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.

The hippocampus integrates context and shock into a configural memory in contextual fear conditioning.

PubMed

Chang, Shih-Dar; Liang, K C

2017-02-01

Contextual fear conditioning involves forming a representation for the context and associating it with a shock, which were attributed by the prevailing view to functions of the hippocampus and amygdala, respectively. Yet our recent evidence suggested that both processes require integrity of the dorsal hippocampus (DH). In view of the DH involvement in uniting multiple stimuli into a configuration, this study examined whether the DH would integrate context and shock into a shocked-context representation. Male Wistar rats were trained on a two-phase training paradigm of contextual fear conditioning. They explored a novel context on the first day to acquire a contextual representation, and received a shock in that context on the second day to form the context-shock memory. Tests of conditioned freezing given on the following days revealed two properties of configural memory-direct and mediated pattern completion: First, the contextual fear memory was retrieved in a novel context by a cue embedded in the configural set-a shock that did not elicit significant freezing on its own. Second, freezing was also elicited in a novel context by a transportation chamber that was not directly paired with the shock but could activate the fear memory inferentially. The effects were specific to the cue and not due to context generalization. Infusion of lidocaine into the DH, but not the amygdala, immediately after context-shock training impaired conditioned freezing elicited through either type of pattern completion. Our data suggest that the DH in contextual fear conditioning associates context and shock in parallel with the amygdala by incorporating the shock into an otherwise neutral context representation and turning it into a shocked-context representation. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Fear Conditioning Increases NREM Sleep

PubMed Central

Hellman, Kevin; Abel, Ted

2010-01-01

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

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

PubMed

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

2015-01-01

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

Chronic fluoxetine dissociates contextual from auditory fear memory.

PubMed

Sanders, Jeff; Mayford, Mark

2016-10-06

Fluoxetine is a medication used to treat Major Depressive Disorder and other psychiatric conditions. These experiments studied the effects of chronic fluoxetine treatment on the contextual versus auditory fear memory of mice. We found that chronic fluoxetine treatment of adult mice impaired their contextual fear memory, but spared auditory fear memory. Hippocampal perineuronal nets, which are involved in contextual fear memory plasticity, were unaltered by fluoxetine treatment. These data point to a selective inability to form contextual fear memory as a result of fluoxetine treatment, and they suggest that a blunting of hippocampal-mediated aversive memory may be a therapeutic action for this medication. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Long-term memory deficits in Pavlovian fear conditioning in Ca2+/calmodulin kinase kinase alpha-deficient mice.

PubMed

Blaeser, Frank; Sanders, Matthew J; Truong, Nga; Ko, Shanelle; Wu, Long Jun; Wozniak, David F; Fanselow, Michael S; Zhuo, Min; Chatila, Talal A

2006-12-01

Signaling by the Ca(2+)/calmodulin kinase (CaMK) cascade has been implicated in neuronal gene transcription, synaptic plasticity, and long-term memory consolidation. The CaM kinase kinase alpha (CaMKKalpha) isoform is an upstream component of the CaMK cascade whose function in different behavioral and learning and memory paradigms was analyzed by targeted gene disruption in mice. CaMKKalpha mutants exhibited normal long-term spatial memory formation and cued fear conditioning but showed deficits in context fear during both conditioning and long-term follow-up testing. They also exhibited impaired activation of the downstream kinase CaMKIV/Gr and its substrate, the transcription factor cyclic AMP-responsive element binding protein (CREB) upon fear conditioning. Unlike CaMKIV/Gr-deficient mice, the CaMKKalpha mutants exhibited normal long-term potentiation and normal levels of anxiety-like behavior. These results demonstrate a selective role for CaMKKalpha in contextual fear memory and suggest that different combinations of upstream and downstream components of the CaMK cascade may serve distinct physiological functions.

MOLECULAR MECHANISMS OF FEAR LEARNING AND MEMORY

PubMed Central

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

2011-01-01

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

Molecular mechanisms of fear learning and memory.

PubMed

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

2011-10-28

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

Contextual fear conditioning in zebrafish.

PubMed

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

2017-10-01

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

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

PubMed

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

2017-08-01

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

Behavioural memory reconsolidation of food and fear memories

PubMed Central

Flavell, Charlotte R.; Barber, David J.; Lee, Jonathan L. C.

2012-01-01

The reactivation of a memory through retrieval can render it subject to disruption or modification through the process of memory reconsolidation. In both humans and rodents, briefly reactivating a fear memory results in effective erasure by subsequent extinction training. Here we show that a similar strategy is equally effective in the disruption of appetitive pavlovian cue–food memories. However, systemic administration of the NMDA receptor partial agonist D-cycloserine under the same behavioural conditions did not potentiate appetitive memory extinction, suggesting that reactivation does not enhance subsequent extinction learning. To confirm that reactivation followed by extinction reflects a behavioural analog of memory reconsolidation, we show that prevention of contextual fear memory reactivation by the LVGCC blocker nimodipine interferes with the amnestic outcome. Therefore, the reconsolidation process can be manipulated behaviourally to disrupt both aversive and appetitive memories. PMID:22009036

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. © 2014 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

Optogenetic stimulation of a hippocampal engram activates fear memory recall.

PubMed

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

2012-03-22

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

Optogenetic stimulation of a hippocampal engram activates fear memory recall

PubMed Central

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

2012-01-01

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

Postreactivation glucocorticoids impair recall of established fear memory.

PubMed

Cai, Wen-Hui; Blundell, Jacqueline; Han, Jie; Greene, Robert W; Powell, Craig M

2006-09-13

Pavlovian fear conditioning provides one of the best rodent models of acquired anxiety disorders, including posttraumatic stress disorder. Injection of a variety of drugs after training in fear-conditioning paradigms can impair consolidation of fear memories. Indeed, early clinical trials suggest that immediate administration of such drugs after a traumatic event may decrease the risk of developing posttraumatic stress disorder in humans (Pitman et al., 2002; Vaiva et al., 2003). The use of such a treatment is limited by the difficulty of treating every patient at risk and by the difficulty in predicting which patients will experience chronic adverse consequences. Recent clinical trials suggest that administration of glucocorticoids may have a beneficial effect on established posttraumatic stress disorder (Aerni et al., 2004) and specific phobia (Soravia et al., 2006). Conversely, glucocorticoid administration after training is known to enhance memory consolidation (McGaugh and Roozendaal, 2002; Roozendaal, 2002). From a clinical perspective, enhancement of a fear memory or a reactivated fear memory would not be desirable. We report here that when glucocorticoids are administered immediately after reactivation of a contextual fear memory, subsequent recall is significantly diminished. Additional experiments support the interpretation that glucocorticoids not only decrease fear memory retrieval but, in addition, augment consolidation of fear memory extinction rather than decreasing reconsolidation. These findings provide a rodent model for a potential treatment of established acquired anxiety disorders in humans, as suggested by others (Aerni et al., 2004; Schelling et al., 2004), based on a mechanism of enhanced extinction.

Modulation of hippocampal NCAM polysialylation and spatial memory consolidation by fear conditioning.

PubMed

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

2003-09-15

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

Reduced Consolidation, Reinstatement, and Renewal of Conditioned Fear Memory by Repetitive Treatment of Radix Polygalae in Mice

PubMed Central

Shin, Jung-Won; Park, Hyunwoo; Cho, Yoonju; Lee, Suck; Yoon, Jiwon; Maeng, Sungho

2017-01-01

The therapeutic goal for the treatment of posttraumatic stress disorder (PTSD) is to promote extinction and to prevent the relapse of fearful memories. Research has identified pharmacological treatments that may regulate the formation and extinction of fear memories, but not many reagents that block the relapse of extinguished fear are known. Radix Polygalae (RP) is an Asian herb used for sedation, and its ingredients have anxiolytic and antidepressant properties. As various neurological effects have been identified, we tested whether RP affects the relapse of fear. Freezing in response to a conditioned context and cues was used to measure the effects of RP in mice. In cohort 1 (n = 30), consolidation, extinction, and reinstatement were tested during the course of 18 days of treatment. In cohort 2 (n = 30), consolidation, extinction, and renewal were tested during 10 days of treatment. The consolidation, extinction, reinstatement, and possibly the renewal of context-induced freezing were inhibited due to the administration of RP in animal subjects. However, the effects of RP on the freezing responses of subjects elicited by conditioned auditory cues were less obvious. Because it effectively suppresses the consolidation of fear memories, RP may be used for primary and secondary prevention of symptoms in PTSD patients. Additionally, because it effectively suppresses the reinstatement and renewal of fear memories, RP may be applied for the prevention of fear relapse in PTSD patients who have undergone exposure therapy. PMID:28620325

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

PubMed

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

2012-05-01

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

Influence of cued-fear conditioning and its impairment on NREM sleep.

PubMed

Kumar, Tankesh; Jha, Sushil K

2017-10-01

Many studies suggest that fear conditioning influences sleep. It is, however, not known if the changes in sleep architecture after fear conditioning are essentially associated with the consolidation of fearful memory or with fear itself. Here, we have observed that within sleep, NREM sleep consistently remained augmented after the consolidation of cued fear-conditioned memory. But a similar change did not occur after impairing memory consolidation by blocking new protein synthesis and glutamate transmission between glial-neuronal loop in the lateral amygdala (LA). Anisomycin (a protein synthesis inhibitor) and DL-α-amino-adipic acid (DL- α -AA) (a glial glutamine synthetase enzyme inhibitor) were microinjected into the LA soon after cued fear-conditioning to induce memory impairment. On the post-conditioning day, animals in both the groups exhibited significantly less freezing. In memory-consolidated groups (vehicle groups), NREM sleep significantly increased during 2nd to 5th hours after training compared to their baseline days. However, in memory impaired groups (anisomycin and DL- α -AA microinjected groups), similar changes were not observed. Our results thus suggest that changes in sleep architecture after cued fear-conditioning are indeed a consolidation dependent event. Copyright © 2017 Elsevier Inc. All rights reserved.

Fear Conditioning is Disrupted by Damage to the Postsubiculum

PubMed Central

Robinson, Siobhan; Bucci, David J.

2011-01-01

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

Stress disrupts the reconsolidation of fear memories in men.

PubMed

Meir Drexler, Shira; Wolf, Oliver T

2017-03-01

Reconsolidation is a post-retrieval process of restabilization of the memory trace. Previous findings from our group suggest that cortisol, a glucocorticoid hormone secreted in response to stress, enhances the reconsolidation of fear memories in healthy men. Cortisol effect was found to be very specific, enhancing only the fear memory that was reactivated (i.e. retrieved), but not the non-reactivated memory. In the current study we aimed to investigate the effects of psychosocial stress, a more ecologically valid intervention, on fear memory reconsolidation in men. Using a similar design, we expected stress induction to have comparable effects to those of cortisol intake. During the three testing days, the participants went through (1) fear acquisition, (2) stress induction and memory reactivation (or the corresponding control conditions), (3) fear extinction, reinstatement and reinstatement test. Salivary cortisol, blood pressure measures and subjective ratings confirmed the success of the stress induction. Skin conductance response, serving as a measure of conditioned fear, confirmed acquisition, fear retrieval, and extinction in all groups. In the three control groups (where either reactivation, stress, or both components were missing) reinstatement effects were seen as expected. Yet in contrast to the hypothesis, the target group (i.e. combining reactivation and stress) showed no reinstatement to any of the stimuli. Stress induction is thus suggested to have a general impairing effect on the reconsolidation of fear memories. The unique characteristic of the stress response and experience compared to a pharmacological intervention are proposed as possible explanations to the findings. This disruptive effect of stress on fear memory reconsolidation may have potential therapeutic implications. Copyright © 2016 Elsevier Ltd. All rights reserved.

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

PubMed

Yoshii, Takahiro; Hosokawa, Hiroshi; Matsuo, Naoki

2017-02-01

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

Vicarious extinction learning during reconsolidation neutralizes fear memory.

PubMed

Golkar, Armita; Tjaden, Cathelijn; Kindt, Merel

2017-05-01

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

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

Effects of medial prefrontal cortex lesions in rats on the what-where-when memory of a fear conditioning event.

PubMed

Li, Jay-Shake; Hsiao, Kun-Yuan; Chen, Wei-Min

2011-03-17

Previous animal studies have defined the ability to remember the details of what, where, and when of an event as an episodic-like memory to be used to model episodic memory in humans. Numerous findings indicate that the hippocampal-frontal cortical circuitry plays a major part in its neural mechanism. Researchers have intensively studied roles of diverse hippocampus sub-regions using animal models. By contrast, the impact of prefrontal cortex lesions on episodic-like memory in animals is still unknown. Here we show that Wistar rats with bilateral medial prefrontal cortex lesions failed to use the temporal-contextual information to retrieve memory of a fear-conditioning event, indicating impairments in their episodic-like memory. Subsequent experiments excluded alternative interpretations that the manipulation impaired the fear-conditioning per se, or interfered with the sensory preconditioning process. We concluded that damages in this area might impair temporal information processing, or interfere with integrating temporal and contextual elements of fear-conditioning events to form a conjunctive entity. These findings can help understand how the medial prefrontal cortex contributes to episodic-like memory. Copyright © 2010 Elsevier B.V. All rights reserved.

Durable fear memories require PSD-95

PubMed Central

Fitzgerald, Paul J.; Pinard, Courtney R.; Camp, Marguerite C.; Feyder, Michael; Sah, Anupam; Bergstrom, Hadley; Graybeal, Carolyn; Liu, Yan; Schlüter, Oliver; Grant, Seth G.N.; Singewald, Nicolas; Xu, Weifeng; Holmes, Andrew

2014-01-01

Traumatic fear memories are highly durable but also dynamic, undergoing repeated reactivation and rehearsal over time. While overly persistent fear memories underlie anxiety disorders such as posttraumatic stress disorder, the key neural and molecular mechanisms underlying fear memory durability remain unclear. Post-synaptic density 95 (PSD-95) is a synaptic protein regulating glutamate receptor anchoring, synaptic stability and certain types of memory. Employing a loss-of-function mutant mouse lacking the guanylate kinase domain of PSD-95 (PSD-95GK), 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 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-95GK mice to retrieve remote cued fear memories was associated with hypoactivation of the infralimbic cortex (IL) (not anterior cingulate (ACC) or prelimbic cortex), reduced IL single-unit firing and bursting, and attenuated IL gamma and theta oscillations. Adeno-associated PSD-95 virus-mediated knockdown in the IL, not 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

Hippocampal Administration of Levothyroxine Impairs Contextual Fear Memory Consolidation in Rats.

PubMed

Yu, Dafu; Zhou, Heng; Zou, Lin; Jiang, Yong; Wu, Xiaoqun; Jiang, Lizhu; Zhou, Qixin; Yang, Yuexiong; Xu, Lin; Mao, Rongrong

2017-01-01

Thyroid hormone (TH) receptors are highly distributed in the hippocampus, which plays a vital role in memory processes. However, how THs are involved in the different stages of memory process is little known. Herein, we used hippocampus dependent contextual fear conditioning to address the effects of hippocampal THs on the different stages of fear memory. First, we found that a single systemic levothyroxine (LT 4 ) administration increased the level of free triiodothyronine (FT 3 ) and free tetraiodothyroxine (FT 4 ) not only in serum but also in hippocampus. In addition, a single systemic LT 4 administration immediately after fear conditioning significantly impaired fear memory. These results indicated the important role of hippocampal THs in fear memory process. To further confirm the effects of hippocampal THs on the different stages of fear memory, LT 4 (0.4 μg/μl, 1 μl/side) was injected bilaterally into hippocampus. Rats given LT 4 into hippocampus before training or tests had no effect on the acquisition or retrieval of fear memory, however rats given LT 4 into hippocampus either immediately or 2 h after training showed being significantly impaired fear memory, which demonstrated LT 4 administration into hippocampus impairs the consolidation but has no effect on the acquisition and retrieval of fear memory. Furthermore, hippocampal injection of LT 4 did not affect rats' locomotor activity, thigmotaxis and THs level in prefrontal cortex (PFC) and serum. These findings may have important implications for understanding mechanisms underlying contribution of THs to memory disorders.

Hippocampal Administration of Levothyroxine Impairs Contextual Fear Memory Consolidation in Rats

PubMed Central

Yu, Dafu; Zhou, Heng; Zou, Lin; Jiang, Yong; Wu, Xiaoqun; Jiang, Lizhu; Zhou, Qixin; Yang, Yuexiong; Xu, Lin; Mao, Rongrong

2017-01-01

Thyroid hormone (TH) receptors are highly distributed in the hippocampus, which plays a vital role in memory processes. However, how THs are involved in the different stages of memory process is little known. Herein, we used hippocampus dependent contextual fear conditioning to address the effects of hippocampal THs on the different stages of fear memory. First, we found that a single systemic levothyroxine (LT4) administration increased the level of free triiodothyronine (FT3) and free tetraiodothyroxine (FT4) not only in serum but also in hippocampus. In addition, a single systemic LT4 administration immediately after fear conditioning significantly impaired fear memory. These results indicated the important role of hippocampal THs in fear memory process. To further confirm the effects of hippocampal THs on the different stages of fear memory, LT4 (0.4 μg/μl, 1 μl/side) was injected bilaterally into hippocampus. Rats given LT4 into hippocampus before training or tests had no effect on the acquisition or retrieval of fear memory, however rats given LT4 into hippocampus either immediately or 2 h after training showed being significantly impaired fear memory, which demonstrated LT4 administration into hippocampus impairs the consolidation but has no effect on the acquisition and retrieval of fear memory. Furthermore, hippocampal injection of LT4 did not affect rats’ locomotor activity, thigmotaxis and THs level in prefrontal cortex (PFC) and serum. These findings may have important implications for understanding mechanisms underlying contribution of THs to memory disorders. PMID:28824379

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.

High trait anxiety: a challenge for disrupting fear memory reconsolidation.

PubMed

Soeter, Marieke; Kindt, Merel

2013-01-01

Disrupting reconsolidation may be promising in the treatment of anxiety disorders but the fear-reducing effects are thus far solely demonstrated in the average organism. A relevant question is whether disrupting fear memory reconsolidation is less effective in individuals who are vulnerable to develop an anxiety disorder. By collapsing data from six previous human fear conditioning studies we tested whether trait anxiety was related to the fear-reducing effects of a pharmacological agent targeting the process of memory reconsolidation--n = 107. Testing included different phases across three consecutive days each separated by 24 h. Fear responding was measured by the eye-blink startle reflex. Disrupting the process of fear memory reconsolidation was manipulated by administering the β-adrenergic receptor antagonist propranolol HCl either before or after memory retrieval. Trait anxiety uniquely predicted the fear-reducing effects of disrupting memory reconsolidation: the higher the trait anxiety, the less fear reduction. Vulnerable individuals with the propensity to develop anxiety disorders may need higher dosages of propranolol HCl or more retrieval trials for targeting and changing fear memory. Our finding clearly demonstrates that we cannot simply translate observations from fundamental research on fear reduction in the average organism to clinical practice.

