same face with congruent expression, the same face with incongruent expression or a new face. Participants showed a significant priming effect for the fearful faces but not for the neutral faces, regardless of their awareness of the masked faces during encoding. These results provided evidence that unconsciously processed stimuli could enhance emotional memory after both short and long delays. It indicates that emotion can enhance memory processing whether the stimuli are encoded consciously or unconsciously. PMID:21408105

  14. Prediction of individual differences in fear response by novelty seeking, and disruption of contextual fear memory reconsolidation by ketamine.

    PubMed

    Duclot, Florian; Perez-Taboada, Iara; Wright, Katherine N; Kabbaj, Mohamed

    2016-10-01

    Only a portion of the population exposed to trauma will develop persistent emotional alterations characteristic of posttraumatic stress disorder (PTSD), which illustrates the necessity for identifying vulnerability factors and novel pharmacotherapeutic alternatives. Interestingly, clinical evidence suggests that novelty seeking is a good predictor for vulnerability to the development of excessive and persistent fear. Here, we first tested this hypothesis by analyzing contextual and cued fear responses of rats selected for their high (high responders, HR) or low (low responders, LR) exploration of a novel environment, indicator of novelty seeking. While HR and LR rats exhibited similar sensitivity to the shock and cued fear memory retention, fewer extinction sessions were required in HR than LR animals to reach extinction, indicating faster contextual and cued memory extinction. In a second part, we found an effective disruption of contextual fear reconsolidation by the N-methyl-d-aspartate receptor antagonist ketamine, associated with a down-regulation of early growth response 1 (Egr1) in the hippocampal CA1 area, and up-regulation of brain-derived neurotrophic factor (Bdnf) mRNA levels in the prelimbic and infralimbic cortices. Altogether, these data demonstrate a link between novelty seeking and conditioned fear extinction, and highlight a promising novel role of ketamine in affecting established fear memory. PMID:27343386

  15. 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

  16. Presynaptic Excitation via GABAB Receptors in Habenula Cholinergic Neurons Regulates Fear Memory Expression.

    PubMed

    Zhang, Juen; Tan, Lubin; Ren, Yuqi; Liang, Jingwen; Lin, Rui; Feng, Qiru; Zhou, Jingfeng; Hu, Fei; Ren, Jing; Wei, Chao; Yu, Tao; Zhuang, Yinghua; Bettler, Bernhard; Wang, Fengchao; Luo, Minmin

    2016-07-28

    Fear behaviors are regulated by adaptive mechanisms that dampen their expression in the absence of danger. By studying circuits and the molecular mechanisms underlying this adaptive response, we show that cholinergic neurons of the medial habenula reduce fear memory expression through GABAB presynaptic excitation. Ablating these neurons or inactivating their GABAB receptors impairs fear extinction in mice, whereas activating the neurons or their axonal GABAB receptors reduces conditioned fear. Although considered exclusively inhibitory, here, GABAB mediates excitation by amplifying presynaptic Ca(2+) entry through Cav2.3 channels and potentiating co-release of glutamate, acetylcholine, and neurokinin B to excite interpeduncular neurons. Activating the receptors for these neurotransmitters or enhancing neurotransmission with a phosphodiesterase inhibitor reduces fear responses of both wild-type and GABAB mutant mice. We identify the role of an extra-amygdalar circuit and presynaptic GABAB receptors in fear control, suggesting that boosting neurotransmission in this pathway might ameliorate some fear disorders. PMID:27426949

  17. Effects of the swimming exercise on the consolidation and persistence of auditory and contextual fear memory.

    PubMed

    Faria, Rodolfo Souza; Gutierres, Luís Felipe Soares; Sobrinho, Fernando César Faria; Miranda, Iris do Vale; Reis, Júlia Dos; Dias, Elayne Vieira; Sartori, Cesar Renato; Moreira, Dalmo Antonio Ribeiro

    2016-08-15

    Exposure to negative environmental events triggers defensive behavior and leads to the formation of aversive associative memory. Cellular and molecular changes in the central nervous system underlie this memory formation, as well as the associated behavioral changes. In general, memory process is established in distinct phases such as acquisition, consolidation, evocation, persistence, and extinction of the acquired information. After exposure to a particular event, early changes in involved neural circuits support the memory consolidation, which corresponds to the short-term memory. Re-exposure to previously memorized events evokes the original memory, a process that is considered essential for the reactivation and consequent persistence of memory, ensuring that long-term memory is established. Different environmental stimuli may modulate the memory formation process, as well as their distinct phases. Among the different environmental stimuli able of modulating memory formation is the physical exercise which is a potent modulator of neuronal activity. There are many studies showing that physical exercise modulates learning and memory processes, mainly in the consolidation phase of the explicit memory. However, there are few reports in the literature regarding the role of physical exercise in implicit aversive associative memory, especially at the persistence phase. Thus, the present study aimed to investigate the relationship between swimming exercise and the consolidation and persistence of contextual and auditory-cued fear memory. Male Wistar rats were submitted to sessions of swimming exercise five times a week, over six weeks. After that, the rats were submitted to classical aversive conditioning training by a pairing tone/foot shock paradigm. Finally, rats were evaluated for consolidation and persistence of fear memory to both auditory and contextual cues. Our results demonstrate that classical aversive conditioning with tone/foot shock pairing induced

  18. Olfactory Fear Conditioning Induces Field Potential Potentiation in Rat Olfactory Cortex and Amygdala

    ERIC Educational Resources Information Center

    Messaoudi, Belkacem; Granjon, Lionel; Mouly, Anne-Marie; Sevelinges, Yannick; Gervais, Remi

    2004-01-01

    The widely used Pavlovian fear-conditioning paradigms used for studying the neurobiology of learning and memory have mainly used auditory cues as conditioned stimuli (CS). The present work assessed the neural network involved in olfactory fear conditioning, using olfactory bulb stimulation-induced field potential signal (EFP) as a marker of…

  19. Contextual fear conditioning depresses infralimbic excitability.

    PubMed

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

    2016-04-01

    Patients with posttraumatic stress disorder (PTSD) show hypo-active ventromedial prefrontal cortices (vmPFC) that correlate with their impaired ability to discriminate between safe and dangerous contexts and cues. Previously, we found that auditory fear conditioning depresses the excitability of neurons populating the homologous structure in rodents, the infralimbic cortex (IL). However, it is undetermined if IL depression was mediated by the cued or contextual information. The objective of this study was to examine whether contextual information was sufficient to depress IL neuronal excitability. After exposing rats to context-alone, pseudoconditioning, or contextual fear conditioning, we used whole-cell current-clamp recordings to examine the excitability of IL neurons in prefrontal brain slices. We found that contextual fear conditioning reduced IL neuronal firing in response to depolarizing current steps. In addition, neurons from contextual fear conditioned animals showed increased slow afterhyperpolarization potentials (sAHPs). Moreover, the observed changes in IL excitability correlated with contextual fear expression, suggesting that IL depression may contribute to the encoding of contextual fear. PMID:26860438

  20. Activity in Prelimbic Cortex Subserves Fear Memory Reconsolidation over Time

    ERIC Educational Resources Information Center

    Stern, Cristina A. J.; Gazarini, Lucas; Vanvossen, Ana C.; Hames, Mayara S.; Bertoglio, Leandro J.

    2014-01-01

    The prelimbic cortex has been implicated in the consolidation of previously learned fear. Herein, we report that temporarily inactivating this medial prefrontal cortex subregion with the GABA [subscript A] agonist muscimol (4.0 nmol in 0.2 µL per hemisphere) was able to equally disrupt 1-, 7-, and 21-d-old contextual fear memories after their…

  1. Stimulation of serotonin 2A receptors facilitates consolidation and extinction of fear memory in C57BL/6J mice.

    PubMed

    Zhang, Gongliang; Ásgeirsdóttir, Herborg N; Cohen, Sarah J; Munchow, Alcira H; Barrera, Mercy P; Stackman, Robert W

    2013-01-01

    Excessive fear is a hallmark of several emotional and mental disorders such as phobias and panic disorders. Considerable attention is focused on defining the neurobiological mechanisms of the extinction of conditioned fear memory in an effort to identify mechanisms that may hold clinical significance for remediating aberrant fear memory. Serotonin modulates the acquisition and retention of conditioned emotional memory, and the serotonin 2A receptor (5HT2AR) may be one of the postsynaptic targets mediating such effects. Here we tested the hypothesis that the 5HT2AR regulates the consolidation and extinction of fear memory in male C57BL/6J mice. The influence of 5HT2ARs on memory consolidation was further confirmed with a novel object recognition task. With a trace fear conditioning paradigm, administration of the 5HT2AR agonist TCB-2 (1.0 mg/kg, i.p.) before the extinction test facilitated the acquisition of extinction of fear memory as compared to vehicle treatment. In contrast, administration of the 5HT2AR antagonist MDL 11,939 (0.5 mg/kg, i.p.) delayed the acquisition of extinction of fear memory. Further, the post-conditioning administration of TCB-2 enhanced contextual and cued fear memory, possibly by facilitating the consolidation of fear memory. Administration of TCB-2 also facilitated the acquisition of extinction of fear memory in delay fear conditioned mice. Stimulation or blockade of 5HT2ARs did not affect the encoding or retrieval of conditioned fear memory. Finally, administration of TCB-2 right after training in an object recognition task enhanced the consolidation of object memory. These results suggest that stimulation of 5HT2ARs facilitates the consolidation and extinction of trace and delay cued fear memory and the consolidation of object memory. Blocking the 5HT2AR impairs the acquisition of fear memory extinction. The results support the view that serotonergic activation of the 5HT2AR provides an important modulatory influence on circuits

  2. Extinction during memory reconsolidation blocks recovery of fear in adolescents.

    PubMed

    Johnson, D C; Casey, B J

    2015-01-01

    Adolescence is a time of intensified emotional experiences, during which anxiety and stress-related disorders peak. The most effective behavioral therapies for treating these disorders share exposure-based techniques as a core component. Exposure-based therapies build on the principles of fear extinction learning and involve desensitizing the individual to cues that trigger anxiety. Yet, recent evidence shows an adolescent-specific diminished capacity to extinguish fear responses, suggesting that adolescents may respond less well to exposure-based therapies than other age groups. Here we demonstrate an alternative method for blocking the recall of fear memories in adolescents, building on principles of memory reconsolidation in adults. During memory reconsolidation, a memory that is recalled becomes labile during which time it can be updated. Prior research has shown that extinction training during memory reconsolidation attenuates the recovery of fear memory in human adults and in rodents. Using this method, we show attenuation of fear memory in adolescent humans. These findings have significant implications for treating one of the most vulnerable populations to anxiety and stress related disorders - adolescents - by optimizing exposure therapy based on principles of memory reconsolidation. PMID:25749583

  3. 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.…

  4. Attenuating fearful memories: effect of cued extinction on intrusions.

    PubMed

    Marks, Elizabeth H; Zoellner, Lori A

    2014-12-01

    Exposure-based therapies for posttraumatic stress disorder are thought to reduce intrusive memories through extinction processes. Methods that enhance extinction may translate to improved treatment. Rat research suggests retrieving a memory via a conditioned stimulus (CS) cue, and then modifying the retrieved memory within a specific reconsolidation window may enhance extinction. In humans, studies (e.g., Kindt & Soeter, 2013; Schiller et al., 2010) using basic learning paradigms show discrepant findings. Using a distressing film paradigm, participants (N = 148) completed fear acquisition and extinction. At extinction, they were randomized to 1 of 3 groups: CS cue within reconsolidation window, CS cue outside window, or non-CS cue within window. Intrusions were assessed 24 hr after extinction. Participants receiving the CS cue and completing extinction within the reconsolidation window had more intrusions (M = 2.40, SD = 2.54) than those cued outside (M = 1.65, SD = 1.70) or those receiving a non-CS cue (M = 1.24, SD = 1.26), F(2, 145) = 4.52, p = .01, d = 0.55. Consistent with the reconsolidation hypothesis, presenting a CS cue does appear to activate a specific period of time during which a memory can be updated. However, the CS cue caused increased, rather than decreased, frequency of intrusions. Understanding parameters of preextinction cueing may help us better understand reconsolidation as a potential memory updating mechanism. PMID:25286077

  5. Post-Retrieval Late Process Contributes to Persistence of Reactivated Fear Memory

    ERIC Educational Resources Information Center

    Nakayama, Daisuke; Yamasaki, Yoshiko; Matsuki, Norio; Nomura, Hiroshi

    2013-01-01

    Several studies have demonstrated the mechanisms involved in memory persistence after learning. However, little is known about memory persistence after retrieval. In this study, a protein synthesis inhibitor, anisomycin, was infused into the basolateral amygdala of mice 9.5 h after retrieval of contextual conditioned fear. Anisomycin attenuated…

  6. Histone acetylation rescues contextual fear conditioning in nNOS KO mice and accelerates extinction of cued fear conditioning in wild type mice.

    PubMed

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

    2012-05-01

    Epigenetic regulation of chromatin structure is an essential molecular mechanism that contributes to the formation of synaptic plasticity and long-term memory (LTM). An important regulatory process of chromatin structure is acetylation and deacetylation of histone proteins. Inhibition of histone deacetylase (HDAC) increases acetylation of histone proteins and facilitate learning and memory. Nitric oxide (NO) signaling pathway has a role in synaptic plasticity, LTM and regulation of histone acetylation. We have previously shown that NO signaling pathway is required for contextual fear conditioning. The present study investigated the effects of systemic administration of the HDAC inhibitor sodium butyrate (NaB) on fear conditioning in neuronal nitric oxide synthase (nNOS) knockout (KO) and wild type (WT) mice. The effect of single administration of NaB on total H3 and H4 histone acetylation in hippocampus and amygdala was also investigated. A single administration of NaB prior to fear conditioning (a) rescued contextual fear conditioning of nNOS KO mice and (b) had long-term (weeks) facilitatory effect on the extinction of cued fear memory of WT mice. The facilitatory effect of NaB on extinction of cued fear memory of WT mice was confirmed in a study whereupon NaB was administered during extinction. Results suggest that (a) the rescue of contextual fear conditioning in nNOS KO mice is associated with NaB-induced increase in H3 histone acetylation and (b) the accelerated extinction of cued fear memory in WT mice is associated with NaB-induced increase in H4 histone acetylation. Hence, a single administration of HDAC inhibitor may rescue NO-dependent cognitive deficits and afford a long-term accelerating effect on extinction of fear memory of WT mice. PMID:22452925

  7. 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. PMID:24930888

  8. The Neuronal PAS Domain Protein 4 (Npas4) Is Required for New and Reactivated Fear Memories

    PubMed Central

    Nguyen, Tam; DiLeone, Ralph J.; Schafe, Glenn E.

    2011-01-01

    The Neuronal PAS domain protein 4 (Npas4) is a neuronal activity-dependent immediate early gene that has recently been identified as a transcription factor which regulates the transcription of genes that control inhibitory synapse development and synaptic plasticity. The role Npas4 in learning and memory, however, is currently unknown. Here, we systematically examine the role of Npas4 in auditory Pavlovian fear conditioning, an amygdala-dependent form of emotional learning. In our first series of experiments, we show that Npas4 mRNA and protein are regulated in the rat lateral nucleus of the amygdala (LA) in a learning-dependent manner. Further, knockdown of Npas4 protein in the LA via adeno-associated viral (AAV) mediated gene delivery of RNAi was observed to impair fear memory formation, while innate fear and the expression of fear memory were not affected. In our second series of experiments, we show that Npas4 protein is regulated in the LA by retrieval of an auditory fear memory and that knockdown of Npas4 in the LA impairs retention of a reactivated, but not a non-reactivated, fear memory. Collectively, our findings provide the first comprehensive look at the functional role of Npas4 in learning and memory. PMID:21887312

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

    ERIC Educational Resources Information Center

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

    2010-01-01

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

  10. Demographic factors predict magnitude of conditioned fear.

    PubMed

    Rosenbaum, Blake L; Bui, Eric; Marin, Marie-France; Holt, Daphne J; Lasko, Natasha B; Pitman, Roger K; Orr, Scott P; Milad, Mohammed R

    2015-10-01

    There is substantial variability across individuals in the magnitudes of their skin conductance (SC) responses during the acquisition and extinction of conditioned fear. To manage this variability, subjects may be matched for demographic variables, such as age, gender and education. However, limited data exist addressing how much variability in conditioned SC responses is actually explained by these variables. The present study assessed the influence of age, gender and education on the SC responses of 222 subjects who underwent the same differential conditioning paradigm. The demographic variables were found to predict a small but significant amount of variability in conditioned responding during fear acquisition, but not fear extinction learning or extinction recall. A larger differential change in SC during acquisition was associated with more education. Older participants and women showed smaller differential SC during acquisition. Our findings support the need to consider age, gender and education when studying fear acquisition but not necessarily when examining fear extinction learning and recall. Variability in demographic factors across studies may partially explain the difficulty in reproducing some SC findings. PMID:26151498

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

    PubMed Central

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

    2014-01-01

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

  12. Differential involvement of amygdala and cortical NMDA receptors activation upon encoding in odor fear memory.

    PubMed

    Hegoburu, Chloé; Parrot, Sandrine; Ferreira, Guillaume; Mouly, Anne-Marie

    2014-12-01

    Although the basolateral amygdala (BLA) plays a crucial role for the acquisition of fear memories, sensory cortices are involved in their long-term storage in rats. However, the time course of their respective involvement has received little investigation. Here we assessed the role of the glutamatergic N-methyl-d-aspartate (NMDA) receptors in the BLA and olfactory cortex at discrete moments of an odor fear conditioning session. We showed that NMDA receptors in BLA are critically involved in odor fear acquisition during the first association but not during the next ones. In the cortex, NMDA receptor activation at encoding is not necessary for recent odor fear memory while its role in remote memory storage needs further investigation. PMID:25403452

  13. Uncertainty-Dependent Extinction of Fear Memory in an Amygdala-mPFC Neural Circuit Model.

    PubMed

    Li, Yuzhe; Nakae, Ken; Ishii, Shin; Naoki, Honda

    2016-09-01

    Uncertainty of fear conditioning is crucial for the acquisition and extinction of fear memory. Fear memory acquired through partial pairings of a conditioned stimulus (CS) and an unconditioned stimulus (US) is more resistant to extinction than that acquired through full pairings; this effect is known as the partial reinforcement extinction effect (PREE). Although the PREE has been explained by psychological theories, the neural mechanisms underlying the PREE remain largely unclear. Here, we developed a neural circuit model based on three distinct types of neurons (fear, persistent and extinction neurons) in the amygdala and medial prefrontal cortex (mPFC). In the model, the fear, persistent and extinction neurons encode predictions of net severity, of unconditioned stimulus (US) intensity, and of net safety, respectively. Our simulation successfully reproduces the PREE. We revealed that unpredictability of the US during extinction was represented by the combined responses of the three types of neurons, which are critical for the PREE. In addition, we extended the model to include amygdala subregions and the mPFC to address a recent finding that the ventral mPFC (vmPFC) is required for consolidating extinction memory but not for memory retrieval. Furthermore, model simulations led us to propose a novel procedure to enhance extinction learning through re-conditioning with a stronger US; strengthened fear memory up-regulates the extinction neuron, which, in turn, further inhibits the fear neuron during re-extinction. Thus, our models increased the understanding of the functional roles of the amygdala and vmPFC in the processing of uncertainty in fear conditioning and extinction. PMID:27617747