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

Hippocampal Arc (Arg3.1) expression is induced by memory recall and required for memory reconsolidation in trace fear conditioning.

PubMed

Chia, Chester; Otto, Tim

2013-11-01

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

Hypobaric hypoxia impairs cued and contextual fear memory in rats.

PubMed

Kumari, Punita; Kauser, Hina; Wadhwa, Meetu; Roy, Koustav; Alam, Shahnawaz; Sahu, Surajit; Kishore, Krishna; Ray, Koushik; Panjwani, Usha

2018-04-26

Fear memory is essential for survival, and its dysregulation leads to disorders. High altitude hypobaric hypoxia (HH) is known to induce cognitive decline. However, its effect on fear memory is still an enigma. We aimed to investigate the temporal effect of HH on fear conditioning and the underlying mechanism. Adult male Sprague-Dawley rats were trained for fear conditioning and exposed to simulated HH equivalent to 25,000 ft for different durations (1, 3, 7, 14 and 21 days). Subsequently, rats were tested for cued and contextual fear conditioning. Neuronal morphology, apoptosis and DNA fragmentation were studied in the medial prefrontal cortex (mPFC), hippocampus and basolateral amygdala (BLA). We observed significant deficit in cued and contextual fear acquisition (at 1, 3 and 7 days) and consolidation (cued at 1 and 3 days and contextual fear at 1, 3 and 7 days) under HH. HH exposure with retraining showed the earlier restoration of contextual fear memory. Further, we found a gradual increase in the number of pyknotic and apoptotic neurons together with the increase in DNA fragmentation in mPFC, hippocampus, and BLA up to 7 days of HH exposure. The present study concludes that HH exposure equivalent to 25000 ft induced cued and contextual fear memory deficit (acquisition and consolidation) which is found to be correlated with the neurodegenerative changes in the limbic brain regions. Copyright © 2018. Published by Elsevier B.V.

Periodical reactivation under the effect of caffeine attenuates fear memory expression in rats.

PubMed

Pedraza, Lizeth K; Sierra, Rodrigo O; Lotz, Fernanda N; Alvares, Lucas de Oliveira

2018-05-08

In the last decade, several studies have shown that fear memories can be attenuated by interfering with reconsolidation. However, most of the pharmacological agents used in preclinical studies cannot be administered to humans. Caffeine is one of the world's most popular psychoactive drugs and its effects on cognitive and mood states are well documented. Nevertheless, the influence of caffeine administration on fear memory processing is not as clear. We employed contextual fear conditioning in rats and acute caffeine administration under a standard memory reconsolidation protocol or periodical memory reactivation. Additionally, potential rewarding/aversion and anxiety effects induced by caffeine were evaluated by conditioning place preference or open field, respectively. Caffeine administration was able to attenuate weak fear memories in a standard memory reconsolidation protocol; however, periodical memory reactivation under caffeine effect was necessary to attenuate strong and remote memories. Moreover, caffeine promoted conditioned place preference and anxiolytic-like behavior, suggesting that caffeine weakens the initial learning during reactivation through counterconditioning mechanisms. Thus, our study shows that rewarding and anxiolytic effects of caffeine during fear reactivation can change the emotional valence of fear memory. It brings a new promising pharmacological approach based on drugs widely used such as caffeine to treat fear-related disorders.

Memory retrieval after contextual fear conditioning induces c-Fos and JunB expression in CA1 hippocampus.

PubMed

Strekalova, T; Zörner, B; Zacher, C; Sadovska, G; Herdegen, T; Gass, P

2003-02-01

Using specific polyclonal antisera against c-Fos, JunB, c-Jun and JunD, we tried to identify the candidate transcription factors of the immediate early gene family which may contribute to the molecular processes during contextual memory reconsolidation. For that purpose we analyzed the expression of these proteins in the hippocampus after contextual memory retrieval in a mouse model of fear conditioning. A single exposure to a foot shock of 0.8 mA was sufficient to induce robust contextual fear conditioning in C57BI/6N mice. In these mice context dependent memory retrieval evoked a marked induction of c-Fos and JunB, but not of c-Jun and JunD, in pyramidal CA1 neurons of the dorsal hippocampus. In contrast, mice exposed and re-exposed only to the context, without foot shock, did not show behavioral signs of contextual fear conditioning and exhibited significantly less expression of c-Fos and JunB in CA1 neurons. Mice which received a foot shock but were not re-exposed to the context revealed no immediate early gene induction. These results demonstrate that contextual memory retrieval is associated with de novo synthesis of specific members of the Fos/Jun transcription factor family. Therefore we suggest that these genes may contribute to plasticity and reconsolidation accompanying the retrieval process. The specific activation of CA1 neurons during the retrieval of contextual fear associations supports the postulated concept of a mnemonic role of this hippocampal subsector during the retrieval of contextual informations.

High Trait Anxiety: A Challenge for Disrupting Fear Memory Reconsolidation

PubMed Central

Soeter, Marieke; Kindt, Merel

2013-01-01

Disrupting reconsolidation may be promising in the treatment of anxiety disorders but the fear-reducing effects are thus far solely demonstrated in the average organism. A relevant question is whether disrupting fear memory reconsolidation is less effective in individuals who are vulnerable to develop an anxiety disorder. By collapsing data from six previous human fear conditioning studies we tested whether trait anxiety was related to the fear-reducing effects of a pharmacological agent targeting the process of memory reconsolidation - n = 107. Testing included different phases across three consecutive days each separated by 24 h. Fear responding was measured by the eye-blink startle reflex. Disrupting the process of fear memory reconsolidation was manipulated by administering the β-adrenergic receptor antagonist propranolol HCl either before or after memory retrieval. Trait anxiety uniquely predicted the fear-reducing effects of disrupting memory reconsolidation: the higher the trait anxiety, the less fear reduction. Vulnerable individuals with the propensity to develop anxiety disorders may need higher dosages of propranolol HCl or more retrieval trials for targeting and changing fear memory. Our finding clearly demonstrates that we cannot simply translate observations from fundamental research on fear reduction in the average organism to clinical practice. PMID:24260096

Repeated Recall and PKM? Maintain Fear Memories in Juvenile Rats

ERIC Educational Resources Information Center

Oliver, Chicora F.; Kabitzke, Patricia; Serrano, Peter; Egan, Laura J.; Barr, Gordon A.; Shair, Harry N.; Wiedenmayer, Christoph

2016-01-01

We examined the neural substrates of fear memory formation and maintenance when repeated recall was used to prevent forgetting in young animals. In contrast to adult rats, juveniles failed to show contextual fear responses at 4 d post-fear conditioning. Reconsolidation sessions 3 and 6 d after conditioning restored contextual fear responses in…

Disrupting reconsolidation of fear memory in humans by a noradrenergic β-blocker.

PubMed

Kindt, Merel; Soeter, Marieke; Sevenster, Dieuwke

2014-12-18

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

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.

Flavones from Erythrina falcata are modulators of fear memory.

PubMed

de Oliveira, Daniela Rodrigues; Zamberlam, Cláudia R; Gaiardo, Renan Barreta; Rêgo, Gizelda Maia; Cerutti, Janete M; Cavalheiro, Alberto J; Cerutti, Suzete M

2014-08-05

Flavonoids, which have been identified in a variety of plants, have been demonstrated to elicit beneficial effects on memory. Some studies have reported that flavonoids derived from Erythrina plants can provide such beneficial effects on memory. The aim of this study was to identify the flavonoids present in the stem bark crude extract of Erythrina falcata (CE) and to perform a bioactivity-guided study on conditioned fear memory. The secondary metabolites of CE were identified by high performance liquid chromatography combined with a diode array detector, electrospray ionization tandem mass spectrometry (HPLC-DAD-ESI/MSn) and nuclear magnetic resonance (NMR). The buthanolic fraction (BuF) was obtained by partitioning. Subfractions from BuF (BuF1 - BuF6) and fraction flavonoidic (FfA and FfB) were obtained by flash chromatography. The BuF3 and BuF4 fractions were used for the isolation of flavonoids, which was performed using HPLC-PAD. The isolated substances were quantified by HPLC-DAD and their structures were confirmed by nuclear magnetic resonance (NMR). The activities of CE and the subfractions were monitored using a one-trial, step-down inhibitory avoidance (IA) task to identify the effects of these substances on the acquisition and extinction of conditioned fear in rats. Six subclasses of flavonoids were identified for the first time in CE. According to our behavioral data, CE, BuF, BuF3 and BuF4, the flavonoidic fractions, vitexin, isovitexin and 6-C-glycoside-diosmetin improved the acquisition of fear memory. Rats treated with BuF, BuF3 and BuF4 were particularly resistant to extinction. Nevertheless, rats treated with FfA and FfB, vitexin, isovitexin and 6-C-glycoside-diosmetin exhibited gradual reduction in conditioned fear response during the extinction retest session, which was measured at 48 to 480 h after conditioning. Our results demonstrate that vitexin, isovitexin and diosmetin-6-C-glucoside and flavonoidic fractions resulted in a significant

Prefrontocortical dopamine loss in rats delays long-term extinction of contextual conditioned fear, and reduces social interaction without affecting short-term social interaction memory.

PubMed

Fernandez Espejo, Emilio

2003-03-01

Prefrontal dopamine loss delays extinction of cued fear conditioning responses, but its role in contextual fear conditioning has not been explored. Medial prefrontal lesions also enhance social interaction in rats, but the role of prefrontal dopamine loss on social interaction memory is not known. Besides, a role for subcortical accumbal dopamine on mnesic changes after prefrontal dopamine manipulation has been proposed but not explored. The objective was to study the involvement of dopaminergic neurotransmission in the medial prefrontal cortex (mPFC) and nucleus accumbens in two mnesic tasks: contextual fear conditioning and social interaction memory. For contextual fear conditioning, short- and long-term freezing responses after an electric shock were studied, as well as extinction retention. Regarding social interaction memory, the recognition of a juvenile, a very sensitive short-term memory test, was used. Dopamine loss was carried out by injection of 6-hydroxydopamine, and postmortem catecholamine levels were analyzed by high-performance liquid chromatography. Prefrontocortical dopamine loss (>76%) led to a reactive enhancement of accumbal dopamine content (p<0.01), supporting the hypothesis that a hyperdopaminergic tone emerges in the nucleus accumbens after prefrontocortical dopamine loss. In lesioned rats, long-term extinction of contextual fear conditioning was significantly delayed and extinction retention was impaired without changes in acquisition and short-term contextual fear conditioning and, on the other hand, acquisition and short-term social interaction memory were not affected, although time spent on social interaction was significantly reduced. Added dopamine loss in the nucleus accumbens (>76%) did not alter these behavioral changes. In summary, the results of the present study indicate that the dopaminergic network in the mPFC (but not in the nucleus accumbens) coordinates the normal long-term extinction of contextual fear conditioning

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

PubMed

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

2014-11-01

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

The Hypocretin/Orexin System Mediates the Extinction of Fear Memories

PubMed Central

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

2014-01-01

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

Neural circuits and mechanisms involved in Pavlovian fear conditioning: A critical review

PubMed Central

Kim, Jeansok J.; Jung, Min Whan

2015-01-01

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

Acute Exercise Enhances the Consolidation of Fear Extinction Memory and Reduces Conditioned Fear Relapse in a Sex-Dependent Manner

ERIC Educational Resources Information Center

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

2017-01-01

Fear extinction-based exposure therapy is the most common behavioral therapy for anxiety and trauma-related disorders, but fear extinction memories are labile and fear tends to return even after successful extinction. The relapse of fear contributes to the poor long-term efficacy of exposure therapy. A single session of voluntary exercise can…

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

PubMed

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

2012-02-19

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

Cortisol effects on fear memory reconsolidation in women.

PubMed

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

2016-07-01

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

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

PubMed

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

2016-01-01

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

Modification of Fear Memory by Pharmacological and Behavioural Interventions during Reconsolidation

PubMed Central

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

2016-01-01

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

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

PubMed

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

2016-09-01

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

Post-retrieval late process contributes to persistence of reactivated fear memory.

PubMed

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

2013-05-16

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 fear memory after 7 d, but not after 2 d. In contrast, infusion of anisomycin 5- or 24-h post-retrieval was ineffective. These findings indicate that anisomycin attenuates the persistence of reactivated fear memory in a time-dependent manner. We propose that late protein synthesis is required for memory persistence after retrieval.

A peripheral immune response to remembering trauma contributes to the maintenance of fear memory in mice.

PubMed

Young, Matthew B; Howell, Leonard L; Hopkins, Lauren; Moshfegh, Cassandra; Yu, Zhe; Clubb, Lauren; Seidenberg, Jessica; Park, Jeanie; Swiercz, Adam P; Marvar, Paul J

2018-05-17

Alterations in peripheral immune markers are observed in individuals with post-traumatic stress disorder (PTSD). PTSD is characterized in part by impaired extinction of fear memory for a traumatic experience. We hypothesized that fear memory extinction is regulated by immune signaling stimulated when fear memory is retrieved. The relationship between fear memory and the peripheral immune response was tested using auditory Pavlovian fear conditioning in mice. Memory for the association was quantified by the amount of conditioned freezing exhibited in response to the conditioned stimulus (CS), extinction and time-dependent changes in circulating inflammatory cytokines. Brief extinction training with 12 CS rapidly and acutely increased circulating levels of the cytokine interleukin-6 (IL-6), downstream IL-6 signaling, other IL-6 related pro-inflammatory cytokines. Transgenic manipulations or neutralizing antibodies that inhibit IL-6 activity did not affect conditioned freezing during the acquisition of fear conditioning or extinction but significantly reduced conditioned freezing 24 h after extinction training with 12 CS. Conversely, conditioned freezing after extinction training was unchanged by IL-6 inhibition when 40 CS were used during the extinction training session. In addition to effectively diminishing conditioned freezing, extinction training with 40 CS also diminished the subsequent IL-6 response to the CS. These data demonstrate that IL-6 released following fear memory retrieval contributes to the maintenance of that fear memory and that this effect is extinction dependent. These findings extend the current understanding for the role of the immune system in PTSD and suggest that IL-6 and other IL-6 related pro-inflammatory cytokines may contribute to the persistence of fear memory in PTSD where fear memory extinction is impaired. Copyright © 2018 Elsevier Ltd. All rights reserved.

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

PubMed Central

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

2014-01-01

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

The Role Of Basal Forebrain Cholinergic Neurons In Fear and Extinction Memory

PubMed Central

Knox, Dayan

2016-01-01

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

Extinction after fear memory reactivation fails to eliminate renewal in rats.

PubMed

Goode, Travis D; Holloway-Erickson, Crystal M; Maren, Stephen

2017-07-01

Retrieving fear memories just prior to extinction has been reported to effectively erase fear memories and prevent fear relapse. The current study examined whether the type of retrieval procedure influences the ability of extinction to impair fear renewal, a form of relapse in which responding to a conditional stimulus (CS) returns outside of the extinction context. Rats first underwent Pavlovian fear conditioning with an auditory CS and footshock unconditional stimulus (US); freezing behavior served as the index of conditioned fear. Twenty-four hours later, the rats underwent a retrieval-extinction procedure. Specifically, 1h prior to extinction (45 CS-alone trials; 44 for rats receiving a CS reminder), fear memory was retrieved by either a single exposure to the CS alone, the US alone, a CS paired with the US, or exposure to the conditioning context itself. Over the next few days, conditional freezing to the extinguished CS was tested in the extinction and conditioning context in that order (i.e., an ABBA design). In the extinction context, rats that received a CS+US trial before extinction exhibited higher levels of conditional freezing than animals in all other groups, which did not differ from one another. In the renewal context, all groups showed renewal, and none of the reactivation procedures reduced renewal relative to a control group that did not receive a reactivation procedure prior to extinction. These data suggest retrieval-extinction procedures may have limited efficacy in preventing fear renewal. Copyright © 2017 Elsevier Inc. All rights reserved.

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

PubMed

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

2017-07-01

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

Brain sites involved in fear memory reconsolidation and extinction of rodents.

PubMed

Baldi, Elisabetta; Bucherelli, Corrado

2015-06-01

Fear memory is a motivational system essential for organisms survival having a central role in organization of defensive behaviors to threat. In the last years there has been a growing interest on conditioned fear memory reconsolidation and extinction, two specific phases of memorization process, both induced by memory retrieval. Understanding the mechanisms underlying these two mnemonic processes may allow to work out therapeutic interventions for treatment of human fear and anxiety disorders, such as specific phobias and post-traumatic stress disorder. Based on the use of one-trial conditioning paradigms, which allow to follow the evolution of a mnemonic trace in its various phases, the present paper has attempted to reorganize the current literature relative to the rodents highlighting both the role of several brain structures in conditioned fear memory reconsolidation and extinction and the selective cellular processes involved. A crucial role seems to be play by medial prefrontal cortex, in particular by prelimbic and infralimbic cortices, and by distinct connections between them and the amygdala, hippocampus and entorhinal cortex. Copyright © 2015 Elsevier Ltd. All rights reserved.

Orexin A Differentially Influences the Extinction Retention of Recent and Remote Fear Memory.

PubMed

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

2018-01-01

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

Orexin A Differentially Influences the Extinction Retention of Recent and Remote Fear Memory

PubMed Central

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

2018-01-01

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

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. Copyright © 2016 Elsevier Inc. All rights reserved.

Selective synaptic remodeling of amygdalocortical connections associated with fear memory.

PubMed

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

2016-10-01

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

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

PubMed

Sevenster, Dieuwke; Beckers, Tom; Kindt, Merel

2012-03-01

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

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

PubMed

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

2009-12-28

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

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

PubMed Central

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

2011-01-01

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

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

PubMed

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

2011-01-01

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

A Comparison of Behavioral and Pharmacological Interventions to Attenuate Reactivated Fear Memories

ERIC Educational Resources Information Center

Monti, Roque I. Ferrer; Alfei, Joaquin M.; Mugnaini, Matias; Bueno, Adrian M.; Beckers, Tom; Urcelay, Gonzalo P.; Molina, Victor A.

2017-01-01

Two experiments using rats in a contextual fear memory preparation compared two approaches to reduce conditioned fear: (1) pharmacological reconsolidation blockade and (2) reactivation-plus-extinction training. In Experiment 1, we explored different combinations of reactivation-plus-extinction parameters to reduce conditioned fear and attenuate…

Selective early-acquired fear memories undergo temporary suppression during adolescence

PubMed Central

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

2011-01-01

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

Arp2/3 and VASP Are Essential for Fear Memory Formation in Lateral Amygdala.

PubMed

Basu, Sreetama; Kustanovich, Irina; Lamprecht, Raphael

2016-01-01

The actin cytoskeleton is involved in key neuronal functions such as synaptic transmission and morphogenesis. However, the roles and regulation of actin cytoskeleton in memory formation remain to be clarified. In this study, we unveil the mechanism whereby actin cytoskeleton is regulated to form memory by exploring the roles of the major actin-regulatory proteins Arp2/3, VASP, and formins in long-term memory formation. Inhibition of Arp2/3, involved in actin filament branching and neuronal morphogenesis, in lateral amygdala (LA) with the specific inhibitor CK-666 during fear conditioning impaired long-term, but not short-term, fear memory. The inactive isomer CK-689 had no effect on memory formation. We observed that Arp2/3 is colocalized with the actin-regulatory protein profilin in LA neurons of fear-conditioned rats. VASP binding to profilin is needed for profilin-mediated stabilization of actin cytoskeleton and dendritic spine morphology. Microinjection of poly-proline peptide [G(GP 5 ) 3 ] into LA, to interfere with VASP binding to profilin, impaired long-term but not short-term fear memory formation. Control peptide [G(GA 5 ) 3 ] had no effect. Inhibiting formins, which regulate linear actin elongation, in LA during fear conditioning by microinjecting the formin-specific inhibitor SMIFH2 into LA had no effect on long-term fear memory formation. We conclude that Arp2/3 and VASP, through the profilin binding site, are essential for the formation of long-term fear memory in LA and propose a model whereby these proteins subserve cellular events, leading to memory consolidation.

Xenon Impairs Reconsolidation of Fear Memories in a Rat Model of Post-Traumatic Stress Disorder (PTSD)

PubMed Central

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

Protein synthesis in the basolateral amygdala complex is required for consolidation of a first-order fear memory, but not for consolidation of a higher-order fear memory.

PubMed

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

2018-04-12

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

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

Divergent effects of brain interleukin-1ß in mediating fever, lethargy, anorexia and conditioned fear memory.

PubMed

Baartman, Tamzyn L; Swanepoel, Tanya; Barrientos, Ruth M; Laburn, Helen P; Mitchell, Duncan; Harden, Lois M

2017-05-01

The influence of brain interleukin-1 (IL-1ß) on memory processes includes both detrimental and beneficial effects. To further explore the dynamics of brain IL-1ß in mediating learning and memory during acute sickness, we injected species-homologous rat IL-1ß (100ng/5μl) or vehicle (0.1% bovine serum albumin, 5μl) directly into the cisterna magna (i.c.m.) of male Sprague-Dawley rats. We measured, in parallel, body temperature, food intake, body mass, cage activity, as well as learning and memory using contextual fear conditioning. To investigate the effects of IL-1ß on learning and memory processes we used: (1) a retrograde experiment that involved injecting rats i.c.m. with IL-1ß immediately after training in the novel context, and (2) an anterograde experiment that involved injecting rats i.c.m. with IL-1ß two hours before training in the novel context. In addition, hypothalamic and hippocampal concentrations of IL-1β were measured at several time points following injection. Administration of IL-1ß induced fever, lethargy and anorexia for∼two-to-three days and increased the concentration of IL-1ß in the hippocampus and hypothalamus for at least eight hours. Training in the context immediately before IL-1ß administration (retrograde experiment), did not impair contextual and auditory fear memory. However, when training in the context occurred concurrently with elevated hippocampal IL-1ß levels, two hours after IL-1ß administration (anterograde experiment), contextual, but not auditory, fear memory was impaired. Our results show that there are instances where memory consolidation can occur concurrently with elevated levels of IL-1ß in the hippocampus, fever, anorexia and lethargy during acute short-term sickness. Copyright © 2017 Elsevier B.V. All rights reserved.

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. Copyright © 2015. Published by Elsevier B.V.

Mechanisms of Pavlovian fear conditioning: has the engram been located?

PubMed

Paré, Denis

2002-09-01

Uncertainty persists as to whether the amygdala is a crucial site of plasticity for classically conditioned fear or merely a sensory relay to structures generating fear responses. A recent Nature study suggests that associative synaptic changes take place in neurons of the amygdala during fear conditioning, and that these changes require dopamine-mediated modulation. Nevertheless, these findings do not prove that the amygdala is a sufficient site of plasticity for fear memory.

Isoflurane causes anterograde but not retrograde amnesia for pavlovian fear conditioning.

PubMed

Dutton, Robert C; Maurer, Anya J; Sonner, James M; Fanselow, Michael S; Laster, Michael J; Eger, Edmond I

2002-05-01

Production of retrograde amnesia by anesthetics would indicate that these drugs can disrupt mechanisms that stabilize memory. Such disruption would allow suppression of memory of previous untoward events. The authors examined whether isoflurane provides retrograde amnesia for classic (Pavlovian) fear conditioning. Rats were trained to fear tone by applying three (three-trial) or one (one-trial) tone-shock pairs while breathing various constant concentrations of isoflurane. Immediately after training, isoflurane administration was either discontinued, maintained unchanged, or rapidly increased to 1.0 minimum alveolar concentration for 1 h longer. Groups of rats were similarly trained to fear context while breathing isoflurane by applying shocks (without tones) in a distinctive environment. The next day, memory for the conditioned stimuli was determined by presenting the tone or context (without shock) and measuring the proportion of time each rat froze (appeared immobile). For each conditioning procedure, the effects of the three posttraining isoflurane treatments were compared. Rapid increases in posttraining isoflurane administration did not suppress conditioned fear for any of the training procedures. In contrast, isoflurane administration during conditioning dose-dependently suppressed conditioning (P < 0.05). Training to tone was more resistant to the effects of isoflurane than training to context (P < 0.05), and the three-trial learning procedure was more was more resistant than the one-trial procedure (P < 0.05). Isoflurane provided intense dose-dependent anterograde but not retrograde amnesia for classic fear conditioning. Isoflurane appears to disrupt memory processes that occur at or within a few minutes of the conditioning procedure.

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.…

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

PubMed Central

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

2016-01-01

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

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.

Fear Memory Recall Potentiates Opiate Reward Sensitivity through Dissociable Dopamine D1 versus D4 Receptor-Dependent Memory Mechanisms in the Prefrontal Cortex.

PubMed

Jing Li, Jing; Szkudlarek, Hanna; Renard, Justine; Hudson, Roger; Rushlow, Walter; Laviolette, Steven R

2018-05-09

Disturbances in prefrontal cortical (PFC) dopamine (DA) transmission are well established features of psychiatric disorders involving pathological memory processing, such as post-traumatic stress disorder and opioid addiction. Transmission through PFC DA D4 receptors (D4Rs) has been shown to potentiate the emotional salience of normally nonsalient emotional memories, whereas transmission through PFC DA D1 receptors (D1Rs) has been demonstrated to selectively block recall of reward- or aversion-related associative memories. In the present study, using a combination of fear conditioning and opiate reward conditioning in male rats, we examined the role of PFC D4/D1R signaling during the processing of fear-related memory acquisition and recall and subsequent sensitivity to opiate reward memory formation. We report that PFC D4R activation potentiates the salience of normally subthreshold fear conditioning memory cues and simultaneously potentiates the rewarding effects of systemic or intra-ventral tegmental area (VTA) morphine conditioning cues. In contrast, blocking the recall of salient fear memories with intra-PFC D1R activation, blocks the ability of fear memory recall to potentiate systemic or intra-VTA morphine place preference. These effects were dependent upon dissociable PFC phosphorylation states involving calcium-calmodulin-kinase II or extracellular signal-related kinase 1-2, following intra-PFC D4 or D1R activation, respectively. Together, these findings reveal new insights into how aberrant PFC DAergic transmission and associated downstream molecular signaling pathways may modulate fear-related emotional memory processing and concomitantly increase opioid addiction vulnerability. SIGNIFICANCE STATEMENT Post-traumatic stress disorder is highly comorbid with addiction. In this study, we use a translational model of fear memory conditioning to examine how transmission through dopamine D1 or D4 receptors, in the prefrontal cortex (PFC), may differentially

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

PubMed

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

2017-05-01

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

Dopamine D1-like receptor signalling in the hippocampus and amygdala modulates the acquisition of contextual fear conditioning.

PubMed

Heath, Florence C; Jurkus, Regimantas; Bast, Tobias; Pezze, Marie A; Lee, Jonathan L C; Voigt, J Peter; Stevenson, Carl W

2015-07-01

Dopamine D1-like receptor signalling is involved in contextual fear conditioning, but the brain regions involved and its role in other contextual fear memory processes remain unclear. The objective of this study was to investigate (1) the effects of SCH 23390, a dopamine D1/D5 receptor antagonist, on contextual fear memory encoding, retrieval and reconsolidation, and (2) if the effects of SCH 23390 on conditioning involve the dorsal hippocampus (DH) and/or basolateral amygdala (BLA). Rats were used to examine the effects of systemically administering SCH 23390 on the acquisition, consolidation, retrieval and reconsolidation of contextual fear memory, and on locomotor activity and shock sensitivity. We also determined the effects of MK-801, an NMDA receptor antagonist, on contextual fear memory reconsolidation. The effects of infusing SCH 23390 locally into DH or BLA on contextual fear conditioning and locomotor activity were also examined. Systemic administration of SCH 23390 impaired contextual fear conditioning but had no effects on fear memory consolidation, retrieval or reconsolidation. MK-801 was found to impair reconsolidation, suggesting that the behavioural parameters used allowed for the pharmacological disruption of memory reconsolidation. The effects of SCH 23390 on conditioning were unlikely the result of any lasting drug effects on locomotor activity at memory test or any acute drug effects on shock sensitivity during conditioning. SCH 23390 infused into either DH or BLA impaired contextual fear conditioning and decreased locomotor activity. These findings suggest that dopamine D1-like receptor signalling in DH and BLA contributes to the acquisition of contextual fear memory.

Muscarinic receptors in amygdala control trace fear conditioning.

PubMed

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

2012-01-01

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

PI3-kinase cascade has a differential role in acquisition and extinction of conditioned fear memory in juvenile and adult rats.

PubMed

Slouzkey, Ilana; Maroun, Mouna

2016-12-01

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

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

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

PubMed Central

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

2012-01-01

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

Chronic Vortioxetine Treatment Reduces Exaggerated Expression of Conditioned Fear Memory and Restores Active Coping Behavior in Chronically Stressed Rats.

PubMed

Hatherall, Lauren; Sánchez, Connie; Morilak, David A

2017-04-01

Stress is a risk factor for depression and anxiety disorders, disrupting neuronal processes leading to exaggerated fear and compromised coping behaviors. Current antidepressants are only partially effective. Vortioxetine, a novel multimodal antidepressant, is a serotonin transporter inhibitor; 5-HT3, 5-HT7, and 5-HT1D receptor antagonist; 5-HT1B partial agonist; and 5-HT1A agonist. We have shown that chronic dietary vortioxetine administration reversed stress-induced deficits in cognitive flexibility. In the present studies, we investigated the generality of vortioxetine's effects on other stress-related behavioral changes after different types of chronic stress. In experiment 1, rats were fear-conditioned by pairing a tone with footshock, then exposed to chronic plus acute prolonged stress. In experiment 2, rats were exposed to chronic unpredictable stress. In both experiments, beginning on day 4 of chronic stress, vortioxetine was given in the diet (24 mg/kg/d). In experiment 1, effects of vortioxetine were tested on stress-induced changes in retention and extinction of cue-conditioned fear, and in experiment 2, on coping behavior on the shock probe defensive burying test after chronic stress. Chronic stress exaggerated the expression of conditioned fear memory. Vortioxetine restored fear memory to control levels and rendered extinction in stressed rats comparable with that in controls. In experiment 2, chronic unpredictable stress caused a shift from active to passive coping behavior, and vortioxetine restored active coping. Vortioxetine reduced exaggerated expression of conditioned fear and restored adaptive coping behavior following 2 different types of chronic stress, adding to the evidence of its therapeutic potential in the management of depression and anxiety disorders. © The Author 2016. Published by Oxford University Press on behalf of CINP.

Corticosterone facilitates extinction of fear memory in BALB/c mice but strengthens cue related fear in C57BL/6 mice.

PubMed

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

2009-04-01

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

Disruption of medial septum and diagonal bands of Broca cholinergic projections to the ventral hippocampus disrupt auditory fear memory.

PubMed

Staib, Jennifer M; Della Valle, Rebecca; Knox, Dayan K

2018-07-01

In classical fear conditioning, a neutral conditioned stimulus (CS) is paired with an aversive unconditioned stimulus (US), which leads to a fear memory. If the CS is repeatedly presented without the US after fear conditioning, the formation of an extinction memory occurs, which inhibits fear memory expression. A previous study has demonstrated that selective cholinergic lesions in the medial septum and vertical limb of the diagonal bands of Broca (MS/vDBB) prior to fear and extinction learning disrupt contextual fear memory discrimination and acquisition of extinction memory. MS/vDBB cholinergic neurons project to a number of substrates that are critical for fear and extinction memory. However, it is currently unknown which of these efferent projections are critical for contextual fear memory discrimination and extinction memory. To address this, we induced cholinergic lesions in efferent targets of MS/vDBB cholinergic neurons. These included the dorsal hippocampus (dHipp), ventral hippocampus (vHipp), medial prefrontal cortex (mPFC), and in the mPFC and dHipp combined. None of these lesion groups exhibited deficits in contextual fear memory discrimination or extinction memory. However, vHipp cholinergic lesions disrupted auditory fear memory. Because MS/vDBB cholinergic neurons are the sole source of acetylcholine in the vHipp, these results suggest that MS/vDBB cholinergic input to the vHipp is critical for auditory fear memory. Taken together with previous findings, the results of this study suggest that MS/vDBB cholinergic neurons are critical for fear and extinction memory, though further research is needed to elucidate the role of MS/vDBB cholinergic neurons in these types of emotional memory. Copyright © 2018 Elsevier Inc. All rights reserved.

Mapping and Deciphering Neural Codes of NMDA Receptor-Dependent Fear Memory Engrams in the Hippocampus

PubMed Central

Tsien, Joe Z.

2013-01-01

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

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). Copyright © 2015 Elsevier Inc. All rights reserved.

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

PubMed

Lucas, Elizabeth K; Clem, Roger L

2017-12-02

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

Acute Ethanol Has Biphasic Effects on Short- and Long-Term Memory in Both Foreground and Background Contextual Fear Conditioning in C57BL/6 Mice

PubMed Central

Gulick, Danielle; Gould, Thomas J.

2009-01-01

Background Ethanol is a frequently abused, addictive drug that impairs cognitive function. Ethanol may disrupt cognitive processes by altering attention, short-term memory, and/ or long-term memory. Interestingly, some research suggests that ethanol may enhance cognitive processes at lower doses. The current research examined the dose-dependent effects of ethanol on contextual and cued fear conditioning. In addition, the present studies assessed the importance of stimulus salience in the effects of ethanol and directly compared the effects of ethanol on short-term and long-term memory. Methods This study employed both foreground and background fear conditioning, which differ in the salience of contextual stimuli, and tested conditioning at 4 hours, 24 hours, and 1 week in order to assess the effects of ethanol on short-term and long-term memory. Foreground conditioning consisted of 2 presentations of a foot shock unconditioned stimulus (US) (2 seconds, 0.57 mA). Background conditioning consisted of 2 auditory conditioned stimulus (30 seconds, 85 dB white noise)–foot shock (US; 2 seconds, 0.57 mA) pairings. Results For both foreground and background conditioning, ethanol enhanced short-term and long-term memory for contextual and cued conditioning at a low dose (0.25 g/kg) and impaired short-term and long-term memory for contextual and cued conditioning at a high dose (1.0 g/kg). Conclusions These results suggest that ethanol has long-lasting, biphasic effects on short-term and long-term memory for contextual and cued conditioning. Furthermore, the effects of ethanol on contextual fear conditioning are independent of the salience of the context. PMID:17760787

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

PubMed

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

2013-07-15

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

Sexual behavior modulates contextual fear memory through dopamine D1/D5 receptors.

PubMed

Bai, Hua-Yi; Cao, Jun; Liu, Na; Xu, Lin; Luo, Jian-Hong

2009-03-01

Traumatic events always lead to aversive emotional memory, i.e., fear memory. In contrast, positive events in daily life such as sex experiences seem to reduce aversive memory after aversive events. Thus, we hypothesized that post-traumatic pleasurable experiences, especially instinctive behaviors such as sex, might modulate traumatic memory through a memory competition mechanism. Here, we first report that male rats persistently expressed much lower fear responses when exposed to females, but not when exposed to males, for 24 h immediately after contextual fear conditioning. Remarkably, this effect of sexual behavior was blocked by either systemic or intrahippocampal injection of the dopamine D1/D5 receptor antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH23390) and was mimicked by systemic but not intrahippocampal injection of the D1/D5 receptor agonist R(+)-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol hydrochloride (SKF39393). Furthermore, as a candidate mechanism underlying contextual fear memory, the impaired induction of hippocampal long-term potentiation (LTP) elicited by conditioned fear was rescued in male rats immediately exposed to female but not male rats for 24 h. Systemic injection of the dopamine D1/D5 receptor antagonist SCH23390 or agonist SKF38393 prevented or mimicked the effect of sexual behavior on the impaired induction of hippocampal LTP. Thus, our finding suggests that dopaminergic functions may, at least partially, govern competition between contextual fear and enjoyable memories through the modulation of hippocampal LTP.