  14. Novel learning accelerates systems consolidation of a contextual fear memory.

    PubMed

    Haubrich, Josue; Cassini, Lindsey Freitas; Diehl, Felipe; Santana, Fabiana; Fürstenau de Oliveira, Lucas; de Oliveira Alvares, Lucas; Quillfeldt, Jorge Alberto

    2016-07-01

    After initial encoding memories may undergo a time-dependent reorganization, becoming progressively independent from the hippocampus (HPC) and dependent on cortical regions such as the anterior cingulate cortex (ACC). Although the mechanisms underlying systems consolidation are somewhat known, the factors determining its temporal dynamics are still poorly understood. Here, we studied the influence of novel learning occurring between training and test sessions on the time-course of HPC- and ACC-dependency of contextual fear conditioning (CFC) memory expression. We found that muscimol was disruptive when infused into the HPC up to 35 days after training, while the ACC is vulnerable only after 45 days. However, when animals were subjected to a series of additional, distinct tasks to be learned within the first 3 weeks, muscimol became effective sooner. Muscimol had no effect in the HPC at 20 days after training, exactly when the ACC becomes responsive to this treatment. Thus, our data indicates that the encoding of new information generates a tight interplay between distinct memories, accelerating the reorganization of previously stored long term memories between the hippocampal and cortical areas. © 2016 Wiley Periodicals, Inc. PMID:26860633

  15. Foreground Contextual Fear Memory Consolidation Requires Two Independent Phases of Hippocampal ERK/CREB Activation

    ERIC Educational Resources Information Center

    Trifilieff, Pierre; Vanhoutte, Peter; Caboche, Jocelyne; Desmedt, Aline; Riedel, Gernot; Mons, Nicole; Micheau, Jacques; Herry, Cyril

    2006-01-01

    Fear conditioning is a popular model for investigating physiological and cellular mechanisms of memory formation. In this paradigm, a footshock is either systematically associated to a tone (paired conditioning) or is pseudorandomly distributed (unpaired conditioning). In the former procedure, the tone/shock association is acquired, whereas in the…

  16. Identification of Genes Expressed in the Amygdala During the Formation of Fear Memory

    PubMed Central

    Stork, Oliver; Stork, Simone; Pape, Hans-Christian; Obata, Kunihiko

    2001-01-01

    In this study we describe changes of gene expression that occur in the basolateral complex of the mouse amygdala (BLA) during the formation of fear memory. Through the combination of a behavioral training scheme with polymerase chain reaction-based expression analysis (subtractive hybridization and virtual Northern analysis) we were able to identify various gene products that are increased in expression after Pavlovian fear conditioning and are of potential significance for neural plasticity and information storage in the amygdala. In particular, a key enzyme of monoamine metabolism, aldehyde reductase, and the protein sorting and ubiquitination factor Praja1, showed pronounced and learning-specific induction six hours after fear conditioning training. Aldehyde reductase and Praja1, including a novel alternatively spliced isoform termed Praja1a, were induced in the BLA depending on the emotional stimulus presented and showed different expression levels in response to associative conditioning, training stress, and experience of conditioned fear. Stress and fear were further found to induce various signal transduction factors (transthyretin, phosphodiesterase1, protein kinase inhibitor-α) and structural reorganization factors (e.g., E2-ubiquitin conjugating enzyme, neuroligin1, actin, UDP-galactose transporter) during training. Our results show that the formation of Pavlovian fear memory is associated with changes of gene expression in the BLA, which may contribute to neural plasticity and the processing of information about both conditioned and unconditioned fear stimuli.[The Praja1a sequence has been deposited in GenBank data base under accession no. AF335250.] PMID:11533224

  17. Abnormal Fear Memory as a Model for Posttraumatic Stress Disorder.

    PubMed

    Desmedt, Aline; Marighetto, Aline; Piazza, Pier-Vincenzo

    2015-09-01

    For over a century, clinicians have consistently described the paradoxical co-existence in posttraumatic stress disorder (PTSD) of sensory intrusive hypermnesia and declarative amnesia for the same traumatic event. Although this amnesia is considered as a critical etiological factor of the development and/or persistence of PTSD, most current animal models in basic neuroscience have focused exclusively on the hypermnesia, i.e., the persistence of a strong fear memory, neglecting the qualitative alteration of fear memory. The latest is characterized by an underrepresentation of the trauma in the context-based declarative memory system in favor of its overrepresentation in a cue-based sensory/emotional memory system. Combining psychological and neurobiological data as well as theoretical hypotheses, this review supports the idea that contextual amnesia is at the core of PTSD and its persistence and that altered hippocampal-amygdalar interaction may contribute to such pathologic memory. In a first attempt to unveil the neurobiological alterations underlying PTSD-related hypermnesia/amnesia, we describe a recent animal model mimicking in mice some critical aspects of such abnormal fear memory. Finally, this line of argument emphasizes the pressing need for a systematic comparison between normal/adaptive versus abnormal/maladaptive fear memory to identify biomarkers of PTSD while distinguishing them from general stress-related, potentially adaptive, neurobiological alterations. PMID:26238378

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

    PubMed Central

    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. PMID

  19. Systems reconsolidation reveals a selective role for the anterior cingulate cortex in generalized contextual fear memory expression.

    PubMed

    Einarsson, Einar Ö; Pors, Jennifer; Nader, Karim

    2015-01-01

    After acquisition, hippocampus-dependent memories undergo a systems consolidation process, during which they become independent of the hippocampus and dependent on the anterior cingulate cortex (ACC) for memory expression. However, consolidated remote memories can become transiently hippocampus-dependent again following memory reactivation. How this systems reconsolidation affects the role of the ACC in remote memory expression is not known. Using contextual fear conditioning, we show that the expression of 30-day-old remote memory can transiently be supported by either the ACC or the dorsal hippocampus following memory reactivation, and that the ACC specifically mediates expression of remote generalized contextual fear memory. We found that suppression of neural activity in the ACC with the AMPA/kainate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) impaired the expression of remote, but not recent, contextual fear memory. Fear expression was not affected by this treatment if preceded by memory reactivation 6 h earlier, nor was it affected by suppression of neural activity in the dorsal hippocampus with the GABA-receptor agonist muscimol. However, simultaneous targeting of both the ACC and the dorsal hippocampus 6 h after memory reactivation disrupted contextual fear memory expression. Second, we observed that expression of a 30-day-old generalized contextual fear memory in a novel context was not affected by memory reactivation 6 h earlier. However, intra-ACC CNQX infusion before testing impaired contextual fear expression in the novel context, but not the original training context. Together, these data suggest that although the dorsal hippocampus may be recruited during systems reconsolidation, the ACC remains necessary for the expression of generalized contextual fear memory. PMID:25091528

  20. Nonlinear developmental trajectory of fear learning and memory.

    PubMed

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

    2013-11-01

    The transition into and out of adolescence is 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, and an estimated 75% of adults with fear-related disorders met diagnostic criteria as children and adolescents. Conserved neural circuitry of rodents and humans has facilitated neurodevelopmental studies of behavioral and molecular processes associated with fear learning and memory that lie at the heart of many anxiety disorders. Here, we review the nonlinear 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

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

    PubMed Central

    Giustino, Thomas F.; Maren, Stephen

    2015-01-01

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

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

    PubMed

    Giustino, Thomas F; Maren, Stephen

    2015-01-01

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

  3. AMPK Signaling in the Dorsal Hippocampus Negatively Regulates Contextual Fear Memory Formation.

    PubMed

    Han, Ying; Luo, Yixiao; Sun, Jia; Ding, Zengbo; Liu, Jianfeng; Yan, Wei; Jian, Min; Xue, Yanxue; Shi, Jie; Wang, Ji-Shi; Lu, Lin

    2016-06-01

    Both the formation of long-term memory (LTM) and dendritic spine growth that serves as a physical basis for the long-term storage of information require de novo protein synthesis. Memory formation also critically depends on transcription. Adenosine monophosphate-activated protein kinase (AMPK) is a transcriptional regulator that has emerged as a major energy sensor that maintains cellular energy homeostasis. However, still unknown is its role in memory formation. In the present study, we found that AMPK is primarily expressed in neurons in the hippocampus, and then we demonstrated a time-dependent decrease in AMPK activity and increase in mammalian target of rapamycin complex 1 (mTORC1) activity after contextual fear conditioning in the CA1 but not CA3 area of the dorsal hippocampus. Using pharmacological methods and adenovirus gene transfer to bidirectionally regulate AMPK activity, we found that increasing AMPK activity in the CA1 impaired the formation of long-term fear memory, and decreasing AMPK activity enhanced fear memory formation. These findings were associated with changes in the phosphorylation of AMPK and p70s6 kinase (p70s6k) and expression of BDNF and membrane GluR1 and GluR2 in the CA1. Furthermore, the prior administration of an mTORC1 inhibitor blocked the enhancing effect of AMPK inhibition on fear memory formation, suggesting that this negative regulation of contextual fear memory by AMPK in the CA1 depends on the mTORC1 signaling pathway. Finally, we found that AMPK activity regulated hippocampal spine growth associated with memory formation. In summary, our results indicate that AMPK is a key negative regulator of plasticity and fear memory formation. PMID:26647974

  4. Prefrontal consolidation supports the attainment of fear memory accuracy

    PubMed Central

    Vieira, Philip A.; Lovelace, Jonathan W.; Corches, Alex; Rashid, Asim J.; Josselyn, Sheena A.

    2014-01-01

    The neural mechanisms underlying the attainment of fear memory accuracy for appropriate discriminative responses to aversive and nonaversive stimuli are unclear. Considerable evidence indicates that coactivator of transcription and histone acetyltransferase cAMP response element binding protein (CREB) binding protein (CBP) is critically required for normal neural function. CBP hypofunction leads to severe psychopathological symptoms in human and cognitive abnormalities in genetic mutant mice with severity dependent on the neural locus and developmental time of the gene inactivation. Here, we showed that an acute hypofunction of CBP in the medial prefrontal cortex (mPFC) results in a disruption of fear memory accuracy in mice. In addition, interruption of CREB function in the mPFC also leads to a deficit in auditory discrimination of fearful stimuli. While mice with deficient CBP/CREB signaling in the mPFC maintain normal responses to aversive stimuli, they exhibit abnormal responses to similar but nonrelevant stimuli when compared to control animals. These data indicate that improvement of fear memory accuracy involves mPFC-dependent suppression of fear responses to nonrelevant stimuli. Evidence from a context discriminatory task and a newly developed task that depends on the ability to distinguish discrete auditory cues indicated that CBP-dependent neural signaling within the mPFC circuitry is an important component of the mechanism for disambiguating the meaning of fear signals with two opposing values: aversive and nonaversive. PMID:25031365

  5. Interplay between serotonin and cannabinoid function in the amygdala in fear conditioning.

    PubMed

    Nasehi, Mohammad; Davoudi, Kamelia; Ebrahimi-Ghiri, Mohaddeseh; Zarrindast, Mohammad-Reza

    2016-04-01

    The possible interactions between the cannabinoid and serotonin systems in the regions of the brain involved in emotional learning and memory formation have been studied by some researchers. In view of the key role of the amygdala in the acquisition and expression of fear memory, we investigated the involvement of basolateral amygdala (BLA) serotonin 5-HT4 receptors in arachidonylcyclopropylamide (ACPA; selective CB1 cannabinoid receptor agonist)-induced fear memory consolidation impairment. In our study, a context and tone fear conditioning apparatus was used for testing fear conditioning in adult male NMRI mice. The results showed that intraperitoneal administration of ACPA 0.5 or 0.05, 0.1 and 0.5mg/kg immediately after training decreased the percentage of freezing time in context or tone fear conditioning respectively, suggesting a context- or tone-dependent fear memory consolidation impairment. Post-training intra-BLA microinjections of RS67333, as 5-HT4 serotonin receptor agonist, at doses of 0.025 and 0.05 µg/mouse also impaired context or tone memory consolidation, while RS23597, as 5-HT4 serotonin receptor antagonist, did not produce a marked difference in both fear memories as compared with the control group. Moreover, a subthreshold dose of RS67333 did not alter ACPA response in both fear conditionings. Interestingly, a subthreshold dose of RS23597 potentiated or reversed ACPA response at the dose of 0.01 or 0.05 respectively. It is concluded that BLA serotonin 5-HT4 receptors are involved in tone-dependent fear memory consolidation impairment induced by CB1 activation using ACPA, suggesting a modulatory role for serotonin 5-HT4 receptor. PMID:26820636

  6. Fear Conditioned Responses and PTSD Symptoms in Children: Sex Differences in Fear-Related Symptoms

    PubMed Central

    Gamwell, Kaitlyn; Nylocks, Maria; Cross, Dorthie; Bradley, Bekh; Norrholm, Seth D.

    2016-01-01

    Fear conditioning studies in adults have found that posttraumatic stress disorder (PTSD) is associated with heightened fear responses and impaired discrimination. The objective of the current study was to examine the association between PTSD symptoms and fear conditioned responses in children from a highly traumatized urban population. Children between 8 and 13 years old participated in a fear conditioning study in addition to providing information about their trauma history and PTSD symptoms. Results showed that females showed less discrimination between danger and safety signals during conditioning compared to age-matched males. In boys, intrusive symptoms were predictive of fear responses, even after controlling for trauma exposure. However, in girls, conditioned fear to the danger cue was predictive of self-blame and fear of repeated trauma. This study suggests there are early sex differences in the patterns of fear conditioning and that these sex differences may translate to differential risk for trauma-related psychopathology. PMID:26011240

  7. Fear conditioned responses and PTSD symptoms in children: Sex differences in fear-related symptoms.

    PubMed

    Gamwell, Kaitlyn; Nylocks, Maria; Cross, Dorthie; Bradley, Bekh; Norrholm, Seth D; Jovanovic, Tanja

    2015-11-01

    Fear conditioning studies in adults have found that posttraumatic stress disorder (PTSD) is associated with heightened fear responses and impaired discrimination. The objective of the current study was to examine the association between PTSD symptoms and fear conditioned responses in children from a highly traumatized urban population. Children between 8 and 13 years old participated in a fear conditioning study in addition to providing information about their trauma history and PTSD symptoms. Results showed that females showed less discrimination between danger and safety signals during conditioning compared to age-matched males. In boys, intrusive symptoms were predictive of fear responses, even after controlling for trauma exposure. However, in girls, conditioned fear to the danger cue was predictive of self-blame and fear of repeated trauma. This study suggests there are early sex differences in the patterns of fear conditioning and that these sex differences may translate to differential risk for trauma-related psychopathology. PMID:26011240

  8. Reciprocal Patterns of c-Fos Expression in the Medial Prefrontal Cortex and Amygdala after Extinction and Renewal of Conditioned Fear

    ERIC Educational Resources Information Center

    Knapska, Ewelina; Maren, Stephen

    2009-01-01

    After extinction of conditioned fear, memory for the conditioning and extinction experiences becomes context dependent. Fear is suppressed in the extinction context, but renews in other contexts. This study characterizes the neural circuitry underlying the context-dependent retrieval of extinguished fear memories using c-Fos immunohistochemistry.…

  9. An egr-1 (zif268) Antisense Oligodeoxynucleotide Infused Into the Amygdala Disrupts Fear Conditioning

    PubMed Central

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

    2004-01-01

    Studies of gene expression following fear conditioning have demonstrated that the inducible transcription factor, egr-1, is increased in the lateral nucleus of the amygdala shortly following fear conditioning. These studies suggest that egr-1 and its protein product Egr-1 in the amygdala are important for learning and memory of fear. To directly test this hypothesis, an egr-1 antisense oligodeoxynucleotide (antisense-ODN) was injected bilaterally into the amygdala prior to contextual fear conditioning. The antisense-ODN reduced Egr-1 protein in the amygdala and interfered with fear conditioning. A 250-pmole dose produced an 11% decrease in Egr-1 protein and reduced long-term memory of fear as measured by freezing in a retention test 24 h after conditioning, but left shock-induced freezing intact. A larger 500-pmole dose produced a 25% reduction in Egr-1 protein and significantly decreased both freezing immediately following conditioning and freezing in the retention test. A nonsense-ODN had no effect on postshock or retention test freezing. In addition, 500 pmole of antisense-ODN infused prior to the retention test in previously trained rats did not reduce freezing, indicating that antisense-ODN did not suppress conditioned fear behavior. Finally, rats infused with 500 pmole of antisense-ODN displayed unconditioned fear to a predator odor, demonstrating that unconditioned freezing was unaffected by the antisense-ODN. The data indicate that the egr-1 antisense-ODN interferes with learning and memory processes of fear without affecting freezing behavior and suggests that the inducible transcription factor Egr-1 within the amygdala plays important functions in long-term learning and memory of fear. PMID:15466317

  10. An appetitive experience after fear memory destabilization attenuates fear retention: involvement GluN2B-NMDA receptors in the Basolateral Amygdala Complex.