Contextual Information Drives the Reconsolidation-Dependent Updating of Retrieved Fear Memories

PubMed Central

Jarome, Timothy J; Ferrara, Nicole C; Kwapis, Janine L; Helmstetter, Fred J

2015-01-01

Stored memories enter a temporary state of vulnerability following retrieval known as ‘reconsolidation', a process that can allow memories to be modified to incorporate new information. Although reconsolidation has become an attractive target for treatment of memories related to traumatic past experiences, we still do not know what new information triggers the updating of retrieved memories. Here, we used biochemical markers of synaptic plasticity in combination with a novel behavioral procedure to determine what was learned during memory reconsolidation under normal retrieval conditions. We eliminated new information during retrieval by manipulating animals' training experience and measured changes in proteasome activity and GluR2 expression in the amygdala, two established markers of fear memory lability and reconsolidation. We found that eliminating new contextual information during the retrieval of memories for predictable and unpredictable fear associations prevented changes in proteasome activity and glutamate receptor expression in the amygdala, indicating that this new information drives the reconsolidation of both predictable and unpredictable fear associations on retrieval. Consistent with this, eliminating new contextual information prior to retrieval prevented the memory-impairing effects of protein synthesis inhibitors following retrieval. These results indicate that under normal conditions, reconsolidation updates memories by incorporating new contextual information into the memory trace. Collectively, these results suggest that controlling contextual information present during retrieval may be a useful strategy for improving reconsolidation-based treatments of traumatic memories associated with anxiety disorders such as post-traumatic stress disorder. PMID:26062788

Short-term inhibition of 11β-hydroxysteroid dehydrogenase type 1 reversibly improves spatial memory but persistently impairs contextual fear memory in aged mice.

PubMed

Wheelan, Nicola; Webster, Scott P; Kenyon, Christopher J; Caughey, Sarah; Walker, Brian R; Holmes, Megan C; Seckl, Jonathan R; Yau, Joyce L W

2015-04-01

High glucocorticoid levels induced by stress enhance the memory of fearful events and may contribute to the development of anxiety and posttraumatic stress disorder. In contrast, elevated glucocorticoids associated with ageing impair spatial memory. We have previously shown that pharmacological inhibition of the intracellular glucocorticoid-amplifying enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) improves spatial memory in aged mice. However, it is not known whether inhibition of 11β-HSD1 will have any beneficial effects on contextual fear memories in aged mice. Here, we examined the effects of UE2316, a selective 11β-HSD1 inhibitor which accesses the brain, on both spatial and contextual fear memories in aged mice using a vehicle-controlled crossover study design. Short-term UE2316 treatment improved spatial memory in aged mice, an effect which was reversed when UE2316 was substituted with vehicle. In contrast, contextual fear memory induced by foot-shock conditioning was significantly reduced by UE2316 in a non-reversible manner. When the order of treatment was reversed following extinction of the original fear memory, and a second foot-shock conditioning was given in a novel context, UE2316 treated aged mice (previously on vehicle) now showed increased fear memory compared to vehicle-treated aged mice (previously on UE2316). Renewal of the original extinguished fear memory triggered by exposure to a new environmental context may explain these effects. Thus 11β-HSD1 inhibition reverses spatial memory impairments with ageing while reducing the strength and persistence of new contextual fear memories. Potentially this could help prevent anxiety-related disorders in vulnerable elderly individuals. Copyright © 2014 Elsevier Ltd. All rights reserved.

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

PubMed

Kim, Woong Bin; Cho, Jun-Hyeong

2017-08-30

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

Cocaine and Pavlovian fear conditioning: dose-effect analysis.

PubMed

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

2007-01-25

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

On the transition from reconsolidation to extinction of contextual fear memories

PubMed Central

Flavell, Charlotte R.; Lee, Jonathan L.C.

2017-01-01

Retrieval of an associative memory can lead to different phenomena. Brief reexposure sessions tend to trigger reconsolidation, whereas more extended ones trigger extinction. In appetitive and fear cued Pavlovian memories, an intermediate “null point” period has been observed where neither process seems to be engaged. Here we investigated whether this phenomenon extends to contextual fear memory. Adult rats were subjected to a contextual fear conditioning paradigm, reexposed to the context 2 d later for 3, 5, 10, 20, or 30 min, with immediate injections of MK-801 or saline following reexposure, and tested on the following day. We observed a significant effect of MK-801 with the 3- and 30-min sessions, impairing reconsolidation and extinction, respectively. However, it did not have significant effects with 5-, 10-, or 20-min sessions, even though freezing decreased from reexposure to test. Further analyses indicated that this is not likely to be due to a variable transition point at the population level. In conclusion, the results show that in contextual fear memories there is a genuine “null point” between the parameters that induce reconsolidation and extinction, as defined by the effects of MK-801, although NMDA receptor-independent decreases in freezing can still occur in these conditions. PMID:28814464

HDAC7 Ubiquitination by the E3 Ligase CBX4 Is Involved in Contextual Fear Conditioning Memory Formation.

PubMed

Jing, Xu; Sui, Wen-Hai; Wang, Shuai; Xu, Xu-Feng; Yuan, Rong-Rong; Chen, Xiao-Rong; Ma, Hui-Xian; Zhu, Ying-Xiao; Sun, Jin-Kai; Yi, Fan; Chen, Zhe-Yu; Wang, Yue

2017-04-05

Histone acetylation, an epigenetic modification, plays an important role in long-term memory formation. Recently, histone deacetylase (HDAC) inhibitors were demonstrated to promote memory formation, which raises the intriguing possibility that they may be used to rescue memory deficits. However, additional research is necessary to clarify the roles of individual HDACs in memory. In this study, we demonstrated that HDAC7, within the dorsal hippocampus of C57BL6J mice, had a late and persistent decrease after contextual fear conditioning (CFC) training (4-24 h), which was involved in long-term CFC memory formation. We also showed that HDAC7 decreased via ubiquitin-dependent degradation. CBX4 was one of the HDAC7 E3 ligases involved in this process. Nur77, as one of the target genes of HDAC7, increased 6-24 h after CFC training and, accordingly, modulated the formation of CFC memory. Finally, HDAC7 was involved in the formation of other hippocampal-dependent memories, including the Morris water maze and object location test. The current findings facilitate an understanding of the molecular and cellular mechanisms of HDAC7 in the regulation of hippocampal-dependent memory. SIGNIFICANCE STATEMENT The current findings demonstrated the effects of histone deacetylase 7 (HDAC7) on hippocampal-dependent memories. Moreover, we determined the mechanism of decreased HDAC7 in contextual fear conditioning (CFC) through ubiquitin-dependent protein degradation. We also verified that CBX4 was one of the HDAC7 E3 ligases. Finally, we demonstrated that Nur77, as one of the important targets for HDAC7, was involved in CFC memory formation. All of these proteins, including HDAC7, CBX4, and Nur77, could be potential therapeutic targets for preventing memory deficits in aging and neurological diseases. Copyright © 2017 the authors 0270-6474/17/373848-16$15.00/0.

Central Ghrelin Resistance Permits the Overconsolidation of Fear Memory.

PubMed

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

2017-06-15

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

Alpha1-adrenergic receptor blockade in the VTA modulates fear memories and stress responses.

PubMed

Solecki, Wojciech B; Szklarczyk, Klaudia; Klasa, Adam; Pradel, Kamil; Dobrzański, Grzegorz; Przewłocki, Ryszard

2017-08-01

Activity of the ventral tegmental area (VTA) and its terminals has been implicated in the Pavlovian associative learning of both stressful and rewarding stimuli. However, the role of the VTA noradrenergic signaling in fear responses remains unclear. We aimed to examine how alpha 1 -adrenergic receptor (α 1 -AR) signaling in the VTA affects conditioned fear. The role of α 1 -AR was assessed using the micro-infusions into the VTA of the selective antagonists (0.1-1µg/0.5µl prazosin and 1µg/0.5µl terazosin) in acquisition and expression of fear memory. In addition, we performed control experiments with α 1 -AR blockade in the mammillary bodies (MB) - a brain region with α 1 -AR expression adjacent to the VTA. Intra-VTA but not intra-MB α 1 -AR blockade prevented formation and retrieval of fear memories. Importantly, local administration of α 1 -AR antagonists did not influence footshock sensitivity, locomotion or anxiety-like behaviors. Similarly, α 1 -AR blockade in the VTA had no effects on negative affect measured as number of 22kHz ultrasonic vocalizations during fear conditioning training. We propose that noradrenergic signaling in the VTA via α 1 -AR regulates formation and retrieval of fear memories but not other behavioral responses to stressful environmental stimuli. It enhances the encoding of environmental stimuli by the VTA to form and retrieve conditioned fear memories and to predict future behavioral outcomes. Our results provide novel insight into the role of the VTA α 1 -AR signaling in the regulation of stress responsiveness and fear memory. Copyright © 2017 Elsevier B.V. and ECNP. All rights reserved.

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

PubMed

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

2015-05-01

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

Fear memory consolidation in sleep requires protein kinase A.

PubMed

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

2018-05-01

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

Circadian waveform bifurcation, but not phase-shifting, leaves cued fear memory intact.

PubMed

Harrison, E M; Carmack, S A; Block, C L; Sun, J; Anagnostaras, S G; Gorman, M R

2017-02-01

In mammals, memory acquisition and retrieval can be affected by time of day, as well as by manipulations of the light/dark cycle. Under bifurcation, a manipulation of circadian waveform, two subjective days and nights are experimentally induced in rodents. We examined the effect of bifurcation on Pavlovian fear conditioning, a prominent model of learning and memory. Here we demonstrate that bifurcation of the circadian waveform produces a small deficit in acquisition, but not on retrieval of fear memory. In contrast, repeated phase-shifting in a simulated jet-lag protocol impairs retrieval of memory for cued fear. The results have implications for those attempting to adjust to shift-work or other challenging schedules. Copyright © 2016 Elsevier Inc. All rights reserved.

Combination of chronic stress and ovariectomy causes conditioned fear memory deficits and hippocampal cholinergic neuronal loss in mice.

PubMed

Takuma, K; Mizoguchi, H; Funatsu, Y; Hoshina, Y; Himeno, Y; Fukuzaki, E; Kitahara, Y; Arai, S; Ibi, D; Kamei, H; Matsuda, T; Koike, K; Inoue, M; Nagai, T; Yamada, K

2012-04-05

We have recently found that the combination of ovariectomy (OVX) and chronic restraint stress (CS) causes hippocampal pyramidal cell loss and cognitive dysfunction in female rats and that estrogen replacement prevents the OVX/CS-induced morphological and behavioral changes. In this study, to clarify the mechanisms underlying the OVX/CS-mediated memory impairment further, we examined the roles of cholinergic systems in the OVX/CS-induced memory impairment in mice. Female Slc:ICR strain mice were randomly divided into two groups: OVX and sham-operated groups. Two weeks after the operation, the mice of each group were further assigned to CS (6 h/day) or non-stress group. Following the 3-week-stress period, all mice were subjected to contextual fear conditioning, and context- and tone-dependent memory tests were conducted 1 or 24 h after the conditioning. Overburden with 3 weeks of CS from 2 weeks after OVX impaired context- and tone-dependent freezing and the OVX/CS caused significant Nissl-stained neuron-like cell loss in the hippocampal CA3 region, although OVX and CS alone did not cause such behavioral and histological changes. Replacement of 17β-estradiol for 5 weeks after OVX suppressed OVX/CS-induced memory impairment and hippocampal Nissl-positive cell loss. Furthermore, the OVX/CS mice exhibited a significant decrease in choline acetyltransferase in the hippocampus compared with other groups. The cholinesterase inhibitors donepezil and galantamine ameliorated OVX/CS-induced memory impairment. These data suggest that cholinergic dysfunction may be involved in the OVX/CS-induced conditioned fear memory impairment. Overall, our findings suggest that the OVX/CS mouse model is useful to study the mechanisms underlying estrogen loss-induced memory deficits. Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.

Fear conditioning selectively disrupts noradrenergic facilitation of GABAergic inhibition in the basolateral amygdala.

PubMed

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

2017-02-01

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

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

PubMed Central

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

2016-01-01

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

Short-term inhibition of 11β-hydroxysteroid dehydrogenase type 1 reversibly improves spatial memory but persistently impairs contextual fear memory in aged mice

PubMed Central

Wheelan, Nicola; Webster, Scott P.; Kenyon, Christopher J.; Caughey, Sarah; Walker, Brian R.; Holmes, Megan C.; Seckl, Jonathan R.; Yau, Joyce L.W.

2015-01-01

High glucocorticoid levels induced by stress enhance the memory of fearful events and may contribute to the development of anxiety and posttraumatic stress disorder. In contrast, elevated glucocorticoids associated with ageing impair spatial memory. We have previously shown that pharmacological inhibition of the intracellular glucocorticoid-amplifying enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) improves spatial memory in aged mice. However, it is not known whether inhibition of 11β-HSD1 will have any beneficial effects on contextual fear memories in aged mice. Here, we examined the effects of UE2316, a selective 11β-HSD1 inhibitor which accesses the brain, on both spatial and contextual fear memories in aged mice using a vehicle-controlled crossover study design. Short-term UE2316 treatment improved spatial memory in aged mice, an effect which was reversed when UE2316 was substituted with vehicle. In contrast, contextual fear memory induced by foot-shock conditioning was significantly reduced by UE2316 in a non-reversible manner. When the order of treatment was reversed following extinction of the original fear memory, and a second foot-shock conditioning was given in a novel context, UE2316 treated aged mice (previously on vehicle) now showed increased fear memory compared to vehicle-treated aged mice (previously on UE2316). Renewal of the original extinguished fear memory triggered by exposure to a new environmental context may explain these effects. Thus 11β-HSD1 inhibition reverses spatial memory impairments with ageing while reducing the strength and persistence of new contextual fear memories. Potentially this could help prevent anxiety-related disorders in vulnerable elderly individuals. PMID:25497454

Fear Conditioning Effects on Sensitivity to Drug Reward

DTIC Science & Technology

2010-06-01

lasting potentiation of cocaine seeking after withdrawal. J Neurosci. 24(7): 1604-11. Martinowich K, Hattori D, Wu H, Fouse S, He F, Hu Y, Fan G...the CS has activated the memory trace. At this time point, the treatment can potentially modify the memory trace directly and alter the CS-CR bond...organism to anticipate and prepare for potentially dangerous conditions (Maren, 2005). Fear conditioning is one of the central features of

Exposure to a fearful context during periods of memory plasticity impairs extinction via hyperactivation of frontal-amygdalar circuits

PubMed Central

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

2013-01-01

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

Hippocampal neurogenesis enhancers promote forgetting of remote fear memory after hippocampal reactivation by retrieval

PubMed Central

Ishikawa, Rie; Fukushima, Hotaka; Frankland, Paul W; Kida, Satoshi

2016-01-01

Forgetting of recent fear memory is promoted by treatment with memantine (MEM), which increases hippocampal neurogenesis. The approaches for treatment of post-traumatic stress disorder (PTSD) using rodent models have focused on the extinction and reconsolidation of recent, but not remote, memories. Here we show that, following prolonged re-exposure to the conditioning context, enhancers of hippocampal neurogenesis, including MEM, promote forgetting of remote contextual fear memory. However, these interventions are ineffective following shorter re-exposures. Importantly, we find that long, but not short re-exposures activate gene expression in the hippocampus and induce hippocampus-dependent reconsolidation of remote contextual fear memory. Furthermore, remote memory retrieval becomes hippocampus-dependent after the long-time recall, suggesting that remote fear memory returns to a hippocampus dependent state after the long-time recall, thereby allowing enhanced forgetting by increased hippocampal neurogenesis. Forgetting of traumatic memory may contribute to the development of PTSD treatment. DOI: http://dx.doi.org/10.7554/eLife.17464.001 PMID:27669409

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

PubMed Central

Ferrer Monti, Roque I.; Giachero, Marcelo; Alfei, Joaquín M.; Bueno, Adrián M.; Cuadra, Gabriel

2016-01-01

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

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

Propranolol–induced Impairment of Contextual Fear Memory Reconsolidation in Rats: A similar Effect on Weak and Strong Recent and Remote Memories

PubMed Central

Taherian, Fatemeh; Vafaei, Abbas Ali; Vaezi, Gholam Hassan; Eskandarian, Sharaf; Kashef, Adel; Rashidy-Pour, Ali

2014-01-01

Introduction Previous studies have demonstrated that the β-adrenergic receptor antagonist propranolol impairs fear memory reconsolidation in experimental animals. There are experimental parameters such as the age and the strength of memory that can interact with pharmacological manipulations of memory reconsolidation. In this study, we investigated the ability of the age and the strength of memory to influence the disrupting effects of propranolol on fear memory reconsolidation in rats. Methods The rats were trained in a contextual fear conditioning using two (weak training) or five (strong training) footshocks (1mA). Propranolol (10mg/kg) injection was immediately followed retrieval of either a one-day recent (weak or strong) or 36-day remote (weak or strong) contextual fear memories. Results We found that propranolol induced a long-lasting impairment of subsequent expression of recent and remote memories with either weak or strong strength. We also found no memory recovery after a weak reminder shock. Furthermore, no significant differences were found on the amount of memory deficit induced by propranolol among memories with different age and strength. Discussion Our data suggest that the efficacy of propranolol in impairing fear memory reconsolidation is not limited to the age or strength of the memory. PMID:25337385

Effects of the beta-blocker propranolol on cued and contextual fear conditioning in humans.

PubMed

Grillon, Christian; Cordova, Jeremy; Morgan, Charles Andrew; Charney, Dennis S; Davis, Michael

2004-09-01

Beta-adrenergic receptors are involved in the consolidation of emotional memories. Yet, a number of studies using Pavlovian cued fear conditioning have been unable to demonstrate an effect of beta-adrenergic blockade on acquisition or retention of fear conditioning. Evidence for the involvement of beta-adrenergic receptors in emotional memories comes mostly from studies using fear inhibitory avoidance in rodents. It is possible that fear inhibitory avoidance is more akin to contextual conditioning than to cued fear conditioning, suggesting that context conditioning may be disrupted by beta-adrenergic blockade. This study investigated the effects of the beta-adrenergic blocker propranolol on cued and contextual fear conditioning in humans. Subjects were given either placebo (n=15) or 40 mg propranolol (n=15) prior to differential cued conditioning. A week later, they were tested for retention of context and cued fear conditioning using physiological (startle reflex and electrodermal activity) and subjective measures of emotional arousal. The results were consistent with the hypothesis. The skin conductance level (SCL) and the subjective measure of arousal suggested reduced emotional arousal upon returning to the conditioning context in the propranolol group, compared to the placebo group. The acquisition and retention of cued fear conditioning were not affected by propranolol. These results suggest that beta-adrenergic receptors are involved in contextual fear conditioning.

Cornering the fear engram: long-term synaptic changes in the lateral nucleus of the amygdala after fear conditioning.

PubMed

Kwon, Jeong-Tae; Choi, June-Seek

2009-08-05

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

Elevation of Hippocampal Neurogenesis Induces a Temporally Graded Pattern of Forgetting of Contextual Fear Memories.

PubMed

Gao, Aijing; Xia, Frances; Guskjolen, Axel J; Ramsaran, Adam I; Santoro, Adam; Josselyn, Sheena A; Frankland, Paul W

2018-03-28

Throughout life neurons are continuously generated in the subgranular zone of the hippocampus. The subsequent integration of newly generated neurons alters patterns of dentate gyrus input and output connectivity, potentially rendering memories already stored in those circuits harder to access. Consistent with this prediction, we previously showed that increasing hippocampal neurogenesis after training induces forgetting of hippocampus-dependent memories, including contextual fear memory. However, the brain regions supporting contextual fear memories change with time, and this time-dependent memory reorganization might regulate the sensitivity of contextual fear memories to fluctuations in hippocampal neurogenesis. By virally expressing the inhibitory designer receptor exclusively activated by designer drugs, hM4Di, we first confirmed that chemogenetic inhibition of dorsal hippocampal neurons impairs retrieval of recent (day-old) but not remote (month-old) contextual fear memories in male mice. We then contrasted the effects of increasing hippocampal neurogenesis at recent versus remote time points after contextual fear conditioning in male and female mice. Increasing hippocampal neurogenesis immediately following training reduced conditioned freezing when mice were replaced in the context 1 month later. In contrast, when hippocampal neurogenesis was increased time points remote to training, conditioned freezing levels were unaltered when mice were subsequently tested. These temporally graded forgetting effects were observed using both environmental and genetic interventions to increase hippocampal neurogenesis. Our experiments identify memory age as a boundary condition for neurogenesis-mediated forgetting and suggest that, as contextual fear memories mature, they become less sensitive to changes in hippocampal neurogenesis levels because they no longer depend on the hippocampus for their expression. SIGNIFICANCE STATEMENT New neurons are generated in the

COCAINE AND PAVLOVIAN FEAR CONDITIONING: DOSE-EFFECT ANALYSIS

PubMed Central

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

2007-01-01

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

Tracking the fear engram: the lateral amygdala is an essential locus of fear memory storage.

PubMed

Schafe, Glenn E; Doyère, Valérie; LeDoux, Joseph E

2005-10-26

Although it is believed that different types of memories are localized in discreet regions of the brain, concrete experimental evidence of the existence of such engrams is often elusive. Despite being one of the best characterized memory systems of the brain, the question of where fear memories are localized in the brain remains a hotly debated issue. Here, we combine site-specific behavioral pharmacology with multisite electrophysiological recording techniques to show that the lateral nucleus of the amygdala, long thought to be critical for the acquisition of fear memories, is also an essential locus of fear memory storage.

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…

A NMDA receptor antagonist, MK-801 impairs consolidating extinction of auditory conditioned fear responses in a Pavlovian model.

PubMed

Liu, Jun-Li; Li, Min; Dang, Xiao-Rong; Wang, Zheng-Hong; Rao, Zhi-Ren; Wu, Sheng-Xi; Li, Yun-Qing; Wang, Wen

2009-10-26

In auditory fear conditioning, repeated presentation of the tone in the absence of shock leads to extinction of the acquired fear responses. The glutamate N-methyl-D-aspartate receptor (NMDAR) is thought to be involved in the extinction of the conditioned fear responses, but its detailed role in initiating and consolidating or maintaining the fear extinction memory is unclear. Here we investigated this issue by using a NMDAR antagonist, MK-801. The effects of immediate (beginning at 10 min after the conditioning) and delayed (beginning at 24 h after conditioning) extinctions were first compared with the finding that delayed extinction caused a better and long-lasting (still significant on the 20(th) day after extinction) depression on the conditioned fear responses. In a second experiment, MK-801 was intraperitoneally (i.p.) injected at 40 min before, 4 h or 12 h after the delayed extinction, corresponding to critical time points for initiating, consolidating or maintaining the fear extinction memory. i.p. injection of MK-801 at either 40 min before or 4 h after delayed extinction resulted in an impairment of initiating and consolidating fear extinction memory, which caused a long lasting increased freezing score that was still significant on the 7th day after extinction, compared with extinction group. However, MK-801 administered at 12 h after the delayed extinction, when robust consolidation has been occurred and stabilized, did not affect the established extinction memory. Furthermore, the changed freezing behaviors was not due to an alteration in general anxiety levels, since MK-801 treatment had no effect on the percentage of open-arm time or open-arm entries in an Elevated Plus Maze (EPM) task. Our data suggested that the activation of NMDARs plays important role in initiation and consolidation but not maintenance of fear extinction memory. Together with the fact that NMDA receptor is very important for memory, our data added experimental evidence to the

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

Contextual Fear Memories Formed in the Absence of the Dorsal Hippocampus Decay Across Time

PubMed Central

Zelikowsky, Moriel; Bissiere, Stephanie; Fanselow, Michael S.

2012-01-01

Mammals suffering damage to the hippocampus display a dramatic loss of explicit, recently formed memories (retrograde amnesia). In contrast, deficits in the ability to form new memories following hippocampal damage (anterograde amnesia) can be overcome with sufficient training. By combining contextual fear conditioning with lesions of the dorsal hippocampus in rats, we discovered that while animals can form long-term contextual fear memories in the absence of the hippocampus, these memories decay with time, lacking the permanence that is a hallmark characteristic of normal fear memories. These findings indicate that while it is initially possible to acquire explicit memories when the hippocampus is compromised, these memories cannot transfer from a recent to remote state. This suggests that memories formed outside the hippocampus may nevertheless require the hippocampus to undergo systems consolidation, which has important clinical implications for the treatment of memory disorders. PMID:22399761

Plastic Synaptic Networks of the Amygdala for the Acquisition, Expression, and Extinction of Conditioned Fear

PubMed Central

Pape, Hans-Christian; Pare, Denis

2009-01-01

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

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

PubMed Central

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

2016-01-01

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

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

High-dose corticosterone after fear conditioning selectively suppresses fear renewal by reducing anxiety-like response.

PubMed

Wang, Hongbo; Xing, Xiaoli; Liang, Jing; Bai, Yunjing; Lui, Zhengkui; Zheng, Xigeng

2014-09-01

Exposure therapy is widely used to treat anxiety disorders, including posttraumatic stress disorder (PTSD). However, preventing the return of fear is still a major challenge after this behavioral treatment. An increasing number of studies suggest that high-dose glucocorticoid treatment immediately after trauma can alleviate the symptoms of PTSD in humans. Unknown is whether high-dose glucocorticoid treatment following fear conditioning suppresses the return of fear. In the present study, a typical fear renewal paradigm (AAB) was used, in which the fear response to an auditory cue can be restored in a novel context (context B) when both training and extinction occur in the same context (context A). We trained rats for auditory fear conditioning and administered corticosterone (CORT; 5 and 25mg/kg, i.p.) or vehicle with different delays (1 and 24h). Forty-eight hours after drug injection, extinction was conducted with no drug in the training context, followed by a test of tone-induced freezing behavior in the same (AAA) or a shifted (AAB) context. Both immediate and delayed administration of high-dose CORT after fear conditioning reduced fear renewal. To examine the anxiolytic effect of CORT, independent rats were trained for cued or contextual fear conditioning, followed by an injection of CORT (5 and 25mg/kg, i.p.) or vehicle at a 1 or 24h delay. One week later, anxiety-like behavior was assessed in the elevated plus maze (EPM) before and after fear expression. We found that high-dose CORT decreased anxiety-like behavior without changing tone- or context-induced freezing. These findings indicate that a single high-dose CORT administration given after fear conditioning may selectively suppress fear renewal by reducing anxiety-like behavior and not by altering the consolidation, retrieval, or extinction of fear memory. Copyright © 2014 Elsevier Inc. All rights reserved.

Impact of Life History on Fear Memory and Extinction

PubMed Central

Remmes, Jasmin; Bodden, Carina; Richter, S. Helene; Lesting, Jörg; Sachser, Norbert; Pape, Hans-Christian; Seidenbecher, Thomas

2016-01-01

Behavioral profiles are strongly shaped by an individual's whole life experience. The accumulation of negative experiences over lifetime is thought to promote anxiety-like behavior in adulthood (“allostatic load hypothesis”). In contrast, the “mismatch hypothesis” of psychiatric disease suggests that high levels of anxiety-like behavior are the result of a discrepancy between early and late environment. The aim of the present study was to investigate how different life histories shape the expression of anxiety-like behavior and modulate fear memory. In addition, we aimed to clarify which of the two hypotheses can better explain the modulation of anxiety and fear. For this purpose, male mice grew up under either adverse or beneficial conditions during early phase of life. In adulthood they were further subdivided in groups that either matched or mismatched the condition experienced before, resulting in four different life histories. The main results were: (i) Early life benefit followed by late life adversity caused decreased levels of anxiety-like behavior. (ii) Accumulation of adversity throughout life history led to impaired fear extinction learning. Late life adversity as compared to late life benefit mainly affected extinction training, while early life adversity as compared to early life benefit interfered with extinction recall. Concerning anxiety-like behavior, the results do neither support the allostatic load nor the mismatch hypothesis, but rather indicate an anxiolytic effect of a mismatched early beneficial and later adverse life history. In contrast, fear memory was strongly affected by the accumulation of adverse experiences over the lifetime, therefore supporting allostatic load hypothesis. In summary, this study highlights that anxiety-like behavior and fear memory are differently affected by specific combinations of adverse or beneficial events experienced throughout life. PMID:27757077

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

PubMed Central

Richardson, Rick

2015-01-01

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

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

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

PubMed Central

Thomas, Kerrie L; Hall, Jeremy

2018-01-01

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

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

PubMed Central

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

2016-01-01

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

The ventromedial hypothalamus mediates predator fear memory

PubMed Central

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

2016-01-01

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

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…

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…

An "egr-1" ("zif268") Antisense Oligodeoxynucleotide Infused into the Amygdala Disrupts Fear Conditioning

ERIC Educational Resources Information Center

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

2004-01-01

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

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…

Dynamic expression of FKBP5 in the medial prefrontal cortex regulates resiliency to conditioned fear

PubMed Central

Criado-Marrero, Marangelie; Morales Silva, Roberto J.; Velazquez, Bethzaly; Hernández, Anixa; Colon, María; Cruz, Emmanuel; Soler-Cedeño, Omar; Porter, James T.

2017-01-01

The factors influencing resiliency to the development of post-traumatic stress disorder (PTSD) remain to be elucidated. Clinical studies associate PTSD with polymorphisms of the FK506 binding protein 5 (FKBP5). However, it is unclear whether changes in FKBP5 expression alone could produce resiliency or susceptibility to PTSD-like symptoms. In this study, we used rats as an animal model to examine whether FKBP5 in the infralimbic (IL) or prelimbic (PL) medial prefrontal cortex regulates fear conditioning or extinction. First, we examined FKBP5 expression in IL and PL during fear conditioning or extinction. In contrast to the stable expression of FKBP5 seen in PL, FKBP5 expression in IL increased after fear conditioning and remained elevated even after extinction suggesting that IL FKBP5 levels may modulate fear conditioning or extinction. Consistent with this possibility, reducing basal FKBP5 expression via local infusion of FKBP5–shRNA into IL reduced fear conditioning. Furthermore, reducing IL FKBP5, after consolidation of the fear memory, enhanced extinction memory indicating that IL FKBP5 opposed formation of the extinction memory. Our findings demonstrate that lowering FKBP5 expression in IL is sufficient to both reduce fear acquisition and enhance extinction, and suggest that lower expression of FKBP5 in the ventral medial prefrontal cortex could contribute to resiliency to PTSD. PMID:28298552

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

PubMed

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

2014-05-01

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

The Melatonergic System in Anxiety Disorders and the Role of Melatonin in Conditional Fear.

PubMed

Huang, F; Yang, Z; Li, C-Q

2017-01-01

Resistance to extinction of certain conditioned responses forms the basis of anxieties, phobias, and compulsions. There has been an available effective means of extinction-based exposure psychotherapy for the treatment of anxiety disorders, such as posttraumatic stress disorder (PTSD) that has been hypothesized to result from impaired extinction of fear memory. PTSD is considered as a memory disorder within a Pavlovian fear conditioning and extinction framework. Therefore, the aim of this review was to report the preclinical profile of melatonin, a pineal gland hormone, as a potential pharmacological option in the treatment of anxiety disorders such as PTSD, tested with the Pavlovian fear conditioning paradigm. We performed a literature review regarding studies that evaluated the effects of melatonin on fear conditioning and fear extinction. Results showed that a single administration 30min before conditioning has no effect on the acquisition of cued fear, but impaired contextual fear conditioning. Compared to rats injected with vehicle, rats injected with melatonin 30min before extinction training presented a significant lower freezing during both extinction training and extinction test phases. However, melatonin injected immediately after extinction training was ineffective on extinction learning. Melatonin impaired contextual fear conditioning, a hippocampus-dependent task. On the contrary, melatonin facilitates the extinction of conditional cued fear without affecting its acquisition or expression, and melatonin facilitates cued fear extinction only when it is present during extinction training. Although further studies are necessary, the research undertaken until now shows that melatonin modulates fear conditioning and fear extinction and consequently melatonin may serve as an agent for the treatment of PTSD. © 2017 Elsevier Inc. All rights reserved.

A NMDA Receptor Antagonist, MK-801 Impairs Consolidating Extinction of Auditory Conditioned Fear Responses in a Pavlovian Model

PubMed Central

Wang, Zheng-Hong; Rao, Zhi-Ren; Wu, Sheng-Xi; Li, Yun-Qing; Wang, Wen

2009-01-01

Background In auditory fear conditioning, repeated presentation of the tone in the absence of shock leads to extinction of the acquired fear responses. The glutamate N-methyl-D-aspartate receptor (NMDAR) is thought to be involved in the extinction of the conditioned fear responses, but its detailed role in initiating and consolidating or maintaining the fear extinction memory is unclear. Here we investigated this issue by using a NMDAR antagonist, MK-801. Methods/Main Findings The effects of immediate (beginning at 10 min after the conditioning) and delayed (beginning at 24 h after conditioning) extinctions were first compared with the finding that delayed extinction caused a better and long-lasting (still significant on the 20th day after extinction) depression on the conditioned fear responses. In a second experiment, MK-801 was intraperitoneally (i.p.) injected at 40 min before, 4 h or 12 h after the delayed extinction, corresponding to critical time points for initiating, consolidating or maintaining the fear extinction memory. i.p. injection of MK-801 at either 40 min before or 4 h after delayed extinction resulted in an impairment of initiating and consolidating fear extinction memory, which caused a long lasting increased freezing score that was still significant on the 7th day after extinction, compared with extinction group. However, MK-801 administered at 12 h after the delayed extinction, when robust consolidation has been occurred and stabilized, did not affect the established extinction memory. Furthermore, the changed freezing behaviors was not due to an alteration in general anxiety levels, since MK-801 treatment had no effect on the percentage of open-arm time or open-arm entries in an Elevated Plus Maze (EPM) task. Conclusions/Significance Our data suggested that the activation of NMDARs plays important role in initiation and consolidation but not maintenance of fear extinction memory. Together with the fact that NMDA receptor is very important for

Memory accuracy predicts hippocampal mTOR pathway activation following retrieval of contextual fear memory.

PubMed

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

2013-09-01

Prior work suggests that hippocampus-dependent memory undergoes a systems consolidation process such that recent memories are stored in the hippocampus, while older memories are independent of the hippocampus and instead dependent on cortical areas. One problem with interpreting these studies is that memory for the contextual stimuli weakens as time passes between the training event and testing and older memories are often less detailed, making it difficult to determine if memory storage in the hippocampus is related to the age or to the accuracy of the memory. Activity of the mammalian target of rapamycin (mTOR) signaling pathway is known to be important for controlling protein translation necessary for both memory consolidation after initial learning and for the reconsolidation of memory after retrieval. We tested whether p70s6 kinase (p70s6K), a key component of the mTOR signaling pathway, is activated following retrieval of context fear memory in the dorsal hippocampus (DH) and anterior cingulate cortex (ACC) at 1, 10, or 36 days after context fear conditioning. We also tested whether strengthening memory for the contextual stimuli changed p70s6K phosphorylation in these structures 36 days after training. We show that under standard training conditions retrieval of a recently formed memory is initially precise and involves the DH. Over time it loses detail, becomes independent of the DH and depends on the ACC. In a subsequent experiment, we preserved the accuracy of older memories through pre-exposure to the training context. We show that remote memory still involved the DH in animals given pre-exposure. These data support the notion that detailed memories depend on the DH regardless of their age. Copyright © 2013 Wiley Periodicals, Inc.

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.

Impaired contextual modulation of memories in PTSD: an fMRI and psychophysiological study of extinction retention and fear renewal.

PubMed

Garfinkel, Sarah N; Abelson, James L; King, Anthony P; Sripada, Rebecca K; Wang, Xin; Gaines, Laura M; Liberzon, Israel

2014-10-01

Post-traumatic stress disorder (PTSD) patients display pervasive fear memories, expressed indiscriminately. Proposed mechanisms include enhanced fear learning and impaired extinction or extinction recall. Documented extinction recall deficits and failure to use safety signals could result from general failure to use contextual information, a hippocampus-dependent process. This can be probed by adding a renewal phase to standard conditioning and extinction paradigms. Human subjects with PTSD and combat controls were conditioned (skin conductance response), extinguished, and tested for extinction retention and renewal in a scanner (fMRI). Fear conditioning (light paired with shock) occurred in one context, followed by extinction in another, to create danger and safety contexts. The next day, the extinguished conditioned stimulus (CS+E) was re-presented to assess extinction recall (safety context) and fear renewal (danger context). PTSD patients showed impaired extinction recall, with increased skin conductance and heightened amygdala activity to the extinguished CS+ in the safety context. However, they also showed impaired fear renewal; in the danger context, they had less skin conductance response to CS+E and lower activity in amygdala and ventral-medial prefrontal cortex compared with combat controls. Control subjects displayed appropriate contextual modulation of memory recall, with extinction (safety) memory prevailing in the safety context, and fear memory prevailing in the danger context. PTSD patients could not use safety context to sustain suppression of extinguished fear memory, but they also less effectively used danger context to enhance fear. They did not display globally enhanced fear expression, but rather showed a globally diminished capacity to use contextual information to modulate fear expression. Copyright © 2014 the authors 0270-6474/14/3413435-09$15.00/0.