    PubMed

    Ferrer Monti, Roque I; Giachero, Marcelo; Alfei, Joaquín M; Bueno, Adrián M; Cuadra, Gabriel; Molina, Victor A

    2016-09-01

    It is known that a consolidated memory can return to a labile state and become transiently malleable following reactivation. This instability is followed by a restabilization phase termed reconsolidation. In this work, we explored whether an unrelated appetitive experience (voluntary consumption of diluted sucrose) can affect a contextual fear memory in rats during the reactivation-induced destabilization phase. Our findings show that exposure to an appetitive experience following reactivation can diminish fear retention. This effect persisted after 1 wk. Importantly, it was achieved only under conditions that induced fear memory destabilization. This result could not be explained as a potentiated extinction, because sucrose was unable to promote extinction. Since GluN2B-containing NMDA receptors in the basolateral amygdala complex (BLA) have been implicated in triggering fear memory destabilization, we decided to block pharmacologically these receptors to explore the neurobiological bases of the observed effect. Intra-BLA infusion with ifenprodil, a GluN2B-NMDA antagonist, prevented the fear reduction caused by the appetitive experience. In sum, these results suggest that the expression of a fear memory can be dampened by an unrelated appetitive experience, as long as memory destabilization is achieved during reactivation. Possible mechanisms behind this effect and its clinical implications are discussed. PMID:27531837

  11. 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. PMID:26459843

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

    ERIC Educational Resources Information Center

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

    2006-01-01

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

  13. Xenon impairs reconsolidation of fear memories in a rat model of post-traumatic stress disorder (PTSD).

    PubMed

    Meloni, Edward G; Gillis, Timothy E; Manoukian, Jasmine; Kaufman, Marc J

    2014-01-01

    Xenon (Xe) is a noble gas that has been developed for use in people as an inhalational anesthestic and a diagnostic imaging agent. Xe inhibits glutamatergic N-methyl-D-aspartate (NMDA) receptors involved in learning and memory and can affect synaptic plasticity in the amygdala and hippocampus, two brain areas known to play a role in fear conditioning models of post-traumatic stress disorder (PTSD). Because glutamate receptors also have been shown to play a role in fear memory reconsolidation--a state in which recalled memories become susceptible to modification--we examined whether Xe administered after fear memory reactivation could affect subsequent expression of fear-like behavior (freezing) in rats. Male Sprague-Dawley rats were trained for contextual and cued fear conditioning and the effects of inhaled Xe (25%, 1 hr) on fear memory reconsolidation were tested using conditioned freezing measured days or weeks after reactivation/Xe administration. Xe administration immediately after fear memory reactivation significantly reduced conditioned freezing when tested 48 h, 96 h or 18 d after reactivation/Xe administration. Xe did not affect freezing when treatment was delayed until 2 h after reactivation or when administered in the absence of fear memory reactivation. These data suggest that Xe substantially and persistently inhibits memory reconsolidation in a reactivation and time-dependent manner, that it could be used as a new research tool to characterize reconsolidation and other memory processes, and that it could be developed to treat people with PTSD and other disorders related to emotional memory. PMID:25162644

  14. Mechanisms underlying the formation of the amygdalar fear memory trace: A computational perspective.

    PubMed

    Feng, F; Samarth, P; Paré, D; Nair, S S

    2016-05-13

    Recent experimental and modeling studies on the lateral amygdala (LA) have implicated intrinsic excitability and competitive synaptic interactions among principal neurons (PNs) in the formation of auditory fear memories. The present modeling studies, conducted over an expanded range of intrinsic excitability in the network, revealed that only excitable PNs that received tone inputs participate in the competition. Strikingly, the number of model PNs integrated into the fear memory trace remained constant despite the much larger range considered, and model runs highlighted several conditioning-induced tone responsive characteristics of the various PN populations. Furthermore, these studies showed that although excitation was important, disynaptic inhibition among PNs is the dominant mechanism that keeps the number of plastic PNs stable despite large variations in the network's excitability. Finally, we found that the overall level of inhibition in the model network determines the number of projection cells integrated into the fear memory trace. PMID:26944604

  15. Selective and protracted effect of nifedipine on fear memory extinction correlates with induced stress response.

    PubMed

    Waltereit, Robert; Mannhardt, Sönke; Nescholta, Sabine; Maser-Gluth, Christiane; Bartsch, Dusan

    2008-05-01

    Memory extinction, defined as a decrease of a conditioned response as a function of a non-reinforced conditioned stimulus presentation, has high biological and clinical relevance. Extinction is not a passive reversing or erasing of the plasticity associated with acquisition, but a novel, active learning process. Nifedipine blocks L-type voltage gated calcium channels (LVGCC) and has been shown previously to selectively interfere with the extinction, but not the acquisition, of fear memory. We studied here the effect of retrograde and anterograde shifts of nifedipine application, with respect to an extinction training, on the extinction of fear conditioning. Subcutaneous injection of 30 mg/kg nifedipine, at least up to 4 h before the extinction session, significantly impaired extinction, as did intraperitoneal injection of 15 mg/kg nifedipine, at least up to 2 h before extinction training. However, the injection of nifedipine also induced a strong and protracted stress response. The pharmacokinetics of nifedipine suggest that it was mainly this stress response that triggered the specific inhibition of extinction, not the blockade of LVGCC in the brain. Our results support recent findings that stress selectively interferes with the extinction, but not the acquisition, of fear memory. They also indicate that a pharmacological approach is not sufficient to study the role of brain LVGCC in learning and memory. Further research using specific genetically modified animals is necessary to delineate the role of LVGCC in fear memory extinction. PMID:18441293

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

    PubMed Central

    Feng, Pan; Zheng, Yong; Feng, Tingyong

    2015-01-01

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

  17. Modulation of cannabinoid signaling by amygdala α2-adrenergic system in fear conditioning.

    PubMed

    Nasehi, Mohammad; Zamanparvar, Majid; Ebrahimi-Ghiri, Mohaddeseh; Zarrindast, Mohammad-Reza

    2016-03-01

    The noradrenergic system plays a critical role in the modulation of emotional state, primarily related to anxiety, arousal, and stress. Growing evidence suggests that the endocannabinoid system mediates stress responses and emotional homeostasis, in part, by targeting noradrenergic circuits. In addition, there is an interaction between the cannabinoid and noradrenergic system that has significant functional and behavioral implications. Considering the importance of these systems in forming memories for fearful events, we have investigated the involvement of basolateral amygdala (BLA) α2-adrenoceptors on ACPA (as selective cannabinoid CB1 agonist)-induced inhibition of the acquisition of contextual and auditory conditioned fear. A contextual and auditory fear conditioning apparatus for assess fear memory in adult male NMRI mice was used. Pre-training, intraperitoneal administration of ACPA decreased the percentage freezing time in contextual (at doses of 0.05 and 0.1mg/kg) and auditory (at dose of 0.1 mg/kg) in the fear conditioning task, indicating memory acquisition deficit. The same result was observed with intra-BLA microinjection of clonidine (0.001-0.5 μg/mouse, for both memories), as α2-adrenoceptor agonist and yohimbine (at doses of 0.005 and 0.05 for contextual and at dose of 0.05 μg/mouse for auditory fear memory), as α2-adrenoceptor antagonist. In addition, intra-BLA microinjection of clonidine (0.0005 μg/mouse) did not alter ACPA response in both conditions, while the same dose of yohimbine potentiated ACPA response at the lower dose on contextual fear memory. It is concluded that BLA α2-adrenergic receptors may be involved in context- but not tone-dependent fear memory impairment induced by activation of CB1 receptors. PMID:26698395

  18. Amygdala kindling disrupts trace and delay fear conditioning with parallel changes in Fos protein expression throughout the limbic brain.

    PubMed

    Botterill, J J; Fournier, N M; Guskjolen, A J; Lussier, A L; Marks, W N; Kalynchuk, L E

    2014-04-18

    Amygdala kindling is well known to increase unconditioned fear and anxiety. However, relatively little is known about whether this form of kindling causes functional changes within the neural circuitry that mediates fear learning and the retrieval of fear memories. To address this issue, we examined the effect of short- (i.e., 30 stimulations) and long-term (i.e., 99 stimulations) amygdala kindling in rats on trace and delay fear conditioning, which are aversive learning tasks that rely predominantly on the hippocampus and amygdala, respectively. After memory retrieval, we analyzed the pattern of neural activity with Fos, the protein product of the immediate early gene c-fos. We found that kindling had no effect on acquisition of the trace fear conditioning task but it did selectively impair retrieval of this fear memory. In contrast, kindling disrupted both acquisition and retrieval of fear memory in the delay fear conditioning task. We also found that kindling-induced impairments in memory retrieval were accompanied by decreased Fos expression in several subregions of the hippocampus, parahippocampus, and amygdala. Interestingly, decreased freezing in the trace conditioning task was significantly correlated with dampened Fos expression in hippocampal and parahippocampal regions whereas decreased freezing in the delay conditioning task was significantly correlated with dampened Fos expression in hippocampal, parahippocampal, and amygdaloid circuits. Overall, these results suggest that amygdala kindling promotes functional changes in brain regions involved in specific types of fear learning and memory. PMID:24486965

  19. Prefrontal Consolidation Supports the Attainment of Fear Memory Accuracy

    ERIC Educational Resources Information Center

    Vieira, Philip A.; Lovelace, Jonathan W.; Corches, Alex; Rashid, Asim J.; Josselyn, Sheena A.; Korzus, Edward

    2014-01-01

    The neural mechanisms underlying the attainment of fear memory accuracy for appropriate discriminative responses to aversive and nonaversive stimuli are unclear. Considerable evidence indicates that coactivator of transcription and histone acetyltransferase cAMP response element binding protein (CREB) binding protein (CBP) is critically required…

  20. Effects of Postnatal Serotonin Agonism on Fear Response and Memory

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The neurotransmitter serotonin (5-HT) also acts as a neurogenic compound in the developing brain. Early administration of a 5-HT agonist could alter the development of the serotonergic circuitry, altering behaviors mediated by 5-HT signaling, such as memory, fear and aggression. White leghorn chicks...

  1. Modulation of fear memory by dietary polyunsaturated fatty acids via cannabinoid receptors.

    PubMed

    Yamada, Daisuke; Takeo, Jiro; Koppensteiner, Peter; Wada, Keiji; Sekiguchi, Masayuki

    2014-07-01

    Although the underlying mechanism remains unknown, several studies have suggested benefits of n-3 long-chain polyunsaturated fatty acid (PUFA) for patients with anxiety disorders. Elevated fear is thought to contribute to the pathogenesis of particular anxiety disorders. The aim of the present study was to evaluate whether the dietary n-3 to n-6 PUFA (3:6) ratio influences fear memory. For this purpose, the effects of various dietary 3:6 ratios on fear memory were examined in mice using contextual fear conditioning, and the effects of these diets on central synaptic transmission were examined to elucidate the mechanism of action of PUFA. We found that fear memory correlated negatively with dietary, serum, and brain 3:6 ratios in mice. The low fear memory in mice fed a high 3:6 ratio diet was increased by the cannabinoid CB1 receptor antagonist rimonabant, reaching a level seen in mice fed a low 3:6 ratio diet. The agonist sensitivity of CB1 receptor was enhanced in the basolateral nucleus of the amygdala (BLA) of mice fed a high 3:6 ratio diet, compared with that of mice fed a low 3:6 ratio diet. Similar enhancement was induced by pharmacological expulsion of cholesterol in the neuronal membrane of brain slices from mice fed a low 3:6 ratio diet. CB1 receptor-mediated short-term synaptic plasticity was facilitated in pyramidal neurons of the BLA in mice fed a high 3:6 ratio diet. These results suggest that the ratio of n-3 to n-6 PUFA is a factor regulating fear memory via cannabinoid CB1 receptors. PMID:24518289

  2. The Cannabinoid System in the Retrosplenial Cortex Modulates Fear Memory Consolidation, Reconsolidation, and Extinction

    ERIC Educational Resources Information Center

    Sachser, Ricardo Marcelo; Crestani, Ana Paula; Quillfeldt, Jorge Alberto; e Souza, Tadeu Mello; de Oliveira Alvares, Lucas

    2015-01-01

    Despite the fact that the cannabinoid receptor type 1 (CB1R) plays a pivotal role in emotional memory processing in different regions of the brain, its function in the retrosplenial cortex (RSC) remains unknown. Here, using contextual fear conditioning in rats, we showed that a post-training intra-RSC infusion of the CB1R antagonist AM251…

  3. Hippocampus and Medial Prefrontal Cortex Contributions to Trace and Contextual Fear Memory Expression over Time

    ERIC Educational Resources Information Center

    Beeman, Christopher L.; Bauer, Philip S.; Pierson, Jamie L.; Quinn, Jennifer J.

    2013-01-01

    Previous work has shown that damage to the dorsal hippocampus (DH) occurring at recent, but not remote, timepoints following acquisition produces a deficit in trace conditioned fear memory expression. The opposite pattern has been observed with lesions to the medial prefrontal cortex (mPFC). The present studies address: (1) whether these lesion…

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

    ERIC Educational Resources Information Center

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

    2009-01-01

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

  5. Effects of Post-Training Hippocampal Injections of Midazolam on Fear Conditioning

    ERIC Educational Resources Information Center

    Gafford, Georgette M.; Parsons, Ryan G.; Helmstetter, Fred J.

    2005-01-01

    Benzodiazepines have been useful tools for investigating mechanisms underlying learning and memory. The present set of experiments investigates the role of hippocampal GABA[subscript A]/benzodiazepine receptors in memory consolidation using Pavlovian fear conditioning. Rats were prepared with cannulae aimed at the dorsal hippocampus and trained…

  6. The Histone Deacetylase Inhibitor Valproic Acid Enhances Acquisition, Extinction, and Reconsolidation of Conditioned Fear

    ERIC Educational Resources Information Center

    Bredy, Timothy W.; Barad, Mark

    2008-01-01

    Histone modifications contribute to the epigenetic regulation of gene expression, a process now recognized to be important for the consolidation of long-term memory. Valproic acid (VPA), used for many years as an anticonvulsant and a mood stabilizer, has effects on learning and memory and enhances the extinction of conditioned fear through its…

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

    PubMed

    Kindt, Merel; Soeter, Marieke

    2013-01-01

    Disrupting reconsolidation seems to be a promising approach to dampen the expression of fear memory. Recently, we demonstrated that disrupting reconsolidation by a pharmacological manipulation specifically targeted the emotional expression of memory (i.e., startle response). Here we test in a human differential fear-conditioning paradigm with fear-relevant stimuli whether the spacing of a single unreinforced retrieval trial relative to extinction learning allows for "rewriting" the original fear association, thereby preventing the return of fear. In contrast to previous findings reported by Schiller et al. (2010), who used a single-method for indexing fear (skin conductance response) and fear-irrelevant stimuli, we found that extinction learning within the reconsolidation window did not prevent the recovery of fear on multiple indices of conditioned responding (startle response, skin conductance response and US-expectancy). These conflicting results ask for further critical testing given the potential impact on the field of emotional memory and its application to clinical practice. PMID:21986472

  8. Prefrontal inputs to the amygdala instruct fear extinction memory formation

    PubMed Central

    Bukalo, Olena; Pinard, Courtney R.; Silverstein, Shana; Brehm, Christina; Hartley, Nolan D.; Whittle, Nigel; Colacicco, Giovanni; Busch, Erica; Patel, Sachin; Singewald, Nicolas; Holmes, Andrew

    2015-01-01

    Persistent anxiety after a psychological trauma is a hallmark of many anxiety disorders. However, the neural circuits mediating the extinction of traumatic fear memories remain incompletely understood. We show that selective, in vivo stimulation of the ventromedial prefrontal cortex (vmPFC)–amygdala pathway facilitated extinction memory formation, but not retrieval. Conversely, silencing the vmPFC-amygdala pathway impaired extinction formation and reduced extinction-induced amygdala activity. Our data demonstrate a critical instructional role for the vmPFC-amygdala circuit in the formation of extinction memories. These findings advance our understanding of the neural basis of persistent fear, with implications for posttraumatic stress disorder and other anxiety disorders. PMID:26504902

  9. Increased stathmin expression strengthens fear conditioning in epileptic rats.

    PubMed

    Zhang, Linna; Feng, Danni; Tao, Hong; DE, Xiangyan; Chang, Qing; Hu, Qikuan

    2015-01-01

    Patients with temporal lobe epilepsy have inexplicable fear attack as the aura. However, the underlying neural mechanisms of seizure-modulated fear are not clarified. Recent studies identified stathmin as one of the key controlling molecules in learning and innate fear. Stathmin binds to tubulin, inhibits microtubule assembly and promotes microtubule catastrophes. Therefore, stathmin is predicted to play a crucial role in the association of epilepsy seizures with fear conditioning. Firstly, a pilocarpine model of epilepsy in rats was established, and subsequently the fear condition training was performed. The epileptic rats with fear conditioning (epilepsy + fear) had a much longer freezing time compared to each single stimulus. The increased freezing levels revealed a significantly strengthened effect of the epileptic seizures on the learned fear of the tone-shock contextual. Subsequently, the stathmin expression was compared in the hippocampus, the amygdale, the insular cortex and the temporal lobe. The significant change of stathmin expression occurred in the insular and the hippocampus, but not in the amygdale. Stathmin expression and dendritic microtubule stability were compared between fear and epilepsy in rats. Epilepsy was found to strengthen the fear conditioning with increased expression of stathmin and a decrease in microtubule stability. Fear conditioning slightly increased the expression of stathmin, whereas epilepsy with fear conditioning increased it significantly in the hippocampus, insular cortex and hypothalamus. The phosphorylated stathmin slightly increased in the epilepsy with fear conditioning. The increased expression of stathmin was contrary to the decrease of the stathmin microtubule-associated protein (MAP2) and α-tubulin in the epileptic rats with fear conditioning in all three areas of the brain. The most significant change of the ratio of MAP2 and α-tubulin/stathmin occurred in the insular cortex and hippocampus. In conclusion

  10. 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

    2013-09-01

    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. PMID:23732229

  11. Equal pain—Unequal fear response: enhanced susceptibility of tooth pain to fear conditioning

    PubMed Central

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

    2014-01-01

    Experimental fear conditioning in humans is widely used as a model to investigate the neural basis of fear learning and to unravel the pathogenesis of anxiety disorders. It has been observed that fear conditioning depends on stimulus salience and subject vulnerability to fear. It is further known that the prevalence of dental-related fear and phobia is exceedingly high in the population. Dental phobia is unique as no other body part is associated with a specific phobia. Therefore, we hypothesized that painful dental stimuli exhibit an enhanced susceptibility to fear conditioning when comparing to equal perceived stimuli applied to other body sites. Differential susceptibility to pain-related fear was investigated by analyzing responses to an unconditioned stimulus (UCS) applied to the right maxillary canine (UCS-c) vs. the right tibia (UCS-t). For fear conditioning, UCS-c and USC-t consisted of painful electric stimuli, carefully matched at both application sites for equal intensity and quality perception. UCSs were paired to simple geometrical forms which served as conditioned stimuli (CS+). Unpaired CS+ were presented for eliciting and analyzing conditioned fear responses. Outcome parameter were (1) skin conductance changes and (2) time-dependent brain activity (BOLD responses) in fear-related brain regions such as the amygdala, anterior cingulate cortex, insula, thalamus, orbitofrontal cortex, and medial prefrontal cortex. A preferential susceptibility of dental pain to fear conditioning was observed, reflected by heightened skin conductance responses and enhanced time-dependent brain activity (BOLD responses) in the fear network. For the first time, this study demonstrates fear-related neurobiological mechanisms that point toward a superior conditionability of tooth pain. Beside traumatic dental experiences our results offer novel evidence that might explain the high prevalence of dental-related fears in the population. PMID:25100974

  12. Pair exposure with conspecific during fear conditioning induces the link between freezing and passive avoidance behaviors in rats.