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.…

Interference effects of transcranial direct current stimulation over the right frontal cortex and adrenergic system on conditioned fear.

PubMed

Nasehi, Mohammad; Soltanpour, Reyhaneh; Ebrahimi-Ghiri, Mohaddeseh; Zarrabian, Shahram; Zarrindast, Mohammad-Reza

2017-11-01

The effects of pharmacological interventions on fear memory have widely been studied, but there are very few studies about the effects of brain electrical stimulation on fear memory function. Therefore, our aim was to determine whether anodal/cathodal transcranial direct current stimulation (tDCS) over the right frontal cortex would modify propranolol-induced contextual and auditory fear memory deficits, before or after training. The adult NMRI male mice were randomly assigned into three groups: the sham group, the anodal tDCS group, and the cathodal tDCS group. Fear memories were evaluated using a classical fear conditioning apparatus. While the anodal stimulation did not affect fear retrieval, post-training cathodal stimulation improved fear memory retrieval. Regardless of when propranolol (0.1 mg/kg) was administered, it impaired fear memory retrieval. However, when anodal stimulation and propranolol were applied prior to the training, contextual fear memory retrieval was increased and auditory fear memory was reversed. An enhanced contextual retrieval was also observed when propranolol was administered prior to the training and stimulation occurred after the training. Only when the stimulation occurred prior to the training and propranolol was administered after the training was there a selective improvement in contextual fear memory retrieval, leaving the auditory fear memory retrieval impaired. Interestingly, cathodal stimulation improved the effects of propranolol on auditory fear memory only when it occurred prior to the training. The results highlight possible improving effects for anodal/cathodal tDCS on propranolol-induced deficits on fear memories. The timing of the interventions related to the specific phases of memory formation is important in modulating fear behaviors.

A study on fear memory retrieval and REM sleep in maternal separation and isolation stressed rats.

PubMed

Sampath, Dayalan; Sabitha, K R; Hegde, Preethi; Jayakrishnan, H R; Kutty, Bindu M; Chattarji, Sumantra; Rangarajan, Govindan; Laxmi, T R

2014-10-15

As rapid brain development occurs during the neonatal period, environmental manipulation during this period may have a significant impact on sleep and memory functions. Moreover, rapid eye movement (REM) sleep plays an important role in integrating new information with the previously stored emotional experience. Hence, the impact of early maternal separation and isolation stress (MS) during the stress hyporesponsive period (SHRP) on fear memory retention and sleep in rats were studied. The neonatal rats were subjected to maternal separation and isolation stress during postnatal days 5-7 (6h daily/3d). Polysomnographic recordings and differential fear conditioning was carried out in two different sets of rats aged 2 months. The neuronal replay during REM sleep was analyzed using different parameters. MS rats showed increased time in REM stage and total sleep period also increased. MS rats showed fear generalization with increased fear memory retention than normal control (NC). The detailed analysis of the local field potentials across different time periods of REM sleep showed increased theta oscillations in the hippocampus, amygdala and cortical circuits. Our findings suggest that stress during SHRP has sensitized the hippocampus-amygdala-cortical loops which could be due to increased release of corticosterone that generally occurs during REM sleep. These rats when subjected to fear conditioning exhibit increased fear memory and increased fear generalization. The development of helplessness, anxiety and sleep changes in human patients, thus, could be related to the reduced thermal, tactile and social stimulation during SHRP on brain plasticity and fear memory functions. Copyright © 2014 Elsevier B.V. All rights reserved.

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

ERIC Educational Resources Information Center

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

2014-01-01

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

Systems Reconsolidation Reveals a Selective Role for the Anterior Cingulate Cortex in Generalized Contextual Fear Memory Expression

PubMed Central

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

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.

Unilateral hippocampal inactivation or lesion selectively impairs remote contextual fear memory.

PubMed

Zhou, Heng; Zhou, Qixin; Xu, Lin

2016-10-01

Contextual fear memory depends on the hippocampus, but the role of unilateral hippocampus in this type of memory remains unclear. Herein, pharmacological inactivation or excitotoxic lesions were used to study the role of unilateral hippocampus in the stages of contextual fear memory. The pharmacological experiments revealed that compared with the control groups, unilateral hippocampal blockade did not impair 1-day recent memory following learning, whereas bilateral hippocampal blockade significantly impaired this memory. The lesion experiments showed that compared with the control groups, the formed contextual fear memory was retained for 7 days and that 30-day remote memory was markedly reduced in unilateral hippocampal lesion groups. These results indicate that an intact bilateral hippocampus is required for the formation of remote memory and that unilateral hippocampus is sufficient for recent contextual fear memory.

A Key Role for Nectin-1 in the Ventral Hippocampus in Contextual Fear Memory

PubMed Central

Grosse, Jocelyn; Krummenacher, Claude; Sandi, Carmen

2013-01-01

Nectins are cell adhesion molecules that are widely expressed in the brain. Nectin expression shows a dynamic spatiotemporal regulation, playing a role in neural migratory processes during development. Nectin-1 and nectin-3 and their heterophilic trans-interactions are important for the proper formation of synapses. In the hippocampus, nectin-1 and nectin-3 localize at puncta adherentia junctions and may play a role in synaptic plasticity, a mechanism essential for memory and learning. We evaluated the potential involvement of nectin-1 and nectin-3 in memory consolidation using an emotional learning paradigm. Rats trained for contextual fear conditioning showed transient nectin-1—but not nectin-3—protein upregulation in synapse-enriched hippocampal fractions at about 2 h posttraining. The upregulation of nectin-1 was found exclusively in the ventral hippocampus and was apparent in the synaptoneurosomal fraction. This upregulation was induced by contextual fear conditioning but not by exposure to context or shock alone. When an antibody against nectin-1, R165, was infused in the ventral-hippocampus immediately after training, contextual fear memory was impaired. However, treatment with the antibody in the dorsal hippocampus had no effect in contextual fear memory formation. Similarly, treatment with the antibody in the ventral hippocampus did not interfere with acoustic memory formation. Further control experiments indicated that the effects of ventral hippocampal infusion of the nectin-1 antibody in contextual fear memory cannot be ascribed to memory non-specific effects such as changes in anxiety-like behavior or locomotor behavior. Therefore, we conclude that nectin-1 recruitment to the perisynaptic environment in the ventral hippocampus plays an important role in the formation of contextual fear memories. Our results suggest that these mechanisms could be involved in the connection of emotional and contextual information processed in the amygdala and dorsal

One-year-old fear memories rapidly activate human fusiform gyrus

PubMed Central

Pizzagalli, Diego A.

2016-01-01

Fast threat detection is crucial for survival. In line with such evolutionary pressure, threat-signaling fear-conditioned faces have been found to rapidly (<80 ms) activate visual brain regions including the fusiform gyrus on the conditioning day. Whether remotely fear conditioned stimuli (CS) evoke similar early processing enhancements is unknown. Here, 16 participants who underwent a differential face fear-conditioning and extinction procedure on day 1 were presented the initial CS 24 h after conditioning (Recent Recall Test) as well as 9-17 months later (Remote Recall Test) while EEG was recorded. Using a data-driven segmentation procedure of CS evoked event-related potentials, five distinct microstates were identified for both the recent and the remote memory test. To probe intracranial activity, EEG activity within each microstate was localized using low resolution electromagnetic tomography analysis (LORETA). In both the recent (41–55 and 150–191 ms) and remote (45–90 ms) recall tests, fear conditioned faces potentiated rapid activation in proximity of fusiform gyrus, even in participants unaware of the contingencies. These findings suggest that rapid processing enhancements of conditioned faces persist over time. PMID:26416784

The Central Nucleus of the Amygdala and Corticotropin-Releasing Factor: Insights into Contextual Fear Memory

PubMed Central

Pitts, Matthew W.; Todorovic, Cedomir; Blank, Thomas; Takahashi, Lorey K.

2009-01-01

The central nucleus of the amygdala (CeA) has been traditionally viewed in fear conditioning to serve as an output neural center that transfers conditioned information formed in the basolateral amygdala to brain structures that generate emotional responses. Recent studies suggest that the CeA may also be involved in fear memory consolidation. In addition, corticotropin-releasing factor systems were shown to facilitate memory consolidation in the amygdala, which contains a high density of CRF immunoreactive cell bodies and fibers in the lateral part of the CeA (CeAl). However, the involvement of CeA CRF in contextual fear conditioning remains poorly understood. Therefore, we first conducted a series of studies using fiber-sparing lesion and reversible inactivation methods to assess the general role of the CeA in contextual fear. We then used identical training and testing procedures to compare and evaluate the specific function of CeA CRF using CRF antisense oligonucleotides (CRF ASO). Rats microinjected with ibotenic acid, muscimol, or a CRF ASO into the CeA prior to contextual fear conditioning showed typical levels of freezing during acquisition training but exhibited significant reductions in contextual freezing in a retention test 48 h later. Furthermore, CeA inactivation induced by either muscimol or CRF ASO administration immediately prior to retention testing did not impair freezing, suggesting that the previously observed retention deficits were due to inhibition of consolidation rather than fear expression. Collectively, our results suggest CeA involvement in the consolidation of contextual fear memory and specifically implicate CeA CRF as an important mediator. PMID:19494159

A Diet Enriched with Curcumin Impairs Newly Acquired and Reactivated Fear Memories

PubMed Central

Monsey, Melissa S; Gerhard, Danielle M; Boyle, Lara M; Briones, Miguel A; Seligsohn, Ma'ayan; Schafe, Glenn E

2015-01-01

Curcumin, a yellow-pigment compound found in the popular Indian spice turmeric (Curcuma longa), has been extensively investigated for its anti-inflammatory, chemopreventative, and antidepressant properties. Here, we examined the efficacy of dietary curcumin at impairing the consolidation and reconsolidation of a Pavlovian fear memory, a widely studied animal model of traumatic memory formation in posttraumatic stress disorder (PTSD). We show that a diet enriched with 1.5% curcumin prevents the training-related elevation in the expression of the immediate early genes (IEGs) Arc/Arg3.1 and Egr-1 in the lateral amygdala (LA) and impairs the ‘consolidation' of an auditory Pavlovian fear memory; short-term memory (STM) is intact, whereas long-term memory (LTM) is significantly impaired. Next, we show that dietary curcumin impairs the ‘reconsolidation' of a recently formed auditory Pavlovian fear memory; fear memory retrieval (reactivation) and postreactivation (PR)-STM are intact, whereas PR-LTM is significantly impaired. Additional experiments revealed that dietary curcumin is also effective at impairing the reconsolidation of an older, well-consolidated fear memory. Furthermore, we observed that fear memories that fail to reconsolidate under the influence of dietary curcumin are impaired in an enduring manner; unlike extinguished fear memories, they are not subject to reinstatement or renewal. Collectively, our findings indicate that a diet enriched with curcumin is capable of impairing fear memory consolidation and reconsolidation processes, findings that may have important clinical implications for the treatment of disorders such as PTSD that are characterized by unusually strong and persistently reactivated fear memories. PMID:25430781

Single dose of l-dopa makes extinction memories context-independent and prevents the return of fear

PubMed Central

Haaker, Jan; Gaburro, Stefano; Sah, Anupam; Gartmann, Nina; Lonsdorf, Tina B.; Meier, Kolja; Singewald, Nicolas; Pape, Hans-Christian; Morellini, Fabio; Kalisch, Raffael

2013-01-01

Traumatic events can engender persistent excessive fear responses to trauma reminders that may return even after successful treatment. Extinction, the laboratory analog of behavior therapy, does not erase conditioned fear memories but generates competing, fear-inhibitory “extinction memories” that, however, are tied to the context in which extinction occurred. Accordingly, a dominance of fear over extinction memory expression—and, thus, return of fear—is often observed if extinguished fear stimuli are encountered outside the extinction (therapy) context. We show that postextinction administration of the dopamine precursor l-dopa makes extinction memories context-independent, thus strongly reducing the return of fear in both mice and humans. Reduced fear is accompanied by decreased amygdala and enhanced ventromedial prefrontal cortex activation in both species. In humans, ventromedial prefrontal cortex activity is predicted by enhanced resting-state functional coupling of the area with the dopaminergic midbrain during the postextinction consolidation phase. Our data suggest that dopamine-dependent boosting of extinction memory consolidation is a promising avenue to improving anxiety therapy. PMID:23754384

An update on contextual fear memory mechanisms: Transition between Amygdala and Hippocampus.

PubMed

Chaaya, Nicholas; Battle, Andrew R; Johnson, Luke R

2018-05-09

Context is an ever-present combination of discrete environmental elements capable of influencing many psychological processes. When context is associated with an aversive stimulus, a permanent contextual fear memory is formed. Context is hypothesized to greatly influence the treatability of various fear-based pathologies, in particular, post-traumatic stress disorder (PTSD). In order to understand how contextual fear memories are encoded and impact underlying fear pathology, delineation of the underlying neural circuitry of contextual fear memory consolidation and maintenance is essential. Past understandings of contextual fear suggest that the hippocampus only creates a unitary, or single, representation of context. This representation is sent to the amygdala, which creates the associative contextual fear memory. In contrast, here we review new evidence from the literature showing contextual fear memories to be consolidated and maintained by both amygdala and hippocampus. Based on this evidence, we revise the current model of contextual fear memory consolidation, highlighting a larger role for hippocampus. This new model may better explain the role of the hippocampus in PTSD. Copyright © 2018 Elsevier Ltd. All rights reserved.

Continuing the search for the engram: examining the mechanism of fear memories.

PubMed

Josselyn, Sheena A

2010-07-01

The goal of my research is to gain insight using rodent models into the fundamental molecular, cellular and systems that make up the base of memory formation. My work focuses on fear memories. Aberrant fear and/or anxiety may be at the heart of many psychiatric disorders. In this article, I review the results of my research group; these results show that particular neurons in the lateral amygdala, a brain region important for fear, are specifically involved in particular fear memories. We started by showing that the transcription factor CREB (cAMP/Ca(2+) response element binding protein) plays a key role in the formation of fear memories. Next, we used viral vectors to overexpress CREB in a subset of lateral amygdala neurons. This not only facilitated fear memory formation but also "drove" the memory into the neurons with relatively increased CREB function. Finally, we showed that selective ablation of the neurons overexpressing CREB in the lateral amygdala selectively erased the fear memory. These findings are the first to show disruption of a specific memory by disrupting select neurons within a distributed network.

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…

The role of calsenilin/DREAM/KChIP3 in contextual fear conditioning.

PubMed

Alexander, Jon C; McDermott, Carmel M; Tunur, Tumay; Rands, Vicky; Stelly, Claire; Karhson, Debra; Bowlby, Mark R; An, W Frank; Sweatt, J David; Schrader, Laura A

2009-03-01

Potassium channel interacting proteins (KChIPs) are members of a family of calcium binding proteins that interact with Kv4 potassium (K(+)) channel primary subunits and also act as transcription factors. The Kv4 subunit is a primary K(+) channel pore-forming subunit, which contributes to the somatic and dendritic A-type currents throughout the nervous system. These A-type currents play a key role in the regulation of neuronal excitability and dendritic processing of incoming synaptic information. KChIP3 is also known as calsenilin and as the transcription factor, downstream regulatory element antagonist modulator (DREAM), which regulates a number of genes including prodynorphin. KChIP3 and Kv4 primary channel subunits are highly expressed in hippocampus, an area of the brain important for learning and memory. Through its various functions, KChIP3 may play a role in the regulation of synaptic plasticity and learning and memory. We evaluated the role of KChIP3 in a hippocampus-dependent memory task, contextual fear conditioning. Male KChIP3 knockout (KO) mice showed significantly enhanced memory 24 hours after training as measured by percent freezing. In addition, we found that membrane association and interaction with Kv4.2 of KChIP3 protein was significantly decreased and nuclear KChIP3 expression was increased six hours after the fear conditioning training paradigm with no significant change in KChIP3 mRNA. In addition, prodynorphin mRNA expression was significantly decreased six hours after fear conditioning training in wild-type (WT) but not in KO animals. These data suggest a role for regulation of gene expression by KChIP3/DREAM/calsenilin in consolidation of contextual fear conditioning memories.

Hippocampal damage causes retrograde but not anterograde memory loss for context fear discrimination in rats.

PubMed

Lee, Justin Q; Sutherland, Robert J; McDonald, Robert J

2017-09-01

There is a substantial body of evidence that the hippocampus (HPC) plays and essential role in context discrimination in rodents. Studies reporting anterograde amnesia (AA) used repeated, alternating, distributed conditioning and extinction sessions to measure context fear discrimination. In addition, there is uncertainty about the extent of damage to the HPC. Here, we induced conditioned fear prior to discrimination tests and rats sustained extensive, quantified pre- or post-training HPC damage. Unlike previous work, we found that extensive HPC damage spares context discrimination, we observed no AA. There must be a non-HPC system that can acquire long-term memories that support context fear discrimination. Post-training HPC damage caused retrograde amnesia (RA) for context discrimination, even when rats are fear conditioned for multiple sessions. We discuss the implications of these findings for understanding the role of HPC in long-term memory. © 2017 Wiley Periodicals, Inc.

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

PubMed

Soeter, Marieke; Kindt, Merel

2015-01-01

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

Dentate Gyrus Contributes to Retrieval as well as Encoding: Evidence from Context Fear Conditioning, Recall, and Extinction

PubMed Central

Krasne, Franklin B.

2017-01-01

Dentate gyrus (DG) is widely thought to provide a teaching signal that enables hippocampal encoding of memories, but its role during retrieval is poorly understood. Some data and models suggest that DG plays no role in retrieval; others encourage the opposite conclusion. To resolve this controversy, we evaluated the effects of optogenetic inhibition of dorsal DG during context fear conditioning, recall, generalization, and extinction in male mice. We found that (1) inhibition during training impaired context fear acquisition; (2) inhibition during recall did not impair fear expression in the training context, unless mice had to distinguish between similar feared and neutral contexts; (3) inhibition increased generalization of fear to an unfamiliar context that was similar to a feared one and impaired fear expression in the conditioned context when it was similar to a neutral one; and (4) inhibition impaired fear extinction. These effects, as well as several seemingly contradictory published findings, could be reproduced by BACON (Bayesian Context Fear Algorithm), a physiologically realistic hippocampal model positing that acquisition and retrieval both involve coordinated activity in DG and CA3. Our findings thus suggest that DG contributes to retrieval and extinction, as well as to the initial establishment of context fear. SIGNIFICANCE STATEMENT Despite abundant evidence that the hippocampal dentate gyrus (DG) plays a critical role in memory, it remains unclear whether the role of DG relates to memory acquisition or retrieval. Using contextual fear conditioning and optogenetic inhibition, we show that DG contributes to both of these processes. Using computational simulations, we identify specific mechanisms through which the suppression of DG affects memory performance. Finally, we show that DG contributes to fear extinction learning, a process in which learned fear is attenuated through exposures to a fearful context in the absence of threat. Our data resolve a

Dentate Gyrus Contributes to Retrieval as well as Encoding: Evidence from Context Fear Conditioning, Recall, and Extinction.

PubMed

Bernier, Brian E; Lacagnina, Anthony F; Ayoub, Adam; Shue, Francis; Zemelman, Boris V; Krasne, Franklin B; Drew, Michael R

2017-06-28

Dentate gyrus (DG) is widely thought to provide a teaching signal that enables hippocampal encoding of memories, but its role during retrieval is poorly understood. Some data and models suggest that DG plays no role in retrieval; others encourage the opposite conclusion. To resolve this controversy, we evaluated the effects of optogenetic inhibition of dorsal DG during context fear conditioning, recall, generalization, and extinction in male mice. We found that (1) inhibition during training impaired context fear acquisition; (2) inhibition during recall did not impair fear expression in the training context, unless mice had to distinguish between similar feared and neutral contexts; (3) inhibition increased generalization of fear to an unfamiliar context that was similar to a feared one and impaired fear expression in the conditioned context when it was similar to a neutral one; and (4) inhibition impaired fear extinction. These effects, as well as several seemingly contradictory published findings, could be reproduced by BACON (Bayesian Context Fear Algorithm), a physiologically realistic hippocampal model positing that acquisition and retrieval both involve coordinated activity in DG and CA3. Our findings thus suggest that DG contributes to retrieval and extinction, as well as to the initial establishment of context fear. SIGNIFICANCE STATEMENT Despite abundant evidence that the hippocampal dentate gyrus (DG) plays a critical role in memory, it remains unclear whether the role of DG relates to memory acquisition or retrieval. Using contextual fear conditioning and optogenetic inhibition, we show that DG contributes to both of these processes. Using computational simulations, we identify specific mechanisms through which the suppression of DG affects memory performance. Finally, we show that DG contributes to fear extinction learning, a process in which learned fear is attenuated through exposures to a fearful context in the absence of threat. Our data resolve a

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

PubMed

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

2018-05-02

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

An unconditioned stimulus retrieval extinction procedure to prevent the return of fear memory.

PubMed

Liu, Jianfeng; Zhao, Liyan; Xue, Yanxue; Shi, Jie; Suo, Lin; Luo, Yixiao; Chai, Baisheng; Yang, Chang; Fang, Qin; Zhang, Yan; Bao, Yanping; Pickens, Charles L; Lu, Lin

2014-12-01

Conditioned fear memories can be updated by extinction during reconsolidation, and this effect is specific to the reactivated conditioned stimulus (CS). However, a traumatic event can be associated with several cues, and each cue can potentially trigger recollection of the event. We introduced a technique to target all diverse cues associated with an aversive event that causes fear. In human experiments, 161 subjects underwent modified fear conditioning, in which they were exposed to an unconditioned stimulus (US) or unreinforced CS to reactivate the memory and then underwent extinction, spontaneous recovery, and reinstatement. In animal experiments, 343 rats underwent contextual fear conditioning under a similar protocol as that used in the human experiments. We also explored the molecular alterations after US reactivation in rats. Presentation of a lower intensity US before extinction disrupted the associations between the different CS and reactivated US in both humans and rats. This effect persisted for at least 6 months in humans and was selective to the reactivated US. This procedure was also effective for remote memories in both humans and rats. Compared with the CS, the US induced stronger endocytosis of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid glutamate receptors 1 and 2 and stronger activation of protein kinase A, p70S6 kinase, and cyclic adenosine monophosphate response element binding protein in the dorsal hippocampus in rats. These findings demonstrate that a modified US retrieval extinction strategy may have a potential impact on therapeutic approaches to prevent the return of fear. Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

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

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

Extended fear conditioning reveals a role for both N-methyl-D-aspartic acid and non-N-methyl-D-aspartic acid receptors in the amygdala in the acquisition of conditioned fear.

PubMed

Pistell, P J; Falls, W A

2008-09-09

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

Pattern Analyses Reveal Separate Experience-Based Fear Memories in the Human Right Amygdala.

PubMed

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

2017-08-23

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

Roles of testosterone and amygdaloid LTP induction in determining sex differences in fear memory magnitude.

PubMed

Chen, Li-Shen; Tzeng, Wen-Yu; Chuang, Jia-Ying; Cherng, Chianfang G; Gean, Po-Wu; Yu, Lung

2014-08-01

Women are thought to form fear memory more robust than men do and testosterone is suspected to play a role in determining such a sex difference. Mouse cued fear freezing was used to study the sex-related susceptibility and the role of testosterone in fear memory in humans. A 75-dB tone was found to provoke weak freezing, while 0.15-mA and 0.20-mA footshock caused strong freezing responses. No sex differences were noticed in the tone- or footshock-induced (naïve fear) freezing. Following the conditionings, female mice exhibited greater tone (cued fear)-induced freezing than did male mice. Nonetheless, female mice demonstrated indistinctive cued fear freezing across the estrous phases and ovariectomy did not affect such freezing in female mice. Orchidectomy enhanced the cued fear freezing in male mice. Systemic testosterone administrations and an intra-lateral nucleus of amygdala (LA) testosterone infusion diminished the cued fear freezing in orchidectomized male mice, while pretreatment with flutamide (Flu) eradicated these effects. Long-term potentiation (LTP) magnitude in LA has been known to correlate with the strength of the cued fear conditioning. We found that LA LTP magnitude was indeed greater in female than male mice. Orchidectomy enhanced LTP magnitude in males' LA, while ovariectomy decreased LTP magnitude in females' LA. Testosterone decreased LTP magnitude in orchidectomized males' LA and estradiol enhanced LTP magnitude in ovariectomized females' LA. Finally, male mice had lower LA GluR1 expression than female mice and orchidectomy enhanced the GluR1 expression in male mice. These findings, taken together, suggest that testosterone plays a critical role in rendering the sex differences in the cued fear freezing and LA LTP. Testosterone is negatively associated with LA LTP and the cued fear memory in male mice. However, ovarian hormones and LA LTP are loosely associated with the cued fear memory in female mice. Copyright © 2014 Elsevier Inc. All

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.

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.

Nucleus reuniens of the thalamus controls fear memory intensity, specificity and long-term maintenance during consolidation.

PubMed

Troyner, Fernanda; Bicca, Maira A; Bertoglio, Leandro J

2018-05-10

The thalamic nucleus reuniens (NR) has been shown to support bidirectional medial prefrontal cortex-hippocampus communication and synchronization relevant for cognitive processing. Using non-selective or prolonged inactivation of the NR, previous studies reported its activity positively modulates aversive memory consolidation. Here we examined the NR's role in consolidating contextual fear memories with varied strength, at both recent and more remote time points, using muscimol-induced temporary inactivation in rats. Results indicate the NR negatively modulates fear memory intensity, specificity and long-term maintenance. The more intense, generalized and enduring fear memory induced by NR inactivation during consolidation was also less prone to behavioral suppression by extinction or reconsolidation disruption induced by clonidine, an alpha-2 adrenergic receptor agonist. Lastly, we used immunohistochemistry for Arc protein, which is involved in synaptic modifications underlying aversive memory consolidation, to investigate whether treatment condition and/or conditioning status could change its levels in the NR, the hippocampus (dorsal and ventral CA1 subregions) and the medial prefrontal cortex (anterior cingulate, prelimbic and infralimbic subregions). Results indicate a significant imbalance in the number of Arc-expressing neurons in the brain areas investigated in muscimol fear conditioned animals when compared with controls. Collectively, present results provide convergent evidence for the NR's role as a hub regulating quantitative and qualitative aspects of a contextual fear memory during its consolidation that seem to influence the subsequent susceptibility to experimental interventions aiming at attenuating its expression. They also indicate the selectivity and duration of a given inactivation approach may influence its outcomes. This article is protected by copyright. All rights reserved. © 2018 Wiley Periodicals, Inc.

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

PubMed

Melo, Irene; Ehrlich, Ingrid

2016-07-01

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

Sustained conditioned responses in prelimbic prefrontal neurons are correlated with fear expression and extinction failure.

PubMed

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

2009-07-01

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

The role of negative and positive memories in fear of dental treatment.

PubMed

Risløv Staugaard, Søren; Jøssing, Marit; Krohn, Christina

2017-12-01

Most young adults transition from childhood dental care to adult dental care without problems. However, a substantial minority leaves childhood dental care with considerable fear of dental treatment. In the present study, we hypothesized that fear of dental treatment in the young adult is influenced by memories of positive and negative childhood experiences with dental care. More specifically, we predicted that the emotional impact, sense of reliving, rehearsal, and belief in the accuracy of a negative treatment memory would be associated with increased dental fear, while positive treatment memories would show the opposite relation. One hundred thirty-six young adults leaving childhood dental care responded to a online measures of dental fear, the most negative and most positive memory of dental treatment, and symptoms of posttraumatic stress disorder. Negative memories of events that involved pain and dentist behaviors such as impatience or scolding were frequently described and significantly associated with dental fear and symptoms of posttraumatic stress. Positive memories were more frequent, but did not show a consistent relationship with dental fear. The importance of negative memories suggests an avenue for intervention against dental fear that focuses on restructuring those memories to emphasize positive aspects. © 2016 American Association of Public Health Dentistry.

Sensitive periods in fear learning and memory.

PubMed

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

2014-01-01

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

Selective inhibition of miR-92 in hippocampal neurons alters contextual fear memory.

PubMed

Vetere, Gisella; Barbato, Christian; Pezzola, Silvia; Frisone, Paola; Aceti, Massimiliano; Ciotti, MariaTeresa; Cogoni, Carlo; Ammassari-Teule, Martine; Ruberti, Francesca

2014-12-01

Post-transcriptional gene regulation mediated by microRNAs (miRNAs) is implicated in memory formation; however, the function of miR-92 in this regulation is uncharacterized. The present study shows that training mice in contextual fear conditioning produces a transient increase in miR-92 levels in the hippocampus and decreases several miR-92 gene targets, including: (i) the neuronal Cl(-) extruding K(+) Cl(-) co-transporter 2 (KCC2) protein; (ii) the cytoplasmic polyadenylation protein (CPEB3), an RNA-binding protein regulator of protein synthesis in neurons; and (iii) the transcription factor myocyte enhancer factor 2D (MEF2D), one of the MEF2 genes which negatively regulates memory-induced structural plasticity. Selective inhibition of endogenous miR-92 in CA1 hippocampal neurons, by a sponge lentiviral vector expressing multiple sequences imperfectly complementary to mature miR-92 under the control of the neuronal specific synapsin promoter, leads to up-regulation of KCC2, CPEB3 and MEF2D, impairs contextual fear conditioning, and prevents a memory-induced increase in the spine density. Taken together, the results indicate that neuronal-expressed miR-92 is an endogenous fine regulator of contextual fear memory in mice. © 2014 Wiley Periodicals, Inc.

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

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

PubMed

Feng, Pan; Zheng, Yong; Feng, Tingyong

2015-11-18

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.

Hippocampal awake replay in fear memory retrieval

PubMed Central

Wu, Chun-Ting; Haggerty, Daniel; Kemere, Caleb; Ji, Daoyun

2017-01-01

Hippocampal place cells are key to episodic memories. How these cells participate in memory retrieval remains unclear. Here, after rats acquired a fear memory by receiving mild foot-shocks at a shock zone of a track, we analyzed place cells when the animals were placed back to the track and displayed an apparent memory retrieval behavior: avoidance of the shock zone. We found that place cells representing the shock zone were reactivated, despite the fact that the animals did not enter the shock zone. This reactivation occurred in ripple-associated awake replay of place cell sequences encoding the paths from the animal’s current positions to the shock zone, but not in place cell sequences within individual cycles of theta oscillation. The result reveals a specific place cell pattern underlying the inhibitory avoidance behavior and provides strong evidence for the involvement of awake replay in fear memory retrieval. PMID:28218916

A microRNA negative feedback loop downregulates vesicle transport and inhibits fear memory

PubMed Central

Mathew, Rebecca S; Tatarakis, Antonis; Rudenko, Andrii; Johnson-Venkatesh, Erin M; Yang, Yawei J; Murphy, Elisabeth A; Todd, Travis P; Schepers, Scott T; Siuti, Nertila; Martorell, Anthony J; Falls, William A; Hammack, Sayamwong E; Walsh, Christopher A; Tsai, Li-Huei; Umemori, Hisashi; Bouton, Mark E; Moazed, Danesh

2016-01-01

The SNARE-mediated vesicular transport pathway plays major roles in synaptic remodeling associated with formation of long-term memories, but the mechanisms that regulate this pathway during memory acquisition are not fully understood. Here we identify miRNAs that are up-regulated in the rodent hippocampus upon contextual fear-conditioning and identify the vesicular transport and synaptogenesis pathways as the major targets of the fear-induced miRNAs. We demonstrate that miR-153, a member of this group, inhibits the expression of key components of the vesicular transport machinery, and down-regulates Glutamate receptor A1 trafficking and neurotransmitter release. MiR-153 expression is specifically induced during LTP induction in hippocampal slices and its knockdown in the hippocampus of adult mice results in enhanced fear memory. Our results suggest that miR-153, and possibly other fear-induced miRNAs, act as components of a negative feedback loop that blocks neuronal hyperactivity at least partly through the inhibition of the vesicular transport pathway. DOI: http://dx.doi.org/10.7554/eLife.22467.001 PMID:28001126

Activation of alpha2 adrenergic receptors suppresses fear conditioning: expression of c-Fos and phosphorylated CREB in mouse amygdala.

PubMed

Davies, M Frances; Tsui, Janet; Flannery, Judy A; Li, Xiangqi; DeLorey, Timothy M; Hoffman, Brian B

2004-02-01

alpha(2) adrenergic agonists such as dexmedetomidine generally suppress noradrenergic transmission and have sedative, analgesic, and antihypertensive properties. Considering the importance of the neurotransmitter norepinephrine in forming memories for fearful events, we have investigated the acute and chronic effects of dexmedetomidine on discrete cue and contextual fear conditioning in mice. When administered before training, dexmedetomidine (10-20 microg/kg, i.p.) selectively suppressed discrete cue fear conditioning without affecting contextual memory. This behavioral change was associated with a decrease in memory retrieval-induced expression of c-Fos and P-CREB in the lateral, basolateral, and central nuclei of the amygdala. Dexmedetomidine's action on discrete cue memory did not occur in alpha(2A) adrenoceptor knockout (KO) mice. When dexmedetomidine was administered after training, it suppressed contextual memory, an effect that did not occur in alpha(2A) adrenoceptor KO mice. We conclude that dexmedetomidine, acting at alpha(2A) adrenoceptors, must be present during the encoding process to decrease discrete cue fear memory; however, its ability to suppress contextual memory is likely the result of blocking the consolidation process. The ability of alpha(2) agonists to suppress fear memory may be a valuable property clinically in order to suppress the formation of memories during stressful situations.

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.

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

PubMed Central

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

2013-01-01

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

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

PubMed

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

2013-11-01

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

Dual Functions of Perirhinal Cortex in Fear Conditioning

PubMed Central

Kent, Brianne A.; Brown, Thomas H.

2012-01-01

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

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

Adenosine A2A Receptors in the Amygdala Control Synaptic Plasticity and Contextual Fear Memory.

PubMed

Simões, Ana Patrícia; Machado, Nuno J; Gonçalves, Nélio; Kaster, Manuella P; Simões, Ana T; Nunes, Ana; Pereira de Almeida, Luís; Goosens, Ki Ann; Rial, Daniel; Cunha, Rodrigo A

2016-11-01

The consumption of caffeine modulates working and reference memory through the antagonism of adenosine A 2A receptors (A 2A Rs) controlling synaptic plasticity processes in hippocampal excitatory synapses. Fear memory essentially involves plastic changes in amygdala circuits. However, it is unknown if A 2A Rs in the amygdala regulate synaptic plasticity and fear memory. We report that A 2A Rs in the amygdala are enriched in synapses and located to glutamatergic synapses, where they selectively control synaptic plasticity rather than synaptic transmission at a major afferent pathway to the amygdala. Notably, the downregulation of A 2A Rs selectively in the basolateral complex of the amygdala, using a lentivirus with a silencing shRNA (small hairpin RNA targeting A 2A R (shA 2A R)), impaired fear acquisition as well as Pavlovian fear retrieval. This is probably associated with the upregulation and gain of function of A 2A Rs in the amygdala after fear acquisition. The importance of A 2A Rs to control fear memory was further confirmed by the ability of SCH58261 (0.1 mg/kg; A 2A R antagonist), caffeine (5 mg/kg), but not DPCPX (0.5 mg/kg; A 1 R antagonist), treatment for 7 days before fear conditioning onwards, to attenuate the retrieval of context fear after 24-48 h and after 7-8 days. These results demonstrate that amygdala A 2A Rs control fear memory and the underlying process of synaptic plasticity in this brain region. This provides a neurophysiological basis for the association between A 2A R polymorphisms and phobia or panic attacks in humans and prompts a therapeutic interest in A 2A Rs to manage fear-related pathologies.

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

PubMed

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

2017-05-01

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

Glutamate receptors in the medial geniculate nucleus are necessary for expression and extinction of conditioned fear in rats.

PubMed

Orsini, Caitlin A; Maren, Stephen

2009-11-01

Auditory fear conditioning requires anatomical projections from the medial geniculate nucleus (MGN) of the thalamus to the amygdala. Several lines of work indicate that the MGN is a critical sensory relay for auditory information during conditioning, but is not itself involved in the encoding of long-term fear memories. In the present experiments, we examined whether the MGN plays a similar role in the extinction of conditioned fear. Twenty-four hours after Pavlovian fear conditioning, rats received bilateral intra-thalamic infusions of either with NBQX (an AMPA receptor antagonist; Experiment 1) or MK-801 (an NMDA receptor antagonist; Experiment 1), anisomycin (a protein synthesis inhibitor; Experiment 2) or U0126 (a MEK inhibitor; Experiment 3) immediately prior to an extinction session in a novel context. The next day rats received a tone test in a drug-free state to assess their extinction memory; freezing served as an index of fear. Glutamate receptor antagonism prevented both the expression and extinction of conditioned fear. In contrast, neither anisomycin nor U0126 affected extinction. These results suggest that the MGN is a critical sensory relay for auditory information during extinction training, but is not itself a site of plasticity underlying the formation of the extinction memory.