    PubMed

    Lee, Hyunchan; Noh, Jihyun

    2016-07-01

    Social factor plays an important role in dealing with posttraumatic stress disorder related to excessive physiological fear response and insufficient fear memory extinction of the brain. However, although social circumstances occurred not only during contextual retrieval but also during fear conditioning, most previous studies focused on the advantageous aspects of social buffering in fear retrieval period. To demonstrate the association between fear responses and fear memory from social stimuli during fear conditioning, pair exposed rats with conspecific as social buffering were subjected to a fear conditioning of passive avoidance test to evaluate memory function and freezing behavior. Whereas single exposed rats showed the significant increase of freezing behaviors and passive avoidance behaviors compared to control rats, pair exposed rats showed significant alleviation of the freezing behaviors and passive avoidance behaviors compared to single exposed rats. Furthermore, we determined a significant correlation between freezing and passive avoidance behavioral alteration in pair exposed rats. Taken together, we suggest that pair exposure with conspecific during fear conditioning helps to cope with both freezing response and fear memory systems and their reciprocal interaction has a crucial potential as a resource for the relief of unreasonable stress responses in posttraumatic stress disorder. PMID:26827818

  13. Involvement of the dopaminergic system in the consolidation of fear conditioning in hippocampal CA3 subregion.

    PubMed

    Wen, Jia-Ling; Xue, Li; Wang, Run-Hua; Chen, Zi-Xiang; Shi, Yan-Wei; Zhao, Hu

    2015-02-01

    The hippocampus, the primary brain structure related to learning and memory, receives sparse but comprehensive dopamine innervations and contains dopamine D1 and D2 receptors. Systematic hippocampal dopaminergic dysfunction can cause deficits in spatial working memory and impair consolidation of contextual fear memories. CA3 is involved in the rapid acquisition of new memories and has extensive nerve fibre connections with other brain structures such as CA1, the amygdala, and the medial prefrontal cortex (mPFC). A bidirectional fibrous connection between CA3 and the amygdala reflects the importance of CA3 in fear conditioning. The present study evaluated the effects of a 6-OHDA lesion in CA3 on the acquisition and expression of conditioned fear. The results showed CA3 involvement in the expression but not the acquisition of conditioned fear. Injection of SCH23390 and quinpirole into the bilateral CA3 attenuated a conditioned fear-related freezing response, whereas SKF38393 and sulpiride were not associated with this effect. The present study found that a 6-OHDA lesion in CA3 up-regulated the expression of GluR1 in BLA and down-regulated NR2B in CA1 and the basolateral amygdala (BLA). Our data suggest that dopamine depletion in hippocampal subdivision CA3 may not be necessary for the acquisition of conditioned fear, but the expression of conditioned fear is likely dependent on the integrity of mesohippocampal dopaminergic connections. It is probable that both D1 and D2 dopaminergic receptors modulate the expression of conditioned fear. Changes in the expression of NR2B and GluR1 indicate that CA3 may modulate the activities of other brain structures. PMID:25446753

  14. Sleep Promotes Generalization of Extinction of Conditioned Fear

    PubMed Central

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

    2009-01-01

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

  15. A temporal shift in the circuits mediating retrieval of fear memory.

    PubMed

    Do-Monte, Fabricio H; Quiñones-Laracuente, Kelvin; Quirk, Gregory J

    2015-03-26

    Fear memories allow animals to avoid danger, thereby increasing their chances of survival. Fear memories can be retrieved long after learning, but little is known about how retrieval circuits change with time. Here we show that the dorsal midline thalamus of rats is required for the retrieval of auditory conditioned fear at late (24 hours, 7 days, 28 days), but not early (0.5 hours, 6 hours) time points after learning. Consistent with this, the paraventricular nucleus of the thalamus (PVT), a subregion of the dorsal midline thalamus, showed increased c-Fos expression only at late time points, indicating that the PVT is gradually recruited for fear retrieval. Accordingly, the conditioned tone responses of PVT neurons increased with time after training. The prelimbic (PL) prefrontal cortex, which is necessary for fear retrieval, sends dense projections to the PVT. Retrieval at late time points activated PL neurons projecting to the PVT, and optogenetic silencing of these projections impaired retrieval at late, but not early, time points. In contrast, silencing of PL inputs to the basolateral amygdala impaired retrieval at early, but not late, time points, indicating a time-dependent shift in retrieval circuits. Retrieval at late time points also activated PVT neurons projecting to the central nucleus of the amygdala, and silencing these projections at late, but not early, time points induced a persistent attenuation of fear. Thus, the PVT may act as a crucial thalamic node recruited into cortico-amygdalar networks for retrieval and maintenance of long-term fear memories. PMID:25600268

  16. Facial expression influences recognition memory for faces: robust enhancement effect of fearful expression.

    PubMed

    Wang, Bo

    2013-04-01

    Memory for faces is important for social interactions. However, it is unclear whether negative or positive expression affects recollection and familiarity for faces and whether the effect can be modulated by retention interval. Two experiments examined the effect of emotional expression on recognition for faces at two delay conditions. In Experiment 1 participants viewed neutral, positive, and negative (including fearful, sad, angry etc.) faces and made gender discrimination for each face. In Experiment 2 they viewed and made gender discrimination for neutral, positive, and fearful faces. Following the incidental learning they were randomly assigned into the immediate and 24-hour (24-h) delay conditions. Findings from the two experiments are as follows: (1) In the immediate and 24-h delay conditions overall recognition and recollection for negative faces (fearful faces in Experiment 2) were better than for neutral faces and positive faces. (2) In the immediate and 24-h delay conditions recollection and familiarity for positive faces was equivalent to recollection for neutral faces. (3) The enhancement effect of fearful expression on recognition and recollection was not due to greater discriminability between the old and new faces in the fearful category. The results indicate that recognition and recollection for faces and the enhancement effect of fearful expression is robust within 24 hours. PMID:23016604

  17. Asymmetrical Stimulus Generalization following Differential Fear Conditioning

    PubMed Central

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

    2008-01-01

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

  18. Overexpression of SIRT6 in the hippocampal CA1 impairs the formation of long-term contextual fear memory

    PubMed Central

    Yin, Xi; Gao, Yuan; Shi, Hai-Shui; Song, Li; Wang, Jie-Chao; Shao, Juan; Geng, Xu-Hong; Xue, Gai; Li, Jian-Li; Hou, Yan-Ning

    2016-01-01

    Histone modifications have been implicated in learning and memory. Our previous transcriptome data showed that expression of sirtuins 6 (SIRT6), a member of Histone deacetylases (HDACs) family in the hippocampal cornu ammonis 1 (CA1) was decreased after contextual fear conditioning. However, the role of SIRT6 in the formation of memory is still elusive. In the present study, we found that contextual fear conditioning inhibited translational expression of SIRT6 in the CA1. Microinfusion of lentiviral vector-expressing SIRT6 into theCA1 region selectively enhanced the expression of SIRT6 and impaired the formation of long-term contextual fear memory without affecting short-term fear memory. The overexpression of SIRT6 in the CA1 had no effect on anxiety-like behaviors or locomotor activity. Also, we also found that SIRT6 overexpression significantly inhibited the expression of insulin-like factor 2 (IGF2) and amounts of proteins and/or phosphoproteins (e.g. Akt, pAkt, mTOR and p-mTOR) related to the IGF2 signal pathway in the CA1. These results demonstrate that the overexpression of SIRT6 in the CA1 impaired the formation of long-term fear memory, and SIRT6 in the CA1 may negatively modulate the formation of contextual fear memory via inhibiting the IGF signaling pathway. PMID:26732053

  19. Overexpression of SIRT6 in the hippocampal CA1 impairs the formation of long-term contextual fear memory.

    PubMed

    Yin, Xi; Gao, Yuan; Shi, Hai-Shui; Song, Li; Wang, Jie-Chao; Shao, Juan; Geng, Xu-Hong; Xue, Gai; Li, Jian-Li; Hou, Yan-Ning

    2016-01-01

    Histone modifications have been implicated in learning and memory. Our previous transcriptome data showed that expression of sirtuins 6 (SIRT6), a member of Histone deacetylases (HDACs) family in the hippocampal cornu ammonis 1 (CA1) was decreased after contextual fear conditioning. However, the role of SIRT6 in the formation of memory is still elusive. In the present study, we found that contextual fear conditioning inhibited translational expression of SIRT6 in the CA1. Microinfusion of lentiviral vector-expressing SIRT6 into theCA1 region selectively enhanced the expression of SIRT6 and impaired the formation of long-term contextual fear memory without affecting short-term fear memory. The overexpression of SIRT6 in the CA1 had no effect on anxiety-like behaviors or locomotor activity. Also, we also found that SIRT6 overexpression significantly inhibited the expression of insulin-like factor 2 (IGF2) and amounts of proteins and/or phosphoproteins (e.g. Akt, pAkt, mTOR and p-mTOR) related to the IGF2 signal pathway in the CA1. These results demonstrate that the overexpression of SIRT6 in the CA1 impaired the formation of long-term fear memory, and SIRT6 in the CA1 may negatively modulate the formation of contextual fear memory via inhibiting the IGF signaling pathway. PMID:26732053

  20. The NO-cGMP-PKG Signaling Pathway Regulates Synaptic Plasticity and Fear Memory Consolidation in the Lateral Amygdala via Activation of ERK/MAP Kinase

    ERIC Educational Resources Information Center

    Ota, Kristie T.; Pierre, Vicki J.; Ploski, Jonathan E.; Queen, Kaila; Schafe, Glenn E.

    2008-01-01

    Recent studies have shown that nitric oxide (NO) signaling plays a crucial role in memory consolidation of Pavlovian fear conditioning and in synaptic plasticity in the lateral amygdala (LA). In the present experiments, we examined the role of the cGMP-dependent protein kinase (PKG), a downstream effector of NO, in fear memory consolidation and…

  1. Post-training activation of Rac1 in the basolateral amygdala is required for the formation of both short-term and long-term auditory fear memory

    PubMed Central

    Gao, Qinqin; Yao, Wenqing; Wang, Junjun; Yang, Tong; Liu, Cao; Tao, Yezheng; Chen, Yuejun; Liu, Xing; Ma, Lan

    2015-01-01

    Rac1, a member of the Rho family of small GTPases, is crucial for morphological changes of the mature neuronal synapse including spine formation and activity-dependent spine enlargement, while its role in the formation of associated memories, such as conditioned fear memory, is not clear. Here, we report that selective deletion of Rac1 in excitatory neurons, but not in parvalbumin inhibitory neurons, impaired short- and long-term memories (STM and LTM) of fear conditioning. Conditional knockout of Rac1 before associative fear training in the basolateral amygdala (BLA), a key area for fear memory acquisition and storage, impaired fear memory. The expression of dominant-negative mutant of Rac1, or infusion of Rac1 inhibitor NSC23766 into BLA blocked both STM and LTM of fear conditioning. Furthermore, selective inhibition of Rac1 activation in BLA immediately following fear conditioning impaired STM and LTM, demonstrating that fear conditioning-induced Rac1 activation in BLA plays a critical role in the formation of both STM and LTM of conditioned fear. PMID:26582975

  2. The effect of adverse rearing environments on persistent memories in young rats: removing the brakes on infant fear memories.

    PubMed

    Callaghan, B L; Richardson, R

    2012-01-01

    Mental health problems are often assumed to have their roots in early-life experiences. However, memories acquired in infancy are rapidly forgotten in nearly all species (including humans). As yet, a testable mechanism on how early-life experiences have a lasting impact on mental health is lacking. In these experiments, we tested the idea that infant adversity leads to an early transition into adult-like fear retention, allowing infant memories to have a longer-lasting influence. Rats were exposed to maternal separation (3 h per day) across postnatal days (P) 2-14, or their mother was given corticosterone in her drinking water across the same period. Infant rats were then trained to fear a conditioned stimulus (CS) paired with an aversive unconditioned stimulus (US) on P17. Retention of the fear association was then tested 1-55 days later. When tested one day after the CS-US association was formed, both standard-reared (SR) and maternally-separated (MS) rats exhibited strong memory. However, when tested 10 days later, SR rats exhibited robust forgetting, whereas MS rats exhibited near-perfect retention. These effects were mimicked by exposing the mother to the stress hormone corticosterone in the drinking water. Finally, fear associations in P17 MS rats were retained for up to 30 days. Our findings point to differences in retention of fear as one factor that might underlie the propensity of stress-exposed individuals to exhibit early anxiety symptoms and suggest that manipulations of the corticosterone system may hold the key to ameliorating some of the effects of early stress on persistent retention of fear. PMID:22781171

  3. Thalamocortical interactions underlying visual fear conditioning in humans.

    PubMed

    Lithari, Chrysa; Moratti, Stephan; Weisz, Nathan

    2015-11-01

    Despite a strong focus on the role of the amygdala in fear conditioning, recent works point to a more distributed network supporting fear conditioning. We aimed to elucidate interactions between subcortical and cortical regions in fear conditioning in humans. To do this, we used two fearful faces as conditioned stimuli (CS) and an electrical stimulation at the left hand, paired with one of the CS, as unconditioned stimulus (US). The luminance of the CS was rhythmically modulated leading to "entrainment" of brain oscillations at a predefined modulation frequency. Steady-state responses (SSR) were recorded by MEG. In addition to occipital regions, spectral analysis of SSR revealed increased power during fear conditioning particularly for thalamus and cerebellum contralateral to the upcoming US. Using thalamus and amygdala as seed-regions, directed functional connectivity was calculated to capture the modulation of interactions that underlie fear conditioning. Importantly, this analysis showed that the thalamus drives the fusiform area during fear conditioning, while amygdala captures the more general effect of fearful faces perception. This study confirms ideas from the animal literature, and demonstrates for the first time the central role of the thalamus in fear conditioning in humans. PMID:26287369

  4. Harnessing Reconsolidation to Weaken Fear and Appetitive Memories: A Meta-Analysis of Post-Retrieval Extinction Effects

    PubMed Central

    Kredlow, M. Alexandra; Unger, Leslie D.; Otto, Michael W.

    2015-01-01

    A new understanding of the mechanisms of memory retrieval and reconsolidation holds the potential for improving exposure-based treatments. Basic research indicates that following fear extinction, safety and fear memories may compete, raising the possibility of return of fear. One possible solution is to modify original fear memories through reconsolidation interference, reducing the likelihood of return of fear. Post-retrieval extinction is a behavioral method of reconsolidation interference that has been explored in the context of conditioned fear and appetitive memory paradigms. This meta-analysis examines the magnitude of post-retrieval extinction effects and potential moderators of these effects. A PubMed and PsycINFO search was conducted through June 2014. Sixty-three comparisons examining post-retrieval extinction for preventing the return of fear or appetitive responses in animals or humans met inclusion criteria. Post-retrieval extinction demonstrated a significant, small-to-moderate effect (g = .40) for further reducing the return of fear in humans and a significant, large effect (g = 0.89) for preventing the return of appetitive responses in animals relative to standard extinction. For fear outcomes in animals, effects were small (g = 0.21) and non-significant, but moderated by the number of animals housed together and the duration of time between post-retrieval extinction/extinction and test. Across paradigms, these findings support the efficacy of this pre-clinical strategy for preventing the return of conditioned fear and appetitive responses. Overall, findings to date support the continued translation of post-retrieval extinction research to human and clinical applications, with particular application to the treatment of anxiety, traumatic stress, and substance use disorders. PMID:26689086

  5. The Role of Muscarinic and Nicotinic Cholinergic Neurotransmission in Aversive Conditioning: Comparing Pavlovian Fear Conditioning and Inhibitory Avoidance

    ERIC Educational Resources Information Center

    Tinsley, Matthew R.; Quinn, Jennifer J.; Fanselow, Michael S.

    2004-01-01

    Aversive conditioning is an ideal model for studying cholinergic effects on the processes of learning and memory for several reasons. First, deficits produced by selective lesions of the anatomical structures shown to be critical for Pavlovian fear conditioning and inhibitory avoidance (such as the amygdala and hippocampus) resemble those deficits…

  6. The cannabinoid system in the retrosplenial cortex modulates fear memory consolidation, reconsolidation, and extinction.

    PubMed

    Sachser, Ricardo Marcelo; Crestani, Ana Paula; Quillfeldt, Jorge Alberto; Mello E Souza, Tadeu; de Oliveira Alvares, Lucas

    2015-12-01

    Despite the fact that the cannabinoid receptor type 1 (CB1R) plays a pivotal role in emotional memory processing in different regions of the brain, its function in the retrosplenial cortex (RSC) remains unknown. Here, using contextual fear conditioning in rats, we showed that a post-training intra-RSC infusion of the CB1R antagonist AM251 impaired, and the agonist CP55940 improved, long-term memory consolidation. Additionally, a post-reactivation infusion of AM251 enhanced memory reconsolidation, while CP55940 had the opposite effect. Finally, AM251 blocked extinction, whereas CP55940 facilitated it and maintained memory extinguished over time. Altogether, our data strongly suggest that the cannabinoid system of the RSC modulates emotional memory. PMID:26572648

  7. Limited Efficacy of Propranolol on the Reconsolidation of Fear Memories

    ERIC Educational Resources Information Center

    Muravieva, Elizaveta V.; Alberini, Cristina M.

    2010-01-01

    Previous studies suggested that the beta-adrenergic receptor antagonist propranolol might be a novel, potential treatment for post-traumatic stress disorder (PTSD). This hypothesis stemmed mainly from rodent studies showing that propranolol interferes with the reconsolidation of Pavlovian fear conditioning (FC). However, subsequent investigations…

  8. 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. PMID:23992769

  9. 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

  10. 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

  11. Role of mGluR4 in acquisition of fear learning and memory.

    PubMed

    Davis, Matthew J; Iancu, Ovidiu D; Acher, Francine C; Stewart, Blair M; Eiwaz, Massarra A; Duvoisin, Robert M; Raber, Jacob

    2013-03-01

    Group III metabotropic glutamate receptors (mGluRs), which are generally located presynaptically, modulate synaptic transmission by regulating neurotransmitter release. Previously we showed enhanced amygdala-dependent cued fear conditioning in mGluR4(-/-) mice 24 h following training involving two tone-shock pairings. In this study, we assessed the effects of modulating mGluR4 signaling on acquisition and extinction of conditioned fear. mGluR4(-/-) and wild-type female and male mice received 10 tone-shock pairings during training. Compared to wild-type mice, mGluR4(-/-) mice showed enhanced acquisition and extinction of cued fear. Next, we assessed whether acute pharmacological stimulation of mGluR4 with the specific orthosteric mGluR4 agonist LSP1-2111 also affects acquisition and extinction of cued fear. Consistent with the enhanced acquisition of cued fear in mGluR4(-/-), LSP1-2111, at 2.5 and 5 mg/kg, inhibited acquisition of cued fear conditioning in wild-type male mice. The drug's effect on extinction was less clear and only a subtle effect was seen at 5 mg/kg. Finally, analysis of microarray data of amygdala tissues from mGluR4(-/-) versus wild-type and from wild-type mice treated with a mGluR4 agonist versus saline revealed a significant overlap in pattern of gene expression. Together, these data support a role for mGluR4 signaling in acquisition of fear learning and memory. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'. PMID:22884897

  12. Extending animal models of fear conditioning to humans.

    PubMed

    Delgado, M R; Olsson, A; Phelps, E A

    2006-07-01

    A goal of fear and anxiety research is to understand how to treat the potentially devastating effects of anxiety disorders in humans. Much of this research utilizes classical fear conditioning, a simple paradigm that has been extensively investigated in animals, helping outline a brain circuitry thought to be responsible for the acquisition, expression and extinction of fear. The findings from non-human animal research have more recently been substantiated and extended in humans, using neuropsychological and neuroimaging methodologies. Research across species concur that the neural correlates of fear conditioning include involvement of the amygdala during all stages of fear learning, and prefrontal areas during the extinction phase. This manuscript reviews how animal models of fear are translated to human behavior, and how some fears are more easily acquired in humans (i.e., social-cultural). Finally, using the knowledge provided by a rich animal literature, we attempt to extend these findings to human models targeted to helping facilitate extinction or abolishment of fears, a trademark of anxiety disorders, by discussing efficacy in modulating the brain circuitry involved in fear conditioning via pharmacological treatments or emotion regulation cognitive strategies. PMID:16472906

  13. DHPG Activation of Group 1 mGluRs in BLA Enhances Fear Conditioning

    ERIC Educational Resources Information Center

    Rudy, Jerry W.; Matus-Amat, Patricia

    2009-01-01

    Group 1 metabotropic glutamate receptors are known to play an important role in both synaptic plasticity and memory. We show that activating these receptors prior to fear conditioning by infusing the group 1 mGluR agonist, (R.S.)-3,5-dihydroxyphenylglycine (DHPG), into the basolateral region of the amygdala (BLA) of adult Sprague-Dawley rats…

  14. 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…

  15. Impaired conditioned fear response and startle reactivity in epinephrine-deficient mice.

    PubMed

    Toth, Mate; Ziegler, Michael; Sun, Ping; Gresack, Jodi; Risbrough, Victoria

    2013-02-01

    Norepinephrine and epinephrine signaling is thought to facilitate cognitive processes related to emotional events and heightened arousal; however, the specific role of epinephrine in these processes is less known. To investigate the selective impact of epinephrine on arousal and fear-related memory retrieval, mice unable to synthesize epinephrine (phenylethanolamine N-methyltransferase knockout, PNMT-KO) were tested for contextual and cued-fear conditioning. To assess the role of epinephrine in other cognitive and arousal-based behaviors these mice were also tested for acoustic startle, prepulse inhibition, novel object recognition, and open-field activity. Our results show that compared with wild-type mice, PNMT-KO mice showed reduced contextual fear but normal cued fear. Mice exhibited normal memory performance in the short-term version of the novel object recognition task, suggesting that PNMT mice exhibit more selective memory effects on highly emotional and/or long-term memories. Similarly, open-field activity was unaffected by epinephrine deficiency, suggesting that differences in freezing are not related to changes in overall anxiety or exploratory drive. Startle reactivity to acoustic pulses was reduced in PNMT-KO mice, whereas prepulse inhibition was increased. These findings provide further evidence for a selective role of epinephrine in contextual-fear learning and support its potential role in acoustic startle. PMID:23268986

  16. Human fear conditioning conducted in full immersion 3-dimensional virtual reality.

    PubMed

    Huff, Nicole C; Zeilinski, David J; Fecteau, Matthew E; Brady, Rachael; LaBar, Kevin S

    2010-01-01

    conditioning and extinction parameters to yield empirical data that can suggest better treatment options and/or analyze mechanistic hypotheses. In order to test the hypothesis that fear conditioning may be richly encoded and context specific when conducted in a fully immersive environment, we developed distinct virtual reality 3-D contexts in which participants experienced fear conditioning to virtual snakes or spiders. Auditory cues co-occurred with the CS in order to further evoke orienting responses and a feeling of "presence" in subjects. Skin conductance response served as the dependent measure of fear acquisition, memory retention and extinction. PMID:20736913

  17. 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. Dev Psychobiol 58: 471-481, 2016. PMID:26798984

  18. Representational similarity analysis offers a preview of the noradrenergic modulation of long-term fear memory at the time of encoding.

    PubMed

    Visser, Renée M; Kunze, Anna E; Westhoff, Bianca; Scholte, H Steven; Kindt, Merel

    2015-05-01

    Neuroimaging research on emotional memory has greatly advanced our understanding of the pathogenesis of anxiety disorders. While the behavioral expression of fear at the time of encoding does not predict whether an aversive experience will evolve into long-term fear memory, the application of multi-voxel pattern analysis (MVPA) for the analysis of BOLD-MRI data has recently provided a unique marker for memory formation. Here, we aimed to further investigate the utility of this marker by modulating the strength of fear memory with an α2-adrenoceptor antagonist (yohimbine HCl). Fifty-two healthy participants were randomly assigned to two conditions - either receiving 20mg yohimbine or a placebo pill (double-blind) - prior to differential fear conditioning and MRI-scanning. We examined the strength of fear associations during acquisition and retention of fear (48 h later) by assessing the similarity of BOLD-MRI patterns and pupil dilation responses. Additionally, participants returned for a follow-up test outside the scanner (2-4 weeks), during which we assessed fear-potentiated startle responses. Replicating our previous findings, neural pattern similarity reflected the development of fear associations over time, and unlike average activation or pupil dilation, predicted the later expression of fear memory (pupil dilation 48 h later). While no effect of yohimbine was observed on markers of autonomic arousal, including salivary α-amylase (sAA), we obtained indirect evidence for the noradrenergic enhancement of fear memory consolidation: sAA levels showed a strong increase prior to fMRI scanning, irrespective of whether participants had received yohimbine, and this increase correlated with the subsequent expression of fear (48 h later). Remarkably, this noradrenergic enhancement of fear was associated with changes in neural response patterns at the time of learning. These findings provide further evidence that representational similarity analysis is a sensitive tool

  19. Differential effects of dorsal hippocampal inactivation on expression of recent and remote drug and fear memory.

    PubMed

    Raybuck, J D; Lattal, K M

    2014-05-21

    Drugs of abuse generate strong drug-context associations, which can evoke powerful drug cravings that are linked to reinstatement in animal models and to relapse in humans. Work in learning and memory has demonstrated that contextual memories become more distributed over time, shifting from dependence on the hippocampus for retrieval to dependence on cortical structures. Implications for such changes in the structure of memory retrieval to addiction are unknown. Thus, to determine if the passage of time alters the substrates of conditioned place preference (CPP) memory retrieval, we investigated the effects of inactivation of the dorsal hippocampus (DH) with the GABA-A receptor agonist muscimol on expression of recent or remote CPP. We compared these effects with the same manipulation on expression of contextual fear conditioning. DH inactivation produced similar deficits in expression of both recent and remote CPP, but blocked expression of recent but not remote contextual fear memory. We describe the implications of these findings for mechanisms underlying long-term storage of contextual information. PMID:24686177

  20. Sex differences in fear conditioning in posttraumatic stress disorder

    PubMed Central

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

    2013-01-01

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

  1. A role for α1-adrenergic receptors in extinction of conditioned fear and cocaine conditioned preference

    PubMed Central

    Bernardi, Rick E.; Lattal, K. Matthew

    2010-01-01

    Previous work has demonstrated an important role for adrenergic receptors in memory processes in fear and drug conditioning paradigms. Recent studies have also demonstrated alterations in extinction in these paradigms using drug treatments targeting β- and α2-adrenergic receptors, but little is known about the role of α1-adrenergic receptors in extinction. The current study examined whether antagonism of α1-adrenergic receptors would impair the consolidation of extinction in fear and cocaine conditioned place preference (CPP) paradigms. After contextual fear conditioning, injections of prazosin (1.0 or 3.0 mg/kg) following nonreinforced context exposures slowed the loss of conditioned freezing over the course of five extinction sessions (Experiment 1). After cocaine place conditioning, prazosin had no effect on the rate of extinction over eight nonreinforced test sessions. Following post-extinction reconditioning, however, prazosin-treated mice showed a robust place preference, but vehicle-treated mice did not, suggesting that prazosin reduced the persistent effects of extinction (Experiment 2). These results confirm the involvement of the α1-adrenergic receptor in extinction processes in both appetitive and aversive preparations. PMID:20364880

  2. Impaired extinction of learned contextual fear memory in early growth response 1 knockout mice.

    PubMed

    Han, Seungrie; Hong, Soontaek; Mo, Jiwon; Lee, Dongmin; Choi, Eunju; Choi, June-seek; Sun, Woong; Lee, Hyun Woo; Kim, Hyun

    2014-01-01

    Inductive expression of early growth response 1 (Egr-1) in neurons is associated with many forms of neuronal activity. However, only a few Egr-1 target genes are known in the brain. The results of this study demonstrate that Egr-1 knockout (KO) mice display impaired contextual extinction learning and normal fear acquisition relative to wild-type (WT) control animals. Genome-wide microarray experiments revealed 368 differentially expressed genes in the hippocampus of Egr-1 WT exposed to different phases of a fear conditioning paradigm compared to gene expression profiles in the hippocampus of KO mice. Some of genes, such as serotonin receptor 2C (Htr2c), neuropeptide B (Npb), neuronal PAS domain protein 4 (Npas4), NPY receptor Y1 (Npy1r), fatty acid binding protein 7 (Fabp7), and neuropeptide Y (Npy) are known to regulate processing of fearful memories, and promoter analyses demonstrated that several of these genes contained Egr-1 binding sites. This study provides a useful list of potential Egr-1 target genes which may be regulated during fear memory processing. PMID:24552706

  3. Cerebellar vermis H₂ receptors mediate fear memory consolidation in mice.

    PubMed

    Gianlorenço, A C L; Riboldi, A M; Silva-Marques, B; Mattioli, R

    2015-02-01

    Histaminergic fibers are present in the molecular and granular layers of the cerebellum and have a high density in the vermis and flocullus. Evidence supports that the cerebellar histaminergic system is involved in memory consolidation. Our recent study showed that histamine injections facilitate the retention of an inhibitory avoidance task, which was abolished by pretreatment with an H2 receptor antagonist. In the present study, we investigated the effects of intracerebellar post training injections of H1 and H2 receptor antagonists as well as the selective H2 receptor agonist on fear memory consolidation. The cerebellar vermi of male mice were implanted with guide cannulae, and after three days of recovery, the inhibitory avoidance test was performed. Immediately after a training session, animals received a microinjection of the following histaminergic drugs: experiment 1, saline or chlorpheniramine (0.016, 0.052 or 0.16 nmol); experiment 2, saline or ranitidine (0.57, 2.85 or 5.07 nmol); and experiment 3, saline or dimaprit (1, 2 or 4 nmol). Twenty-four hours later, a retention test was performed. The data were analyzed using one-way analysis of variance (ANOVA) and Duncan's tests. Animals microinjected with chlorpheniramine did not show any behavioral effects at the doses that we used. Intra-cerebellar injection of the H2 receptor antagonist ranitidine inhibited, while the selective H2 receptor agonist dimaprit facilitated, memory consolidation, suggesting that H2 receptors mediate memory consolidation in the inhibitory avoidance task in mice. PMID:25524412

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

    PubMed

    Stein, Dan J; Matsunaga, Hisato

    2006-04-01

    Specific phobia is the most prevalent of the anxiety disorders. Although there have been relatively few studies of its psychobiology and pharmacotherapy, there is a rich laboratory of literature on fear conditioning and extinction and a clear evolutionary perspective. Advances in the cognitive-affective neuroscience of fear processing may ultimately lead to new approaches to the clinical management of phobias. PMID:16641829

  5. TRPC3 channels critically regulate hippocampal excitability and contextual fear memory.

    PubMed

    Neuner, Sarah M; Wilmott, Lynda A; Hope, Kevin A; Hoffmann, Brian; Chong, Jayhong A; Abramowitz, Joel; Birnbaumer, Lutz; O'Connell, Kristen M; Tryba, Andrew K; Greene, Andrew S; Savio Chan, C; Kaczorowski, Catherine C

    2015-03-15

    Memory formation requires de novo protein synthesis, and memory disorders may result from misregulated synthesis of critical proteins that remain largely unidentified. Plasma membrane ion channels and receptors are likely candidates given their role in regulating neuron excitability, a candidate memory mechanism. Here we conduct targeted molecular monitoring and quantitation of hippocampal plasma membrane proteins from mice with intact or impaired contextual fear memory to identify putative candidates. Here we report contextual fear memory deficits correspond to increased Trpc3 gene and protein expression, and demonstrate TRPC3 regulates hippocampal neuron excitability associated with memory function. These data provide a mechanistic explanation for enhanced contextual fear memory reported herein following knockdown of TRPC3 in hippocampus. Collectively, TRPC3 modulates memory and may be a feasible target to enhance memory and treat memory disorders. PMID:25513972

  6. Chronic stress enhanced fear memories are associated with increased amygdala zif268 mRNA expression and are resistant to reconsolidation

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2016-09-01

    A brief 10-min time delay between an initial and subsequent exposure to extinction trials has been found to impair memory reconsolidation in fear-conditioned rodents and humans, providing a potential means to reduce fearfulness in anxiety disorders and posttraumatic stress disorder (PTSD). The present study used videos of biologically prepared, conditioned stimuli (tarantulas) to test the efficacy of delayed extinction in blocking reconsolidation of conditioned fear in healthy young adults. Strong differential conditioning, measured by skin conductance, was observed among a screened subset of participants during acquisition. However, the delayed-extinction intervention failed to reduce reactivity to the conditioned stimulus paired with the extinction delay. These results are partially consistent with other recent, mixed findings and point to a need for testing other candidate interventions designed to interfere with the reconsolidation process. PMID:27314560

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

    PubMed

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

    2015-03-01

    Pharmacologic blockade of memory reconsolidation has been demonstrated in fear-conditioned rodents and humans and may provide a means to reduce fearfulness in anxiety disorders and posttraumatic stress disorder. Studying the efficacy of potential interventions in clinical populations is challenging, creating a need for paradigms within which candidate reconsolidation-blocking interventions can be readily tested. We used videos of biologically prepared conditioned stimuli (tarantulas) to test the efficacy of propranolol in blocking reconsolidation of conditioned fear in healthy young adults. Strong differential conditioning, measured by skin conductance, was observed among a screened subset of participants during acquisition. However, subsequent propranolol failed to reduce reactivity to the reactivated conditioned stimulus. These results are consistent with other recent findings and point to a need for testing other candidate drugs. PMID:25224026

  9. Protocol for Studying Extinction of Conditioned Fear in Naturally Cycling Female Rats

    PubMed Central

    Maeng, Lisa Y.; Cover, Kara K.; Landau, Aaron J.; Milad, Mohammed R.; Lebron-Milad, Kelimer

    2015-01-01

    Extinction of conditioned fear has been extensively studied in male rodents. Recently, there have been an increasing number of studies indicating that neural mechanisms for certain behavioral tasks and response behaviors are different in females and males. Using females in research studies can represent a challenge because of the variation of gonadal hormones during their estrous cycle. This protocol describes well-established procedures that are useful in investigating the role of estrogen in fear extinction memory consolidation in female rats. Phase of the estrous cycle and exogenous estrogen administration prior to extinction training can influence extinction recall 24 hr later. The vaginal swabbing technique for estrous phase identification described here aids the examination and manipulation of naturally cycling gonadal hormones. The use of this basic rodent model may further delineate the mechanisms by which estrogen can modulate fear extinction memory in females. PMID:25741747

  10. Protocol for studying extinction of conditioned fear in naturally cycling female rats.

    PubMed

    Maeng, Lisa Y; Cover, Kara K; Landau, Aaron J; Milad, Mohammed R; Lebron-Milad, Kelimer

    2015-01-01

    Extinction of conditioned fear has been extensively studied in male rodents. Recently, there have been an increasing number of studies indicating that neural mechanisms for certain behavioral tasks and response behaviors are different in females and males. Using females in research studies can represent a challenge because of the variation of gonadal hormones during their estrous cycle. This protocol describes well-established procedures that are useful in investigating the role of estrogen in fear extinction memory consolidation in female rats. Phase of the estrous cycle and exogenous estrogen administration prior to extinction training can influence extinction recall 24 hr later. The vaginal swabbing technique for estrous phase identification described here aids the examination and manipulation of naturally cycling gonadal hormones. The use of this basic rodent model may further delineate the mechanisms by which estrogen can modulate fear extinction memory in females. PMID:25741747

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

    PubMed Central

    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. PMID:26696855

  12. Functional Integrity of the Retrosplenial Cortex Is Essential for Rapid Consolidation and Recall of Fear Memory

    ERIC Educational Resources Information Center

    Katche, Cynthia; Dorman, Guido; Slipczuk, Leandro; Cammarota, Martin; Medina, Jorge H.

    2013-01-01

    Memory storage is a temporally graded process involving different phases and different structures in the mammalian brain. Cortical plasticity is essential to store stable memories, but little is known regarding its involvement in memory processing. Here we show that fear memory consolidation requires early post-training macromolecular synthesis in…

  13. Deficits in trace fear memory in a mouse model of the schizophrenia risk gene TCF4.

    PubMed

    Brzózka, Magdalena M; Rossner, Moritz J

    2013-01-15

    The basic helix-loop-helix (bHLH) transcription factor TCF4 was confirmed in the combined analysis of several large genome-wide association studies (GWAS) as one of the rare highly replicated significant schizophrenia (SZ) susceptibility genes in large case-control cohorts. Focused genetic association studies showed that TCF4 influences verbal learning and memory, and modulates sensorimotor gating. Mice overexpressing Tcf4 in the forebrain (Tcf4tg) display cognitive deficits in hippocampus-dependent learning tasks and impairment of prepulse inhibition, a well-established endophenotype of SZ. The spectrum of cognitive deficits in SZ subjects, however, is broad and covers attention, working memory, and anticipation. Collectively, these higher order cognitive processes and the recall of remote memories are thought to depend mainly on prefrontal cortical networks. To further investigate cognitive disturbances in Tcf4tg mice, we employed the trace fear conditioning paradigm that requires attention and critically depends on the anterior cingulate cortex (ACC). We show that Tcf4tg mice display deficits in recent and remote trace fear memory and are impaired at anticipating aversive stimuli. We also assessed mRNA expression of the neuronal activity-regulated gene Fos in the ACC and hippocampus. Upon trace conditioning, Fos expression is reduced in Tcf4tg mice as compared to controls, which parallels cognitive impairments in this learning paradigm. Collectively, these data indicate that the reduced cognitive performance in Tcf4tg mice includes deficits at the level of attention and behavioral anticipation. PMID:23069005

  14. Knockdown of corticotropin-releasing factor 1 receptors in the ventral tegmental area enhances conditioned fear.

    PubMed

    Chen, Nicola A; Ganella, Despina E; Bathgate, Ross A D; Chen, Alon; Lawrence, Andrew J; Kim, Jee Hyun

    2016-09-01

    The neuropeptide corticotropin-releasing factor (CRF) coordinates the physiological and behavioural responses to stress. CRF receptors are highly expressed in the ventral tegmental area (VTA), an important region for motivated behaviour. Therefore, we examined the role of CRF receptor type 1 (CRFR1) in the VTA in conditioned fear, using a viral-mediated RNA interference approach. Following stereotaxic injection of a lentivirus that contained either shCRF-R1 or a control sequence, mice received tone-footshock pairings. Intra-VTA shCRF-R1 did not affect tone-elicited freezing during conditioning. Once conditioned fear was acquired, however, shCRF-R1 mice consistently showed stronger freezing to the tone even after extinction and reinstatement. These results implicate a novel role of VTA CRF-R1 in conditioned fear, and suggest how stress may modulate aversive learning and memory. PMID:27397862

  15. Trace and Contextual Fear Conditioning Require Neural Activity and NMDA Receptor-Dependent Transmission in the Medial Prefrontal Cortex

    ERIC Educational Resources Information Center

    Gilmartin, Marieke R.; Helmstetter, Fred J.

    2010-01-01

    The contribution of the medial prefrontal cortex (mPFC) to the formation of memory is a subject of considerable recent interest. Notably, the mechanisms supporting memory acquisition in this structure are poorly understood. The mPFC has been implicated in the acquisition of trace fear conditioning, a task that requires the association of a…

  16. Voluntary exercise during extinction of auditory fear conditioning reduces the relapse of fear associated with potentiated activity of striatal direct pathway neurons.

    PubMed

    Mika, Agnieszka; Bouchet, Courtney A; Bunker, Preston; Hellwinkel, Justin E; Spence, Katie G; Day, Heidi E W; Campeau, Serge; Fleshner, Monika; Greenwood, Benjamin N

    2015-11-01

    Relapse of previously extinguished fear presents a significant, pervasive obstacle to the successful long-term treatment of anxiety and trauma-related disorders. Thus, identification of a novel means to enhance fear extinction to stand the passage of time and generalize across contexts is of the utmost importance. Acute bouts of exercise can be used as inexpensive, noninvasive treatment strategies to reduce anxiety, and have been shown to enhance memory for extinction when performed in close temporal proximity to the extinction session. However, it is unclear whether acute exercise can be used to prevent relapse of fear, and the neural mechanisms underlying this potential effect are unknown. The current study therefore examined whether acute exercise during extinction of auditory fear can protect against the later relapse of fear. Male F344 rats lacking an extended history of wheel running were conditioned to fear a tone CS and subsequently extinguished within either a freely mobile running wheel, a locked wheel, or a control context lacking a wheel. Rats exposed to fear extinction within a freely mobile wheel ran during fear extinction, and demonstrated reduced fear as well as attenuated corticosterone levels during re-exposure to the extinguished CS during the relapse test in a novel context 1week later. Examination of cfos mRNA patterns elicited by re-exposure to the extinguished CS during the relapse test revealed that acute exercise during extinction decreased activation of brain circuits classically involved in driving fear expression and interestingly, increased activity within neurons of the direct striatal pathway involved in reward signaling. These data suggest that exercise during extinction reduces relapse through a mechanism involving the direct pathway of the striatum. It is suggested that a positive affective state could become associated with the CS during exercise during extinction, thus resulting in a relapse-resistant extinction memory. PMID

  17. Psychopaths Show Enhanced Amygdala Activation during Fear Conditioning

    PubMed Central

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

    2016-01-01

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

  18. Conditioning- and Time-Dependent Increases in Context Fear and Generalization

    ERIC Educational Resources Information Center

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

    2016-01-01

    A prominent feature of fear memories and anxiety disorders is that they endure across extended periods of time. Here, we examine how the severity of the initial fear experience influences incubation, generalization, and sensitization of contextual fear memories across time. Adult rats were presented with either five, two, one, or zero shocks (1.2…

  19. Resting-state connectivity of the amygdala is altered following Pavlovian fear conditioning

    PubMed Central

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

    2012-01-01

    Neural plasticity in the amygdala is necessary for the acquisition and storage of memory in Pavlovian fear conditioning, but most neuroimaging studies have focused only on stimulus-evoked responses during the conditioning session. This study examined changes in the resting-state functional connectivity (RSFC) of the amygdala before and after Pavlovian fear conditioning, an emotional learning task. Behavioral results from the conditioning session revealed that participants learned normally and fMRI data recorded during learning identified a number of stimulus-evoked changes that were consistent with previous work. A direct comparison between the pre- and post-conditioning amygdala connectivity revealed a region of dorsal prefrontal cortex (PFC) in the superior frontal gyrus that showed a significant increase in connectivity following the conditioning session. A behavioral measure of explicit memory performance was positively correlated with the change in amygdala connectivity within a neighboring region in the superior frontal gyrus. Additionally, an implicit autonomic measure of conditioning was positively correlated with the change in connectivity between the amygdala and the anterior cingulate cortex (ACC). The resting-state data show that amygdala connectivity is altered following Pavlovian fear conditioning and that these changes are also related to behavioral outcomes. These alterations may reflect the operation of a consolidation process that strengthens neural connections to support memory after the learning event. PMID:22936906

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

    PubMed

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

    2016-05-01

    The stress experienced by an animal is ameliorated when the animal is exposed to distressing stimuli along with a conspecific animal(s). This is known as social buffering. Previously, we found that the presence of an unfamiliar male rat induced social buffering and ameliorated conditioned fear responses of a male rat subjected to an auditory conditioned stimulus (CS). However, because our knowledge of social buffering is highly biased towards findings in male subjects, analyses using female subjects are crucial for comprehensively understanding the social buffering phenomenon. In the present studies, we assessed social buffering of conditioned fear responses in female rats. We found that the estrus cycle did not affect the intensity of the rats' fear responses to the CS or their degree of vigilance due to the presence of a conspecific animal. Based on these findings, we then assessed whether social buffering ameliorated conditioned fear responses in female rats without taking into account their estrus cycles. When fear conditioned female rats were exposed to the CS without the presence of a conspecific, they exhibited behavioral responses, including freezing, and elevated corticosterone levels. By contrast, the presence of an unfamiliar female rat suppressed these responses. Based on these findings, we conclude that social buffering can ameliorate conditioned fear responses in female rats. PMID:27060333

  1. Stress-induced enhancement of fear conditioning and sensitization facilitates extinction-resistant and habituation-resistant fear behaviors in a novel animal model of posttraumatic stress disorder.

    PubMed

    Corley, Michael J; Caruso, Michael J; Takahashi, Lorey K

    2012-01-18

    Posttraumatic stress disorder (PTSD) is characterized by stress-induced symptoms including exaggerated fear memories, hypervigilance and hyperarousal. However, we are unaware of an animal model that investigates these hallmarks of PTSD especially in relation to fear extinction and habituation. Therefore, to develop a valid animal model of PTSD, we exposed rats to different intensities of footshock stress to determine their effects on either auditory predator odor fear extinction or habituation of fear sensitization. In Experiment 1, rats were exposed to acute footshock stress (no shock control, 0.4 mA, or 0.8 mA) immediately prior to auditory fear conditioning training involving the pairing of auditory clicks with a cloth containing cat odor. When presented to the conditioned auditory clicks in the next 5 days of extinction testing conducted in a runway apparatus with a hide box, rats in the two shock groups engaged in higher levels of freezing and head out vigilance-like behavior from the hide box than the no shock control group. This increase in fear behavior during extinction testing was likely due to auditory activation of the conditioned fear state because Experiment 2 demonstrated that conditioned fear behavior was not broadly increased in the absence of the conditioned auditory stimulus. Experiment 3 was then conducted to determine whether acute exposure to stress induces a habituation resistant sensitized fear state. We found that rats exposed to 0.8 mA footshock stress and subsequently tested for 5 days in the runway hide box apparatus with presentations of nonassociative auditory clicks exhibited high initial levels of freezing, followed by head out behavior and culminating in the occurrence of locomotor hyperactivity. In addition, Experiment 4 indicated that without delivery of nonassociative auditory clicks, 0.8 mA footshock stressed rats did not exhibit robust increases in sensitized freezing and locomotor hyperactivity, albeit head out vigilance

  2. Cannabinoid modulation of chronic mild stress-induced selective enhancement of trace fear conditioning in adolescent rats.

    PubMed

    Reich, Christian G; Iskander, Anthony N; Weiss, Michael S

    2013-10-01

    History of stress is considered a major risk factor for the development of major depression and posttraumatic stress disorder (PTSD). Elucidating the neurobiological mechanisms of Pavlovian fear conditioning may provide insight into the etiology of PTSD. In the current study, adolescent male Sprague-Dawley rats were exposed to 3 weeks of a chronic-mild-unpredictable stress (CMS) protocol. Immediately following the CMS, the animals were subjected to hippocampal-dependent (trace and contextual) and hippocampal-independent (delay) fear conditioning. CMS exposure enhanced trace freezing behavior compared to non-stress controls. This effect was not observed in contextual or delay conditioned animals. Given that the endocannabinoid system is negatively affected by CMS procedures, separate groups of stressed rats were administered the CB1 receptor agonist, ACEA (0.1 mg/kg), prior to trace fear conditioning or a memory-recall test. Regardless of administration time, ACEA significantly reduced freezing behavior in stressed animals. Furthermore, when administered during the first memory recall test, ACEA enhanced long-term extinction in both stress and non-stress groups. The results demonstrate that chronic unpredictable stress selectively enhances hippocampal-dependent episodic fear memories. Pathologies of the episodic memory and fear response may increase the susceptibility of developing PTSD. Reduction in fear responses via exogenous activation of the CB1 receptor suggests that a deficiency in the endocannabinoid system contributes to this pathology. PMID:23926242

  3. Ensemble coding of context-dependent fear memory in the amygdala

    PubMed Central

    Orsini, Caitlin A.; Yan, Chen; Maren, Stephen

    2013-01-01

    After fear conditioning, presenting the conditioned stimulus (CS) alone yields a context-specific extinction memory; fear is suppressed in the extinction context, but renews in any other context. The context-dependence of extinction is mediated by a brain circuit consisting of the hippocampus, prefrontal cortex (PFC) and amygdala. In the present work, we sought to determine at what level of this circuit context-dependent representations of the CS emerge. To explore this question, we used cellular compartment analysis of temporal activity by fluorescent in situ hybridization (catFISH). This method exploits the intracellular expression profile of the immediate early gene (IEG), Arc, to visualize neuronal activation patterns to two different behavioral experiences. Rats were fear conditioned in one context and extinguished in another; 24 h later, they were sequentially exposed to the CS in the extinction context and another context. Control rats were also tested in each context, but were never extinguished. We assessed Arc mRNA expression within the basal amygdala (BA), lateral amygdala (LA), ventral hippocampus (VH), prelimbic cortex (PL) and infralimbic cortex (IL). We observed that the sequential retention tests induced context-dependent patterns of Arc expression in the BA, LA, and IL of extinguished rats; this was not observed in non-extinguished controls. In general, non-extinguished animals had proportionately greater numbers of non-selective (double-labeled) neurons than extinguished animals. Collectively, these findings suggest that extinction learning results in pattern separation, particularly within the BA, in which unique neuronal ensembles represent fear memories after extinction. PMID:24379767

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

    ERIC Educational Resources Information Center

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

    2016-01-01

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

  5. Incubation of conditioned fear in the conditioned suppression model in rats: role of food-restriction conditions, length of conditioned stimulus, and generality to conditioned freezing

    PubMed Central

    Pickens, Charles L.; Navarre, Brittany M.; Nair, Sunila G.

    2010-01-01

    We recently adapted the conditioned suppression of operant responding method to study fear incubation. We found that food-restricted rats show low fear 2 days after extended (10 d; 100 30-sec tone-shock pairings) fear training and high fear after 1–2 months. Here, we studied a potential mechanism of fear incubation: extended food-restriction stress. We also studied whether fear incubation is observed after fear training with a prolonged-duration (6-min) tone conditioned stimulus (CS), and whether conditioned freezing incubates after extended training in rats with or without a concurrent operant task. Conditioned fear was assessed 2 days and 1 month after training. In the conditioned suppression method, fear incubation was reliably observed in rats under moderate food-restriction conditions (18–20 g food/day) that allowed for weight gain, and after extended (10 d), but not limited (1 d), fear training with the 6-min CS. Incubation of conditioned freezing was observed after extended fear training in rats lever-pressing for food and, to a lesser degree, in rats not performing an operant task. Results indicate that prolonged hunger-related stress does not account for fear incubation in the conditioned suppression method, and that fear incubation occurs to a longer-duration (6-min) fear CS. Extended training also leads to robust fear incubation of conditioned freezing in rats performing an operant task and weaker fear incubation in rats not performing an operant task. PMID:20600654

  6. Unconditioned responses and functional fear networks in human classical conditioning

    PubMed Central

    Linnman, Clas; Rougemont-Bücking, Ansgar; Beucke, Jan Carl; Zeffiro, Thomas A; Milad, Mohammed R

    2011-01-01

    Human imaging studies examining fear conditioning have mainly focused on the neural responses to conditioned cues. In contrast, the neural basis of the unconditioned response and the mechanisms by which fear modulates inter-regional functional coupling have received limited attention. We examined the neural responses to an unconditioned stimulus using a partial-reinforcement fear conditioning paradigm and functional MRI. The analysis focused on: (1) the effects of an unconditioned stimulus (an electric shock) that was either expected and actually delivered, or expected but not delivered, and (2) on how related brain activity changed across conditioning trials, and (3) how shock expectation influenced inter-regional coupling within the fear network. We found that: (1) the delivery of the shock engaged the red nucleus, amygdale, dorsal striatum, insula, somatosensory and cingulate cortices, (2) when the shock was expected but not delivered, only the red nucleus, the anterior insular and dorsal anterior cingulate cortices showed activity increases that were sustained across trials, and (3) psycho-physiological interaction analysis demonstrated that fear led to increased red nucleus coupling to insula but decreased hippocampus coupling to the red nucleus, thalamus and cerebellum. The hippocampus and the anterior insula may serve as hubs facilitating the switch between engagement of a defensive immediate fear network and a resting network. PMID:21377494

  7. Unconditioned responses and functional fear networks in human classical conditioning.

    PubMed

    Linnman, Clas; Rougemont-Bücking, Ansgar; Beucke, Jan Carl; Zeffiro, Thomas A; Milad, Mohammed R

    2011-08-01

    Human imaging studies examining fear conditioning have mainly focused on the neural responses to conditioned cues. In contrast, the neural basis of the unconditioned response and the mechanisms by which fear modulates inter-regional functional coupling have received limited attention. We examined the neural responses to an unconditioned stimulus using a partial-reinforcement fear conditioning paradigm and functional MRI. The analysis focused on: (1) the effects of an unconditioned stimulus (an electric shock) that was either expected and actually delivered, or expected but not delivered, and (2) on how related brain activity changed across conditioning trials, and (3) how shock expectation influenced inter-regional coupling within the fear network. We found that: (1) the delivery of the shock engaged the red nucleus, amygdale, dorsal striatum, insula, somatosensory and cingulate cortices, (2) when the shock was expected but not delivered, only the red nucleus, the anterior insular and dorsal anterior cingulate cortices showed activity increases that were sustained across trials, and (3) psycho-physiological interaction analysis demonstrated that fear led to increased red nucleus coupling to insula but decreased hippocampus coupling to the red nucleus, thalamus and cerebellum. The hippocampus and the anterior insula may serve as hubs facilitating the switch between engagement of a defensive immediate fear network and a resting network. PMID:21377494

  8. Long-lasting regulation of hippocampal Bdnf gene transcription after contextual fear conditioning.

    PubMed

    Mizuno, K; Dempster, E; Mill, J; Giese, K P

    2012-08-01

    Long-term memory formation requires de novo protein synthesis and gene transcription. During contextual long-term memory formation brain-derived neurotrophic factor (BDNF) gene expression changes in conjunction with alterations of DNA methylation in the Bdnf gene. However, little is known about the molecular mechanisms underlying the maintenance and persistence of contextual long-term memory. Here, we examined the transcription of specific Bdnf exons in the hippocampus for long periods after contextual fear conditioning. We found changes in transcription lasting for at least 24 h after contextual fear conditioning, with some sex-specific effects. In addition, hypomethylation at a CpG site in CpG island 2 located at the end of Bdnf exon III sequence was detected at 0.5 h and maintained for up to 24 h after contextual fear conditioning. The identification of these long-lasting changes in transcription and DNA methylation at the Bdnf gene suggests that BDNF might have a role for storage of contextual long-term memory in the hippocampus. PMID:22574690

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

    PubMed

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

    2014-01-01

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

  10. 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. PMID:27109918

  11. Cholinergic neuronal lesions in the medial septum and vertical limb of the diagonal bands of Broca induce contextual fear memory generalization and impair acquisition of fear extinction.

    PubMed

    Knox, Dayan; Keller, Samantha M

    2016-06-01

    Previous research has shown that the ventral medial prefrontal cortex (vmPFC) and hippocampus (Hipp) are critical for extinction memory. Basal forebrain (BF) cholinergic input to the vmPFC and Hipp is critical for neural function in these substrates, which suggests BF cholinergic neurons may be critical for extinction memory. In order to test this hypothesis, we applied cholinergic lesions to different regions of the BF and observed the effects these lesions had on extinction memory. Complete BF cholinergic lesions induced contextual fear memory generalization, and this generalized fear was resistant to extinction. Animals with complete BF cholinergic lesions could not acquire cued fear extinction. Restricted cholinergic lesions in the medial septum and vertical diagonal bands of Broca (MS/vDBB) mimicked the effects that BF cholinergic lesions had on contextual fear memory generalization and acquisition of fear extinction. Cholinergic lesions in the horizontal diagonal band of Broca and nucleus basalis (hDBB/NBM) induced a small deficit in extinction of generalized contextual fear memory with no accompanying deficits in cued fear extinction. The results of this study reveal that MS/vDBB cholinergic neurons are critical for inhibition and extinction of generalized contextual fear memory, and via this process, may be critical for acquisition of cued fear extinction. Further studies delineating neural circuits and mechanisms through which MS/vDBB cholinergic neurons facilitate these emotional memory processes are needed. © 2015 Wiley Periodicals, Inc. PMID:26606423

  12. Cholinergic Signaling Controls Conditioned Fear Behaviors and Enhances Plasticity of Cortical-Amygdala Circuits.

    PubMed

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

    2016-06-01

    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. Photostimulation 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

  13. Characterization of fear conditioning and fear extinction by analysis of electrodermal activity.

    PubMed

    Faghih, Rose T; Stokes, Patrick A; Marin, Marie-France; Zsido, Rachel G; Zorowitz, Sam; Rosenbaum, Blake L; Huijin Song; Milad, Mohammed R; Dougherty, Darin D; Eskandar, Emad N; Widge, Alik S; Brown, Emery N; Barbieri, Riccardo

    2015-08-01

    Electrodermal activity (EDA) is a measure of physical arousal, which is frequently measured during psychophysical tasks relevant for anxiety disorders. Recently, specific protocols and procedures have been devised in order to examine the neural mechanisms of fear conditioning and extinction. EDA reflects important responses associated with stimuli specifically administrated during these procedures. Although several previous studies have demonstrated the reproducibility of measures estimated from EDA, a mathematical framework associated with the stimulus-response experiments in question and, at the same time, including the underlying emotional state of the subject during fear conditioning and/or extinction experiments is not well studied. We here propose an ordinary differential equation model based on sudomotor nerve activity, and estimate the fear eliciting stimulus using a compressed sensing algorithm. Our results show that we are able to recover the underlying stimulus (visual cue or mild electrical shock). Moreover, relating the time-delay in the estimated stimulation to the visual cue during extinction period shows that fear level decreases as visual cues are presented without shock, suggesting that this feature might be used to estimate the fear state. These findings indicate that a mathematical model based on electrodermal responses might be critical in defining a low-dimensional representation of essential cognitive features in order to describe dynamic behavioral states. PMID:26738104

  14. Neurons activated during fear memory consolidation and reconsolidation are mapped to a common and new topography in the lateral amygdala.

    PubMed

    Bergstrom, Hadley C; McDonald, Craig G; Dey, Smita; Fernandez, Gina M; Johnson, Luke R

    2013-07-01

    A key question in neuroscience is how memory is selectively allocated to neural networks in the brain. This question remains a significant research challenge, in both rodent models and humans alike, because of the inherent difficulty in tracking and deciphering large, highly dimensional neuronal ensembles that support memory (i.e., the engram). In a previous study we showed that consolidation of a new fear memory is allocated to a common topography of amygdala neurons. When a consolidated memory is retrieved, it may enter a labile state, requiring reconsolidation for it to persist. What is not known is whether the original spatial allocation of a consolidated memory changes during reconsolidation. Knowledge about the spatial allocation of a memory, during consolidation and reconsolidation, provides fundamental insight into its core physical structure (i.e., the engram). Using design-based stereology, we operationally define reconsolidation by showing a nearly identical quantity of neurons in the dorsolateral amygdala (LAd) that expressed a plasticity-related protein, phosphorylated mitogen-activated protein kinase, following both memory acquisition and retrieval. Next, we confirm that Pavlovian fear conditioning recruits a stable, topographically organized population of activated neurons in the LAd. When the stored fear memory was briefly reactivated in the presence of the relevant conditioned stimulus, a similar topography of activated neurons was uncovered. In addition, we found evidence for activated neurons allocated to new regions of the LAd. These findings provide the first insight into the spatial allocation of a fear engram in the LAd, during its consolidation and reconsolidation phase. PMID:23322210

  15. Δ9-Tetrahydrocannabinol alone and combined with cannabidiol mitigate fear memory through reconsolidation disruption.

    PubMed

    Stern, Cristina A J; Gazarini, Lucas; Vanvossen, Ana C; Zuardi, Antonio W; Galve-Roperh, Ismael; Guimaraes, Francisco S; Takahashi, Reinaldo N; Bertoglio, Leandro J

    2015-06-01

    Δ(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD) are the major constituents of the Cannabis sativa plant, which is frequently consumed by subjects exposed to life-threatening situations to relief their symptomatology. It is still unknown, however, whether THC could also affect the maintenance of an aversive memory formed at that time when taken separately and/or in conjunction with CBD. The present study sought to investigate this matter at a preclinical level. We report that THC (0.3-10mg/kg, i.p.) was able to disrupt the reconsolidation of a contextual fear memory, resulting in reduced conditioned freezing expression for over 22 days. This effect was dependent on activation of cannabinoid type-1 receptors located in prelimbic subregion of the medial prefrontal cortex and on memory retrieval/reactivation. Since CBD may counteract the negative psychotropic effects induced by THC and has been shown to be a reconsolidation blocker, we then investigated and demonstrated that associating sub-effective doses of these two compounds was equally effective in attenuating fear memory maintenance in an additive fashion and in a dose ratio of 10 to 1, which contrasts with that commonly found in C. sativa recreational samples. Of note, neither THC alone nor CBD plus THC interfered with anxiety-related behaviors and locomotor activity, as assessed in the elevated plus-maze test, at a time point coinciding with that used to evaluate their effects on memory reconsolidation. Altogether, present findings suggest a potential therapeutic value of using THC and/or CBD to mitigate a dysfunctional aversive memory through reconsolidation disruption in post-traumatic stress disorder patients. PMID:25799920

  16. Activation of LVGCCs and CB1 Receptors Required for Destabilization of Reactivated Contextual Fear Memories

    ERIC Educational Resources Information Center

    Suzuki, Akinobu; Mukawa, Takuya; Tsukagoshi, Akinori; Frankland, Paul W.; Kida, Satoshi

    2008-01-01

    Previous studies have shown that inhibiting protein synthesis shortly after reactivation impairs the subsequent expression of a previously consolidated fear memory. This has suggested that reactivation returns a memory to a labile state and that protein synthesis is required for the subsequent restabilization of memory. While the molecular…

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

    PubMed Central

    Dunsmoor, Joseph E.; Murphy, Gregory L.

    2015-01-01

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

  18. RNA sequencing from neural ensembles activated during fear conditioning in the mouse temporal association cortex.

    PubMed

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

    2016-01-01

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

  19. RNA sequencing from neural ensembles activated during fear conditioning in the mouse temporal association cortex

    PubMed Central

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

    2016-01-01

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

  20. Reactivating fear memory under propranolol resets pre-trauma levels of dendritic spines in basolateral amygdala but not dorsal hippocampus neurons

    PubMed Central

    Vetere, Gisella; Piserchia, Valentina; Borreca, Antonella; Novembre, Giovanni; Aceti, Massimiliano; Ammassari-Teule, Martine

    2013-01-01

    Fear memory enhances connectivity in cortical and limbic circuits but whether treatments disrupting fear reset connectivity to pre-trauma level is unknown. Here we report that C56BL/6J mice exposed to a tone-shock association in context A (conditioning), and briefly re-exposed to the same tone-shock association in context B (reactivation), exhibit strong freezing to the tone alone delivered 48 h later in context B (long term fear memory). This intense fear response is associated with a massive increase in dendritic spines and phospho-Erk (p-ERK) signaling in basolateral amygdala (BLA) but neurons. We then show that propranolol (a central/peripheral β-adrenergic receptor blocker) administered before, but not after, the reactivation trial attenuates long term fear memory assessed drug free 48 h later, and completely prevents the increase in spines and p-ERK signaling in BLA neurons. An increase in spines, but not of p-ERK, was also detected in the dorsal hippocampus (DH) of the conditioned mice. DH spines, however, were unaffected by propranolol suggesting their independence from the ERK/β-ARs cascade. We conclude that propranolol selectively blocks dendritic spines and p-ERK signaling enhancement in the BLA; its effect on fear memory is, however, less pronounced suggesting that the persistence of spines at other brain sites decreases the sensitivity of the fear memory trace to treatments selectively targeting β ARs in the BLA. PMID:24391566

  1. Serotonin 5-HT7 Receptor in the Ventral Hippocampus Modulates the Retrieval of Fear Memory and Stress-Induced Defecation

    PubMed Central

    Yoshida, Takayuki; Konno, Kohtarou; Minami, Masabumi; Watanabe, Masahiko; Yoshioka, Mitsuhiro

    2016-01-01

    Background: Patients with posttraumatic stress disorder or panic disorder are often troubled by inappropriate retrieval of fear memory. Moreover, these disorders are often comorbid with irritable bowel syndrome. The main aim of the present study is to elucidate the involvement of hippocampal serotonergic systems in fear memory retrieval and stress-induced defecation. Methods and Results: Microinjection of serotonin7 receptor antagonist, but not other serotonin receptor antagonists (serotonin 1A, 2A, 2C, 3, 4, and 6), into the rat ventral hippocampus significantly suppressed the expression of freezing behavior, an index of fear memory retrieval, and decreased the amount of feces, an index of stress-induced defecation, in the contextual fear conditioning test. Electrophysiological data indicated that the serotonin7 receptor agonist increased the frequency of action potentials in the ventral hippocampal CA3 pyramidal neuron via the activation of the hyperpolarization-activated nonselective cation current Ih. Moreover, in situ hybridization demonstrated that Htr7 mRNA was abundantly expressed in the CA3 compared with other subregions of the hippocampus and that these Htr7 mRNA-positive cells coexpressed hyperpolarization-activated cyclic nucleotide-gated channel 2 and 4 mRNAs, which are components of the Ih channel. Conclusions: These results indicated that the released serotonin activates the serotonin7 receptor in the CA3 ventral hippocampus subregion, enhances the sensitivity to inputs via hyperpolarization-activated cyclic nucleotide 2 and 4 channels, and thereby facilitates fear memory retrieval. The serotonin7 receptor might be a target of drug development for the treatment of mental disorders involving fear memory and gastrointestinal problems. PMID:26647382

  2. Prior fear conditioning and reward learning interact in fear and reward networks

    PubMed Central

    Bulganin, Lisa; Bach, Dominik R.; Wittmann, Bianca C.

    2014-01-01

    The ability to flexibly adapt responses to changes in the environment is important for survival. Previous research in humans separately examined the mechanisms underlying acquisition and extinction of aversive and appetitive conditioned responses. It is yet unclear how aversive and appetitive learning interact on a neural level during counterconditioning in humans. This functional magnetic resonance imaging (fMRI) study investigated the interaction of fear conditioning and subsequent reward learning. In the first phase (fear acquisition), images predicted aversive electric shocks or no aversive outcome. In the second phase (counterconditioning), half of the CS+ and CS− were associated with monetary reward in the absence of electric stimulation. The third phase initiated reinstatement of fear through presentation of electric shocks, followed by CS presentation in the absence of shock or reward. Results indicate that participants were impaired at learning the reward contingencies for stimuli previously associated with shock. In the counterconditioning phase, prior fear association interacted with reward representation in the amygdala, where activation was decreased for rewarded compared to unrewarded CS− trials, while there was no reward-related difference in CS+ trials. In the reinstatement phase, an interaction of previous fear association and previous reward status was observed in a reward network consisting of substantia nigra/ventral tegmental area (SN/VTA), striatum and orbitofrontal cortex (OFC), where activation was increased by previous reward association only for CS− but not for CS+ trials. These findings suggest that during counterconditioning, prior fear conditioning interferes with reward learning, subsequently leading to lower activation of the reward network. PMID:24624068

  3. Tracking explicit and implicit long-lasting traces of fearful memories in humans.

    PubMed

    Packard, Pau Alexander; Rodríguez-Fornells, Antoni; Stein, Lilian Milnitsky; Nicolás, Berta; Fuentemilla, Lluís

    2014-12-01

    Recent accounts of Posttraumatic Stress Disorder (PTSD) suggest that the encoding of an episode within a fearful context generates different implicit and explicit memory representations. Whilst implicit memory traces include the associated emotional states, explicit traces include a recoding into an abstract or gist-based structural context of the episode. Theoretically, the long-term preservation of implicit memory traces may facilitate the often untreatable memory intrusions in PTSD. Here, we tracked in two experiments how implicit and explicit memory traces for fearful episodes dissociate and evolve over time. Subjects (N=86) were presented with semantically-related word-lists in a contextual fear paradigm and tested for explicit memories either immediately (i.e., 30 min) or after a delay (i.e., 1 or 2 weeks) with a verbal recognition task. Skin Conductance Response (SCR) was used to assess implicit memory responses. Subjects showed high memory accuracy for words when tested immediately after encoding. At test, SCR was higher during the presentation of verbatim but not gist-based words encoded in a fearful context, and remained unchanged after 2 weeks, despite subjects being unaware of words' encoding context. We found no clear evidence of accurate explicit memory traces for the fearful or neutral contexts of words presented during encoding, either 30 min or 2 weeks afterwards. These findings indicate that the implicit, but not the explicit, memory trace of a fearful context of an episode can be detected at long-term through SCR and is dissociated from the gist-based memory. They may have implicationstowards the understanding of how the processing of fearful memoriescould lead to PTSD. PMID:25256154

  4. Requirement of Mammalian Target of Rapamycin Complex 1 Downstream Effectors in Cued Fear Memory Reconsolidation and Its Persistence

    PubMed Central

    Huynh, Thu N.; Santini, Emanuela

    2014-01-01

    Memory retrieval, often termed reconsolidation, can render previously consolidated memories susceptible to manipulation that can lead to alterations in memory strength. Although it is known that reconsolidation requires mammalian target of rapamycin complex 1 (mTORC1)-dependent translation, the specific contributions of its downstream effectors in reconsolidation are unclear. Using auditory fear conditioning in mice, we investigated the role of eukaryotic translation initiation factor 4E (eIF4E)–eIF4G interactions and p70 S6 kinase polypeptide 1 (S6K1) in reconsolidation. We found that neither 4EGI-1 (2-[(4-(3,4-dichlorophenyl)-thiazol-2-ylhydrazono)-3-(2-nitrophenyl)]propionic acid), an inhibitor of eFI4E–eIF4G interactions, nor PF-4708671 [2-((4-(5-ethylpyrimidin-4-yl)piperazin-1-yl)methyl)-5-(trifluoromethyl)-1H-benzo[d]imidazole], an inhibitor of S6K1, alone blocked the reconsolidation of auditory fear memory. In contrast, using these drugs in concert to simultaneously block eIF4E–eIF4G interactions and S6K1 immediately after memory reactivation significantly attenuated fear memory reconsolidation. Moreover, the combination of 4EGI-1 and PF-4708671 further destabilized fear memory 10 d after memory reactivation, which was consistent with experiments using rapamycin, an mTORC1 inhibitor. Furthermore, inhibition of S6K1 immediately after retrieval resulted in memory destabilization 10 d after reactivation, whereas inhibition of eIF4E–eIF4G interactions did not. These results indicate that the reconsolidation of fear memory requires concomitant association of eIF4E to eIF4G as well as S6K1 activity and that the persistence of memory at longer intervals after memory reactivation also requires mTORC1-dependent processes that involve S6K1. These findings suggest a potential mechanism for how mTORC1-dependent translation is fine tuned to alter memory persistence. PMID:24990923

  5. Improvement in γ-hydroxybutyrate-induced contextual fear memory deficit by systemic administration of NCS-382.

    PubMed

    Ishiwari, Keita; Sircar, Ratna

    2016-06-15

    Low, nonsedative doses of γ-hydroxybutyric acid (GHB) produce short-term anterograde amnesia in humans and memory impairments in experimental animals. We have previously shown that acute systemic treatment of GHB in adolescent female rats impairs the acquisition, but not the expression, of contextual fear memory while sparing both the acquisition and the expression of auditory cued fear memory. In the brain, GHB binds to specific GHB-binding sites as well as to γ-aminobutyric acid type B (GABAB) receptors. Although many of the behavioral effects of GHB at high doses have been attributed to its effects on the GABAB receptor, it is unclear which receptor mediates its relatively low-dose memory-impairing effects. The present study examined the ability of the putative GHB receptor antagonist NCS-382 to block the disrupting effects of GHB on fear memory in adolescent rat. Groups of rats received either a single dose of NCS-382 (3-10 mg/kg, intraperitoneally) or vehicle, followed by an injection of either GHB (100 mg/kg, intraperitoneally) or saline. All rats were trained in the fear paradigm, and tested for contextual fear memory and auditory cued fear memory. NCS-382 dose-dependently reversed deficits in the acquisition of contextual fear memory induced by GHB in adolescent rats, with 5 mg/kg of NCS-382 maximally increasing freezing to the context compared with the group administered GHB alone. When animals were tested for cued fear memory, treatment groups did not differ in freezing responses to the tone. These results suggest that low-dose amnesic effects of GHB are mediated by GHB receptors. PMID:27105320

  6. Improvement in γ-hydroxybutyrate-induced contextual fear memory deficit by systemic administration of NCS-382

    PubMed Central

    Ishiwari, Keita

    2016-01-01

    Low, nonsedative doses of γ-hydroxybutyric acid (GHB) produce short-term anterograde amnesia in humans and memory impairments in experimental animals. We have previously shown that acute systemic treatment of GHB in adolescent female rats impairs the acquisition, but not the expression, of contextual fear memory while sparing both the acquisition and the expression of auditory cued fear memory. In the brain, GHB binds to specific GHB-binding sites as well as to γ-aminobutyric acid type B (GABAB) receptors. Although many of the behavioral effects of GHB at high doses have been attributed to its effects on the GABAB receptor, it is unclear which receptor mediates its relatively low-dose memory-impairing effects. The present study examined the ability of the putative GHB receptor antagonist NCS-382 to block the disrupting effects of GHB on fear memory in adolescent rat. Groups of rats received either a single dose of NCS-382 (3–10 mg/kg, intraperitoneally) or vehicle, followed by an injection of either GHB (100 mg/kg, intraperitoneally) or saline. All rats were trained in the fear paradigm, and tested for contextual fear memory and auditory cued fear memory. NCS-382 dose-dependently reversed deficits in the acquisition of contextual fear memory induced by GHB in adolescent rats, with 5 mg/kg of NCS-382 maximally increasing freezing to the context compared with the group administered GHB alone. When animals were tested for cued fear memory, treatment groups did not differ in freezing responses to the tone. These results suggest that low-dose amnesic effects of GHB are mediated by GHB receptors. PMID:27105320

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

    ERIC Educational Resources Information Center

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

    2007-01-01

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

  8. Synaptic transmission changes in fear memory circuits underlie key features of an animal model of schizophrenia.

    PubMed

    Pollard, Marie; Varin, Christophe; Hrupka, Brian; Pemberton, Darrel J; Steckler, Thomas; Shaban, Hamdy

    2012-02-01

    Non-competitive antagonists of the N-methyl-d-aspartate receptor (NMDA) such as phencyclidine (PCP) elicit schizophrenia-like symptoms in healthy individuals. Similarly, PCP dosing in rats produces typical behavioral phenotypes that mimic human schizophrenia symptoms. Although schizophrenic behavioral phenotypes of the PCP model have been extensively studied, the underlying alterations of intrinsic neuronal properties and synaptic transmission in relevant limbic brain microcircuits remain elusive. Acute brain slice electrophysiology and immunostaining of inhibitory neurons were used to identify neuronal circuit alterations of the amygdala and hippocampus associated with changes in extinction of fear learning in rats following PCP treatment. Subchronic PCP application led to impaired long-term potentiation (LTP) and marked increases in the ratio of NMDA to 2-amino-3(5-methyl-3-oxo-1,2-oxazol-4-yl)propionic acid (AMPA) receptor-mediated currents at lateral amygdala (LA) principal neurons without alterations in parvalbumin (PV) as well as non-PV, glutamic acid decarboxylase 67 (GAD 67) immunopositive neurons. In addition, LTP was impaired at the Schaffer collateral to CA1 hippocampal pathway coincident with a reduction in colocalized PV and GAD67 immunopositive neurons in the CA3 hippocampal area. These effects occurred without changes in spontaneous events or intrinsic membrane properties of principal cells in the LA. The impairment of LTP at both amygdalar and hippocampal microcircuits, which play a key role in processing relevant survival information such as fear and extinction memory concurred with a disruption of extinction learning of fear conditioned responses. Our results show that subchronic PCP administration in rats impairs synaptic functioning in the amygdala and hippocampus as well as processing of fear-related memories. PMID:22085880

  9. Reprint of: "Demographic factors predict magnitude of conditioned fear".

    PubMed

    Rosenbaum, Blake L; Bui, Eric; Marin, Marie-France; Holt, Daphne J; Lasko, Natasha B; Pitman, Roger K; Orr, Scott P; Milad, Mohammed R

    2015-12-01

    There is substantial variability across individuals in the magnitudes of their skin conductance (SC) responses during the acquisition and extinction of conditioned fear. To manage this variability, subjects may be matched for demographic variables, such as age, gender and education. However, limited data exist addressing how much variability in conditioned SC responses is actually explained by these variables. The present study assessed the influence of age, gender and education on the SC responses of 222 subjects who underwent the same differential conditioning paradigm. The demographic variables were found to predict a small but significant amount of variability in conditioned responding during fear acquisition, but not fear extinction learning or extinction recall. A larger differential change in SC during acquisition was associated with more education. Older participants and women showed smaller differential SC during acquisition. Our findings support the need to consider age, gender and education when studying fear acquisition but not necessarily when examining fear extinction learning and recall. Variability in demographic factors across studies may partially explain the difficulty in reproducing some SC findings. PMID:26608179

  10. Erasure of fear memories is prevented by Nogo Receptor 1 in adulthood.

    PubMed

    Bhagat, S M; Butler, S S; Taylor, J R; McEwen, B S; Strittmatter, S M

    2016-09-01

    Critical periods are temporary windows of heightened neural plasticity early in development. For example, fear memories in juvenile rodents are subject to erasure following extinction training, while after closure of this critical period, extinction training only temporarily and weakly suppresses fear memories. Persistence of fear memories is important for survival, but the inability to effectively adapt to the trauma is a characteristic of post-traumatic stress disorder (PTSD). We examined whether Nogo Receptor 1 (NgR1) regulates the plasticity associated with fear extinction. The loss of NgR1 function in adulthood eliminates spontaneous fear recovery and fear renewal, with a restoration of fear reacquisition rate equal to that of naive mice; thus, mimicking the phenotype observed in juvenile rodents. Regional gene disruption demonstrates that NgR1 expression is required in both the basolateral amygdala (BLA) and infralimbic (IL) cortex to prevent fear erasure. NgR1 expression by parvalbumin expressing interneurons is essential for limiting extinction-dependent plasticity. NgR1 gene deletion enhances anatomical changes of inhibitory synapse markers after extinction training. Thus, NgR1 robustly inhibits elimination of fear expression in the adult brain and could serve as a therapeutic target for anxiety disorders, such as PTSD. PMID:26619810

  11. Distinctive Roles for Amygdalar CREB in Reconsolidation and Extinction of Fear Memory

    ERIC Educational Resources Information Center

    Tronson, Natalie C.; Wiseman, Shari L.; Neve, Rachael L.; Nestler, Eric J.; Olausson, Peter; Taylor, Jane R.

    2012-01-01

    Cyclic AMP response element binding protein (CREB) plays a critical role in fear memory formation. Here we determined the role of CREB selectively within the amygdala in reconsolidation and extinction of auditory fear. Viral overexpression of the inducible cAMP early repressor (ICER) or the dominant-negative mCREB, specifically within the lateral…

  12. Differing Effects of Systemically Administered Rapamycin on Consolidation and Reconsolidation of Context vs. Cued Fear Memories

    ERIC Educational Resources Information Center

    Glover, Ebony M.; Ressler, Kerry J.; Davis, Michael

    2010-01-01

    Rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR) kinase, has attracted interest as a possible prophylactic for post-traumatic stress disorder (PTSD)-associated fear memories. We report here that although rapamycin (40 mg/kg, i.p.) disrupted the consolidation and reconsolidation of fear-potentiated startle paradigm to a…

  13. Dynamic changes in neural circuitry during adolescence are associated with persistent attenuation of fear memories.

    PubMed

    Pattwell, Siobhan S; Liston, Conor; Jing, Deqiang; Ninan, Ipe; Yang, Rui R; Witztum, Jonathan; Murdock, Mitchell H; Dincheva, Iva; Bath, Kevin G; Casey, B J; Deisseroth, Karl; Lee, Francis S

    2016-01-01

    Fear can be highly adaptive in promoting survival, yet it can also be detrimental when it persists long after a threat has passed. Flexibility of the fear response may be most advantageous during adolescence when animals are prone to explore novel, potentially threatening environments. Two opposing adolescent fear-related behaviours-diminished extinction of cued fear and suppressed expression of contextual fear-may serve this purpose, but the neural basis underlying these changes is unknown. Using microprisms to image prefrontal cortical spine maturation across development, we identify dynamic BLA-hippocampal-mPFC circuit reorganization associated with these behavioural shifts. Exploiting this sensitive period of neural development, we modified existing behavioural interventions in an age-specific manner to attenuate adolescent fear memories persistently into adulthood. These findings identify novel strategies that leverage dynamic neurodevelopmental changes during adolescence with the potential to extinguish pathological fears implicated in anxiety and stress-related disorders. PMID:27215672

  14. Role of adult neurogenesis in hippocampus-dependent memory, contextual fear extinction and remote contextual memory: new insights from ERK5 MAP kinase.

    PubMed

    Pan, Yung-Wei; Storm, Daniel R; Xia, Zhengui

    2013-10-01

    Adult neurogenesis occurs in two discrete regions of the adult mammalian brain, the subgranular zone (SGZ) of the dentate gyrus (DG) and the subventricular zone (SVZ) along the lateral ventricles. Signaling mechanisms regulating adult neurogenesis in the SGZ are currently an active area of investigation. Adult-born neurons in the DG functionally integrate into the hippocampal circuitry and form functional synapses, suggesting a role for these neurons in hippocampus-dependent memory formation. Although results from earlier behavioral studies addressing this issue were inconsistent, recent advances in conditional gene targeting technology, viral injection and optogenetic approaches have provided convincing evidence supporting a role for adult-born neurons in the more challenging forms of hippocampus-dependent learning and memory. Here, we briefly summarize these recent studies with a focus on extra signal-regulated kinase (ERK) 5, a MAP kinase whose expression in the adult brain is restricted to the neurogenic regions including the SGZ and SVZ. We review evidence identifying ERK5 as a novel endogenous signaling pathway that regulates the pro-neural transcription factor Neurogenin 2, is activated by neurotrophins and is critical for adult neurogenesis. We discuss studies demonstrating that specific deletion of ERK5 in the adult neurogenic regions impairs several forms of hippocampus-dependent memory formation in mice. These include contextual fear memory extinction, the establishment and maintenance of remote contextual fear memory, and several other challenging forms of hippocampus-dependent memory formation including 48h memory for novel object recognition, contextual fear memory established by a weak foot shock, pattern separation, and reversal of spatial learning and memory. We also briefly discuss current evidence that increasing adult neurogenesis, by small molecules or genetic manipulation, improves memory formation and long-term memory. PMID:23871742

  15. Ketamine administration diminishes operant responding but does not impair conditioned fear.

    PubMed

    Groeber Travis, Caitlin M; Altman, Daniel E; Genovese, Raymond F

    2015-12-01

    While not well understood, the NMDA (N-methyl-D-aspartate) antagonist ketamine, a dissociative anesthetic, has been reported to be efficacious in depression and related psychological disorders. Conditioned fear is a normal emotional conditioning process that is known to become dysfunctional in individuals suffering from Post-Traumatic Stress Disorder (PTSD) and related stress disorders. We examined the effects of ketamine to determine the potential modulation of the acquisition and extinction of a conditioned fear using a conditioned suppression procedure. Rats were trained on a variable interval (VI), food maintained, operant conditioning task to establish a general measure of performance. Rats were exposed to inescapable shock (IES, unconditioned stimulus) paired (×20) with an audio/visual conditioned stimulus (CS) to establish conditioning. Conditioning was quantified by measuring response suppression following CS presentation during subsequent extinction trials where the CS alone was presented. Ketamine or vehicle was administered either after initial conditioning or after each of the subsequent extinction trials. For each regimen, a series of four injections were administered 60 min apart (100, 50, 50, 50 mg/kg, respectively) in order to sustain a ketamine effect for a minimum of 4 h. Ketamine produced a general decrease in responding on the VI, relative to baseline, as response rates were slower on the operant task when tested 24 h later and longer. Ketamine did not affect the acquisition of the conditioned fear when the regimen was administered shortly after the initial pairings of IES and CS. Ketamine did not alter extinction to the conditioned fear when the regimen was administered following each CS only presentation following initial conditioning. Our conclusion from these findings is that while ketamine alters behavior on an appetitively motivated operant task it does not, however, appear to directly modulate learning and memory processes associated

  16. Enhanced Generalization of Auditory Conditioned Fear in Juvenile Mice

    ERIC Educational Resources Information Center

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

    2009-01-01

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

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

    ERIC Educational Resources Information Center

    Kelly, Megan M.; Forsyth, John P.

    2007-01-01

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

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

    ERIC Educational Resources Information Center

    Vervliet, Bram; Vansteenwegen, Debora; Eelen, Paul

    2004-01-01

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

  19. Mindfulness-Based Stress Reduction, Fear Conditioning, and The Uncinate Fasciculus: A Pilot Study.

    PubMed

    Hölzel, Britta K; Brunsch, Vincent; Gard, Tim; Greve, Douglas N; Koch, Kathrin; Sorg, Christian; Lazar, Sara W; Milad, Mohammed R

    2016-01-01

    Mindfulness has been suggested to impact emotional learning, but research on these processes is scarce. The classical fear conditioning/extinction/extinction retention paradigm is a well-known method for assessing emotional learning. The present study tested the impact of mindfulness training on fear conditioning and extinction memory and further investigated whether changes in white matter fiber tracts might support such changes. The uncinate fasciculus (UNC) was of particular interest in the context of emotional learning. In this pilot study, 46 healthy participants were quasi-randomized to a Mindfulness-Based Stress Reduction (MBSR, N = 23) or waitlist control (N = 23) group and underwent a two-day fear conditioning, extinction learning, and extinction memory protocol before and after the course or control period. Skin conductance response (SCR) data served to measure the physiological response during conditioning and extinction memory phases. Diffusion tensor imaging (DTI) data were analyzed with probabilistic tractography and analyzed for changes of fractional anisotropy in the UNC. During conditioning, participants were able to maintain a differential response to conditioned vs. not conditioned stimuli following the MBSR course (i.e., higher sensitivity to the conditioned stimuli), while controls dropped the response. Extinction memory results were not interpretable due to baseline differences. MBSR participants showed a significant increase in fractional anisotropy in the UNC, while controls did not (group by time interaction missed significance). Pre-post changes in UNC were correlated with changes in the response to the conditioned stimuli. The findings suggest effects of mindfulness practice on the maintenance of sensitivity of emotional responses and suggest underlying neural plasticity. (ClinicalTrials.gov, Identifier NCT01320969, https://clinicaltrials.gov/ct2/show/NCT01320969). PMID:27378875

  20. Mindfulness-Based Stress Reduction, Fear Conditioning, and The Uncinate Fasciculus: A Pilot Study

    PubMed Central

    Hölzel, Britta K.; Brunsch, Vincent; Gard, Tim; Greve, Douglas N.; Koch, Kathrin; Sorg, Christian; Lazar, Sara W.; Milad, Mohammed R.

    2016-01-01

    Mindfulness has been suggested to impact emotional learning, but research on these processes is scarce. The classical fear conditioning/extinction/extinction retention paradigm is a well-known method for assessing emotional learning. The present study tested the impact of mindfulness training on fear conditioning and extinction memory and further investigated whether changes in white matter fiber tracts might support such changes. The uncinate fasciculus (UNC) was of particular interest in the context of emotional learning. In this pilot study, 46 healthy participants were quasi-randomized to a Mindfulness-Based Stress Reduction (MBSR, N = 23) or waitlist control (N = 23) group and underwent a two-day fear conditioning, extinction learning, and extinction memory protocol before and after the course or control period. Skin conductance response (SCR) data served to measure the physiological response during conditioning and extinction memory phases. Diffusion tensor imaging (DTI) data were analyzed with probabilistic tractography and analyzed for changes of fractional anisotropy in the UNC. During conditioning, participants were able to maintain a differential response to conditioned vs. not conditioned stimuli following the MBSR course (i.e., higher sensitivity to the conditioned stimuli), while controls dropped the response. Extinction memory results were not interpretable due to baseline differences. MBSR participants showed a significant increase in fractional anisotropy in the UNC, while controls did not (group by time interaction missed significance). Pre-post changes in UNC were correlated with changes in the response to the conditioned stimuli. The findings suggest effects of mindfulness practice on the maintenance of sensitivity of emotional responses and suggest underlying neural plasticity. (ClinicalTrials.gov, Identifier NCT01320969, https://clinicaltrials.gov/ct2/show/NCT01320969). PMID:27378875

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

    PubMed

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

    2015-09-01

    Although generally associated with cardiovascular regulation, angiotensin II receptor type 1a (AT1a R) blockade in mouse models and humans has also been associated with enhanced fear extinction and decreased post-traumatic stress disorder (PTSD) symptom severity, respectively. The mechanisms mediating these effects remain unknown, but may involve alterations in the activities of corticotropin-releasing factor (CRF)-expressing cells, which are known to be involved in fear regulation. To test the hypothesis that AT1a R signaling in CRFergic neurons is involved in conditioned fear expression, we generated and characterized a conditional knockout mouse strain with a deletion of the AT1a R gene from its CRF-releasing cells (CRF-AT1a R((-/-)) ). These mice exhibit normal baseline heart rate, blood pressure, anxiety and locomotion, and freeze at normal levels during acquisition of auditory fear conditioning. However, CRF-AT1a R((-/-)) mice exhibit less freezing than wild-type mice during tests of conditioned fear expression-an effect that may be caused by a decrease in the consolidation of fear memory. These results suggest that central AT1a R activity in CRF-expressing cells plays a role in the expression of conditioned fear, and identify CRFergic cells as a population on which AT1 R antagonists may act to modulate fear extinction. PMID:26257395

  2. Brain-derived neurotrophic factor in the anterior cingulate cortex is involved in the formation of fear memory.

    PubMed

    Li, Qing-Qing; Li, Bao-Ming

    2015-10-25

    Brain-derived neurotrophic factor (BDNF), a small dimeric secretory protein, plays a vital role in activity-dependent synaptic plasticity, learning and memory. It has been shown that BDNF in the hippocampus and amygdala participates in the formation of fear memory. However, little is known about the functional role of BDNF in the anterior cingulate cortex (ACC). To address this question, we examined the mRNA and protein levels of BDNF in the ACC of rats at various time points after fear conditioning, using quantitative real-time PCR and enzyme-linked immunosorbent assay (ELISA). The results showed that BDNF exhibited a temporally specific increase in both mRNA and protein levels after CS (tone) and US (foot shock) was paired. Such increase did not occur after the animals were exposed to CS or US alone. When BDNF antibody was locally infused into the ACC prior to CS-US pairing, both contextual and auditory fear memories were severely impaired. Taken together, these results suggest that BDNF in the ACC is required for the formation of fear memory. PMID:26490062

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

    PubMed

    Poplawski, Shane G; Schoch, Hannah; Wimmer, Mathieu E; 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. PMID:25242102

  4. 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

  5. Post-weaning Social Isolation Impairs Observational Fear Conditioning

    PubMed Central

    Yusufishaq, Shabana; Rosenkranz, J. Amiel

    2013-01-01

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

  6. Regulation of amygdalar PKA by β-arrestin-2/phosphodiesterase-4 complex is critical for fear conditioning

    PubMed Central

    Li, Yuting; Li, Haohong; Liu, Xing; Bao, Guobin; Tao, Yezheng; Wu, Ziyan; Xia, Peng; Wu, Chunfu; Li, Baoming; Ma, Lan

    2009-01-01

    β-arrestins, key regulators of receptor signaling, are highly expressed in the central nervous system, but their roles in brain physiology are largely unknown. Here we show that β-arrestin-2 is critically involved in the formation of associative fear memory and amygdalar synaptic plasticity. In response to fear conditioning, β-arrestin-2 translocates to amygdalar membrane where it interacts with PDE-4, a cAMP-degrading enzyme, to inhibit PKA activation. Arrb2−/− mice exhibit impaired conditioned fear memory and long-term potentiation at the lateral amygdalar synapses. Moreover, expression of the β-arrestin-2 in the lateral amygdala of Arrb2−/− mice, but not its mutant form that is incapable of binding PDE-4, restores basal PKA activity and rescues conditioned fear memory. Taken together, our data demonstrate that the feedback regulation of amygdalar PKA activation by β-arrestin-2 and PDE-4 complex is critical for the formation of conditioned fear memory. PMID:19955404

  7. Genome-wide analysis of H4K5 acetylation associated with fear memory in mice

    PubMed Central

    2013-01-01

    Background Histone acetylation has been implicated in learning and memory in the brain, however, its function at the level of the genome and at individual genetic loci remains poorly investigated. This study examines a key acetylation mark, histone H4 lysine 5 acetylation (H4K5ac), genome-wide and its role in activity-dependent gene transcription in the adult mouse hippocampus following contextual fear conditioning. Results Using ChIP-Seq, we identified 23,235 genes in which H4K5ac correlates with absolute gene expression in the hippocampus. However, in the absence of transcription factor binding sites 150 bp upstream of the transcription start site, genes were associated with higher H4K5ac and expression levels. We further establish H4K5ac as a ubiquitous modification across the genome. Approximately one-third of all genes have above average H4K5ac, of which ~15% are specific to memory formation and ~65% are co-acetylated for H4K12. Although H4K5ac is prevalent across the genome, enrichment of H4K5ac at specific regions in the promoter and coding region are associated with different levels of gene expression. Additionally, unbiased peak calling for genes differentially acetylated for H4K5ac identified 114 unique genes specific to fear memory, over half of which have not previously been associated with memory processes. Conclusions Our data provide novel insights into potential mechanisms of gene priming and bookmarking by histone acetylation following hippocampal memory activation. Specifically, we propose that hyperacetylation of H4K5 may prime genes for rapid expression following activity. More broadly, this study strengthens the importance of histone posttranslational modifications for the differential regulation of transcriptional programs in cognitive processes. PMID:23927422

  8. Origins of common fears: effects on severity, anxiety responses and memories of onset.

    PubMed

    Withers, R D; Deane, F P

    1995-11-01

    The purpose of the present study was twofold: First, to test Rachman's (1976) theory (Behaviour Research and Therapy, 14, 125-131) which predicts that "directly" conditioned fears will differ from "indirectly" conditioned fears in magnitude and anxiety response patterns. Secondly, to explore validity issues related to the questionnaire methodology typically used in fear acquisition research. The questionnaire comprised 3 anxiety scales and 3 fear-onset questions used in prior research, a specifically developed 36-item fear list and 2 validity-check items. One hundred and ninety-one Ss completed the questionnaire. After selecting and rank-ordering 10 fears from the fear list, Ss answered questionnaire items for their first- and then their tenth-ranked fear. Results failed to confirm Rachman's predictions: A significantly greater proportion of Ss ascribed highly-feared and moderately-feared situations or things to direct conditioning. In addition, differential anxiety response patterns were not present for different levels of fear. However, results supported the prediction that direct-conditioning ascriptions would be endorsed with greater certainty. The findings suggest that direct-conditioning experiences may be more memorable than indirect-conditioning events. The theoretical and methodological implications of the findings are discussed. It is suggested that future research either employ methodologies more suited to investigating causal relationships or that Rachman's (1976) theory be blended with an attributional account of fear acquisition. PMID:7487850

  9. Venlafaxine facilitates between-session extinction and prevents reinstatement of auditory-cue conditioned fear.

    PubMed

    Yang, Cheng-Hao; Shi, Hai-Shui; Zhu, Wei-Li; Wu, Ping; Sun, Li-Li; Si, Ji-Jian; Liu, Meng-Meng; Zhang, Yan; Suo, Lin; Yang, Jian-Li

    2012-04-21

    Anxiety disorders, characterized by anxiety and fearfulness, are found to be able to cause abnormal emotional responses' associated with memories of negative events, which implicate pressure on society with an increasingly large burden. Better treatment has been of concern to the community. Venlafaxine (VEN), a nonclassical antidepressant agent, is applied in the treatment of social phobia, major depression (MD) and general anxiety disorder (GAD) and, to a certain extent, posttraumatic stress disorder (PTSD), which improves working memory and spatial memory as well as ameliorates emotion by affecting specified brain regions. In this study, we committed to seek a new way for using VEN on treatment of anxiety disorders. To investigate the effect of VEN on extinction of auditory-cue conditioned fear, conditioned rats received a treatment with VEN before extinction training and tests for freezing level of within-session and between-session extinction. To investigate the effect of VEN on reinstatement, all conditioned rats received a treatment with VEN over a period for 21 days. After a rest for 7 days, two tests for freezing level were conducted. We found that: (1) VEN (40mg/kg) treatment at 30min prior to extinction training significantly facilitated the between-session extinction, but not the within-session extinction; (2) chronic administration with VEN (40mg/kg) prevented the return of extinguished auditory-cue fear. These data elucidate the critical role of VEN in auditory-cue fear memory, suggesting that VEN may be an ideal choice for the exposure-based drug treatment and maintenance treatment in patients with GAD, SAD and PTSD. PMID:22366271

  10. Role of L-type Ca2+ channel isoforms in the extinction of conditioned fear.

    PubMed

    Busquet, Perrine; Hetzenauer, Alfred; Sinnegger-Brauns, Martina J; Striessnig, Jörg; Singewald, Nicolas

    2008-05-01

    Dihydropyridine (DHP) L-type Ca(2+) channel (LTCC) antagonists, such as nifedipine, have been reported to impair the extinction of conditioned fear without interfering with its acquisition. Identification of the LTCC isoforms mediating this DHP effect is an essential basis to reveal their role as potential drug targets for the treatment of specific anxiety disorders. Ca(V)1.2 and Ca(V)1.3 are the predominant LTCCs in the mammalian brain. However, since no isoform-selective DHP blockers are available, their individual contribution to fear memory extinction is unknown. We used a novel mouse model expressing DHP-insensitive Ca(V)1.2 LTCCs (Ca(V)1.2DHP(-/-) mice) to address this question. In line with previous studies, wild-type (WT) mice treated with systemic nifedipine displayed markedly impaired fear extinction. This DHP effect was completely abolished in Ca(V)1.2DHP(-/-) mice, indicating that it is mediated by Ca(V)1.2, but not by Ca(V)1.3 LTCCs. Supporting this conclusion, Ca(V)1.3-deficient mice (Ca(V)1.3(-/-)) showed extinction identical to the respective WT mice. The inhibition of fear extinction was not observed after intracerebroventricular (i.c.v.) application of different doses of nifedipine, suggesting that this effect is secondary to inhibition of peripheral Ca(V)1.2 channels. The LTCC activator BayK, which lacks neurotoxic effects in Ca(V)1.2DHP(-/-) mice, did not influence the extinction time course. In summary, we demonstrate that LTCC signaling through the Ca(V)1.2 isoform of LTCCs interferes with fear memory extinction, presumably via a peripherally mediated mechanism. Activation of other LTCC isoforms (predominantly Ca(V)1.3) is not sufficient to accelerate extinction of conditioned fear in mice. PMID:18441296