Sensitive periods in fear learning and memory

PubMed Central

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

2015-01-01

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

The Genetic Covariation between Fear Conditioning and Self-Report Fears

PubMed Central

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

2008-01-01

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

NMDA receptor- and ERK-dependent histone methylation changes in the lateral amygdala bidirectionally regulate fear memory formation.

PubMed

Gupta-Agarwal, Swati; Jarome, Timothy J; Fernandez, Jordan; Lubin, Farah D

2014-07-01

It is well established that fear memory formation requires de novo gene transcription in the amygdala. We provide evidence that epigenetic mechanisms in the form of histone lysine methylation in the lateral amygdala (LA) are regulated by NMDA receptor (NMDAR) signaling and involved in gene transcription changes necessary for fear memory consolidation. Here we found increases in histone H3 lysine 9 dimethylation (H3K9me2) levels in the LA at 1 h following auditory fear conditioning, which continued to be temporally regulated up to 25 h following behavioral training. Additionally, we demonstrate that inhibiting the H3K9me2 histone lysine methyltransferase G9a (H/KMTs-G9a) in the LA impaired fear memory, while blocking the H3K9me2 histone lysine demethylase LSD1 (H/KDM-LSD1) enhanced fear memory, suggesting that H3K9me2 in the LA can bidirectionally regulate fear memory formation. Furthermore, we show that NMDAR activity differentially regulated the recruitment of H/KMT-G9a, H/KDM-LSD1, and subsequent H3K9me2 levels at a target gene promoter. This was largely regulated by GluN2B- but not GluN2A-containing NMDARs via ERK activation. Moreover, fear memory deficits associated with NMDAR or ERK blockade were successfully rescued through pharmacologically inhibiting LSD1, suggesting that enhancements of H3K9me2 levels within the LA can rescue fear memory impairments that result from hypofunctioning NMDARs or loss of ERK signaling. Together, the present study suggests that histone lysine methylation regulation in the LA via NMDAR-ERK-dependent signaling is involved in fear memory formation. © 2014 Gupta-Agarwal et al.; Published by Cold Spring Harbor Laboratory Press.

Encoding of contextual fear memory requires de novo proteins in the prelimbic cortex

PubMed Central

Rizzo, Valerio; Touzani, Khalid; Raveendra, Bindu L.; Swarnkar, Supriya; Lora, Joan; Kadakkuzha, Beena M.; Liu, Xin-An; Zhang, Chao; Betel, Doron; Stackman, Robert W.; Puthanveettil, Sathyanarayanan V.

2016-01-01

Background Despite our understanding of the significance of the prefrontal cortex in the consolidation of long-term memories (LTM), its role in the encoding of LTM remains elusive. Here we investigated the role of new protein synthesis in the mouse medial prefrontal cortex (mPFC) in encoding contextual fear memory. Methods Because a change in the association of mRNAs to polyribosomes is an indicator of new protein synthesis, we assessed the changes in polyribosome-associated mRNAs in the mPFC following contextual fear conditioning (CFC) in the mouse. Differential gene expression in mPFC was identified by polyribosome profiling (n = 18). The role of new protein synthesis in mPFC was determined by focal inhibition of protein synthesis (n = 131) and by intra-prelimbic cortex manipulation (n = 56) of Homer 3, a candidate identified from polyribosome profiling. Results We identified several mRNAs that are differentially and temporally recruited to polyribosomes in the mPFC following CFC. Inhibition of protein synthesis in the prelimbic (PL), but not in the anterior cingulate cortex (ACC) region of the mPFC immediately after CFC disrupted encoding of contextual fear memory. Intriguingly, inhibition of new protein synthesis in the PL 6 hours after CFC did not impair encoding. Furthermore, expression of Homer 3, an mRNA enriched in polyribosomes following CFC, in the PL constrained encoding of contextual fear memory. Conclusions Our studies identify several molecular substrates of new protein synthesis in the mPFC and establish that encoding of contextual fear memories require new protein synthesis in PL subregion of mPFC. PMID:28503670

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…

A Naturally-Occurring Histone Acetyltransferase Inhibitor Derived from Garcinia indica Impairs Newly Acquired and Reactivated Fear Memories

PubMed Central

Maddox, Stephanie A.; Watts, Casey S.; Doyère, Valérie; Schafe, Glenn E.

2013-01-01

The study of the cellular and molecular mechanisms underlying the consolidation and reconsolidation of traumatic fear memories has progressed rapidly in recent years, yet few compounds have emerged that are readily useful in a clinical setting for the treatment of anxiety disorders such as post-traumatic stress disorder (PTSD). Here, we use a combination of biochemical, behavioral, and neurophysiological methods to systematically investigate the ability of garcinol, a naturally-occurring histone acetyltransferase (HAT) inhibitor derived from the rind of the fruit of the Kokum tree (Garcina indica), to disrupt the consolidation and reconsolidation of Pavlovian fear conditioning, a widely studied rodent model of PTSD. We show that local infusion of garcinol into the rat lateral amygdala (LA) impairs the training and retrieval-related acetylation of histone H3 in the LA. Further, we show that either intra-LA or systemic administration of garcinol within a narrow window after either fear conditioning or fear memory retrieval significantly impairs the consolidation and reconsolidation of a Pavlovian fear memory and associated neural plasticity in the LA. Our findings suggest that a naturally-occurring compound derived from the diet that regulates chromatin function may be useful in the treatment of newly acquired or recently reactivated traumatic memories. PMID:23349897

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. Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.

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

PubMed Central

Gilmartin, Marieke R.; Helmstetter, Fred J.

2010-01-01

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

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. © 2015 Bae et al.; Published by Cold Spring Harbor Laboratory Press.

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

PubMed

Seifert, A Ronald

2012-01-01

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

Deficient fear extinction memory in posttraumatic stress disorder.

PubMed

Wicking, Manon; Steiger, Frauke; Nees, Frauke; Diener, Slawomira J; Grimm, Oliver; Ruttorf, Michaela; Schad, Lothar R; Winkelmann, Tobias; Wirtz, Gustav; Flor, Herta

2016-12-01

Posttraumatic stress disorder (PTSD) might be maintained by deficient extinction memory. We used a cued fear conditioning design with extinction and a post-extinction phase to provoke the return of fear and examined the role of the interplay of amygdala, hippocampus and prefrontal regions. We compared 18 PTSD patients with two healthy control groups: 18 trauma-exposed subjects without PTSD (nonPTSD) and 18 healthy controls (HC) without trauma experience. They underwent a three-day ABC-conditioning procedure in a functional magnetic resonance imaging scanner. Two geometric shapes that served as conditioned stimuli (CS) were presented in the context of virtual reality scenes. Electric painful stimuli were delivered after one of the two shapes (CS+) during acquisition (in context A), while the other (CS-) was never paired with pain. Extinction was performed in context B and extinction memory was tested in a novel context C. The PTSD patients showed significantly higher differential skin conductance responses than the non-PTSD and HC and higher differential amygdala and hippocampus activity than the HC in context C. In addition, elevated arousal to the CS+ during extinction and to the CS- throughout the experiment was present in the PTSD patients but self-reported differential valence or contingency were not different. During extinction recall, differential amygdala activity correlated positively with the intensity of numbing and ventromedial prefrontal cortex activity correlated positively with behavioral avoidance. PTSD patients show heightened return of fear in neural and peripheral measures. In addition, self-reported arousal was high to both danger (CS+) and safety (CS-) cues. These results suggest that a deficient maintenance of extinction and a failure to identify safety signals might contribute to PTSD symptoms, whereas non-PTSD subjects seem to show normal responses. Copyright © 2016 Elsevier Inc. All rights reserved.

Encoding of Fear Memory in High and Low Fear Mice

DTIC Science & Technology

2013-11-18

82.  Maren S, Fanselow MS. 1995. Synaptic plasticity in the basolateral amygdala  induced  by  hippocampal formation  stimulation  in vivo. The Journal of...sensory stimulus with something fear- inducing ) exhibit fear memory at or below the level of low fear mice following MEK inhibition. These findings...psychology 75:671‐82  23.  Bordi F, LeDoux J. 1992. Sensory tuning beyond the sensory system: an initial analysis of  auditory  response properties of

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…

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

PubMed Central

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

2013-01-01

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

Double Dissociation of Amygdala and Hippocampal Contributions to Trace and Delay Fear Conditioning

PubMed Central

Raybuck, Jonathan D.; Lattal, K. Matthew

2011-01-01

A key finding in studies of the neurobiology of learning memory is that the amygdala is critically involved in Pavlovian fear conditioning. This is well established in delay-cued and contextual fear conditioning; however, surprisingly little is known of the role of the amygdala in trace conditioning. Trace fear conditioning, in which the CS and US are separated in time by a trace interval, requires the hippocampus and prefrontal cortex. It is possible that recruitment of cortical structures by trace conditioning alters the role of the amygdala compared to delay fear conditioning, where the CS and US overlap. To investigate this, we inactivated the amygdala of male C57BL/6 mice with GABA A agonist muscimol prior to 2-pairing trace or delay fear conditioning. Amygdala inactivation produced deficits in contextual and delay conditioning, but had no effect on trace conditioning. As controls, we demonstrate that dorsal hippocampal inactivation produced deficits in trace and contextual, but not delay fear conditioning. Further, pre- and post-training amygdala inactivation disrupted the contextual but the not cued component of trace conditioning, as did muscimol infusion prior to 1- or 4-pairing trace conditioning. These findings demonstrate that insertion of a temporal gap between the CS and US can generate amygdala-independent fear conditioning. We discuss the implications of this surprising finding for current models of the neural circuitry involved in fear conditioning. PMID:21283812

Post-conditioning experience with acute or chronic inflammatory pain reduces contextual fear conditioning in the rat

PubMed Central

Johnston, Ian N.; Maier, Steven F.; Rudy, Jerry W.; Watkins, Linda R.

2017-01-01

There is evidence that pain can impact cognitive function in people. The present study evaluated whether Pavlovian fear conditioning in rats would be reduced if conditioning were followed by persistent inflammatory pain induced by a subcutaneous injection of dilute formalin or complete Freund's adjuvant (CFA) on the dorsal lumbar surface of the back. Formalin-induced pain specifically impaired contextual fear conditioning but not auditory cue conditioning (Experiment 1A). Moreover, formalin pain only impaired contextual fear conditioning if it was initiated within 1 h of conditioning and did not have a significant effect if initiated 2, 8 or 32 h after (Experiments 1A and 1B). Experiment 2 showed that formalin pain initiated after a session of context pre-exposure reduced the ability of that pre-exposure to facilitate contextual fear when the rat was limited to a brief exposure to the context during conditioning. Similar impairments in context- but not CS-fear conditioning were also observed if the rats received an immediate post-conditioning injection with CFA (Experiment 3). Finally, we confirmed that formalin and CFA injected s.c. on the back induced pain-indicative behaviours, hyperalgesia and allodynia with a similar timecourse to intraplantar injections (Experiment 4). These results suggest that persistent pain impairs learning in a hippocampus-dependent task, and may disrupt processes that encode experiences into long-term memory. PMID:21920390

Corticosterone administration after a single-trial contextual fear conditioning does not influence the strength and specificity of recent and remote memory in rats.

PubMed

Bueno, Ana Paula A; de Paiva, Joselisa Péres Queiroz; Corrêa, Moisés Dos Santos; Tiba, Paula Ayako; Fornari, Raquel Vecchio

2017-03-15

It is well established that corticosterone (CORT) enhances memory consolidation of emotionally arousing experiences. Despite emotional memories being usually referred to as well remembered for long periods, there are no studies that have investigated the effects of CORT in modulating the duration and specificity of memory. In the present study, we trained Wistar rats in a single-trial contextual fear conditioning protocol and injected CORT (0.3, 1.0 or 3.0mg/kg), immediately after training, to investigate its effects on memory consolidation. Rats were tested 2 and 29days after the training session or only 29days after training to assess recent or remote memory. Our results show that animals tested for recent memory discriminated the training context from a novel one, while those tested only for remote memory generalized the fear response to both contexts. Animals tested for remote memory after being tested for recent memory were able to discriminate both contexts. These results support the literature regarding memory specificity and duration. However, CORT treatment, even at the dose of 1.0mg/kg that effectively enhanced the plasmatic hormone levels, did not affect the strength or the specificity of memory in either recent or remote memory tests. We hypothesize that the lack of effect of CORT treatment could be due to the low arousing training experience of the single-trial protocol which, despite being sufficient to induce significant recent and remote memory consolidation, may not be sufficient to allow the memory-enhancing effect of CORT. Copyright © 2017 Elsevier Inc. All rights reserved.

Orexin receptor-1 in the locus coeruleus plays an important role in cue-dependent fear memory consolidation.

PubMed

Soya, Shingo; Shoji, Hirotaka; Hasegawa, Emi; Hondo, Mari; Miyakawa, Tsuyoshi; Yanagisawa, Masashi; Mieda, Michihiro; Sakurai, Takeshi

2013-09-04

The noradrenergic (NA) projections arising from the locus ceruleus (LC) to the amygdala and bed nucleus of the stria terminalis have been implicated in the formation of emotional memory. Since NA neurons in the LC (LC-NA neurons) abundantly express orexin receptor-1 (OX1R) and receive prominent innervation by orexin-producing neurons, we hypothesized that an OX1R-mediated pathway is involved in the physiological fear learning process via regulation of LC-NA neurons. To evaluate this hypothesis, we examined the phenotype of Ox1r(-/-) mice in the classic cued and contextual fear-conditioning test. We found that Ox1r(-/-) mice showed impaired freezing responses in both cued and contextual fear-conditioning paradigms. In contrast, Ox2r(-/-) mice showed normal freezing behavior in the cued fear-conditioning test, while they exhibited shorter freezing time in the contextual fear-conditioning test. Double immunolabeling of Fos and tyrosine hydroxylase showed that double-positive LC-NA neurons after test sessions of both cued and contextual stimuli were significantly fewer in Ox1r(-/-) mice. AAV-mediated expression of OX1R in LC-NA neurons in Ox1r(-/-) mice restored the freezing behavior to the auditory cue to a comparable level to that in wild-type mice in the test session. Decreased freezing time during the contextual fear test was not affected by restoring OX1R expression in LC-NA neurons. These observations support the hypothesis that the orexin system modulates the formation and expression of fear memory via OX1R in multiple pathways. Especially, OX1R in LC-NA neurons plays an important role in cue-dependent fear memory formation and/or retrieval.

Generalization of conditioned fear along a dimension of increasing fear intensity

PubMed Central

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

2009-01-01

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

Updating Procedures Can Reorganize the Neural Circuit Supporting a Fear Memory.

PubMed

Kwapis, Janine L; Jarome, Timothy J; Ferrara, Nicole C; Helmstetter, Fred J

2017-07-01

Established memories undergo a period of vulnerability following retrieval, a process termed 'reconsolidation.' Recent work has shown that the hypothetical process of reconsolidation is only triggered when new information is presented during retrieval, suggesting that this process may allow existing memories to be modified. Reconsolidation has received increasing attention as a possible therapeutic target for treating disorders that stem from traumatic memories, yet little is known about how this process changes the original memory. In particular, it is unknown whether reconsolidation can reorganize the neural circuit supporting an existing memory after that memory is modified with new information. Here, we show that trace fear memory undergoes a protein synthesis-dependent reconsolidation process following exposure to a single updating trial of delay conditioning. Further, this reconsolidation-dependent updating process appears to reorganize the neural circuit supporting the trace-trained memory, so that it better reflects the circuit supporting delay fear. Specifically, after a trace-to-delay update session, the amygdala is now required for extinction of the updated memory but the retrosplenial cortex is no longer required for retrieval. These results suggest that updating procedures could be used to force a complex, poorly defined memory circuit to rely on a better-defined neural circuit that may be more amenable to behavioral or pharmacological manipulation. This is the first evidence that exposure to new information can fundamentally reorganize the neural circuit supporting an existing memory.

Transient acidosis while retrieving a fear-related memory enhances its lability

PubMed Central

Du, Jianyang; Price, Margaret P; Taugher, Rebecca J; Grigsby, Daniel; Ash, Jamison J; Stark, Austin C; Hossain Saad, Md Zubayer; Singh, Kritika; Mandal, Juthika; Wemmie, John A; Welsh, Michael J

2017-01-01

Attenuating the strength of fearful memories could benefit people disabled by memories of past trauma. Pavlovian conditioning experiments indicate that a retrieval cue can return a conditioned aversive memory to a labile state. However, means to enhance retrieval and render a memory more labile are unknown. We hypothesized that augmenting synaptic signaling during retrieval would increase memory lability. To enhance synaptic transmission, mice inhaled CO2 to induce an acidosis and activate acid sensing ion channels. Transient acidification increased the retrieval-induced lability of an aversive memory. The labile memory could then be weakened by an extinction protocol or strengthened by reconditioning. Coupling CO2 inhalation to retrieval increased activation of amygdala neurons bearing the memory trace and increased the synaptic exchange from Ca2+-impermeable to Ca2+-permeable AMPA receptors. The results suggest that transient acidosis during retrieval renders the memory of an aversive event more labile and suggest a strategy to modify debilitating memories. DOI: http://dx.doi.org/10.7554/eLife.22564.001 PMID:28650315

Epigenetic mechanisms in fear conditioning: Implications for treating post-traumatic stress disorder

PubMed Central

Kwapis, Janine L.; Wood, Marcelo A.

2014-01-01

Post-traumatic stress disorder (PTSD) and other anxiety disorders stemming from dysregulated fear memory are problematic and costly. Understanding the molecular mechanisms that contribute to the formation and maintenance of these persistent fear associations is critical to developing treatments for PTSD. Epigenetic mechanisms, which control gene expression to produce long-lasting changes in cellular function, may support the formation of fear memory underlying PTSD. Here, we address the role of epigenetic mechanisms in the formation, storage, updating, and extinction of fear memories and discuss methods of targeting these epigenetic mechanisms to reduce the initial formation of fear memory or to enhance its extinction. Epigenetic mechanisms may provide a novel target for pharmaceutical and other treatments to reduce aversive memory contributing to PTSD. PMID:25220045

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

PubMed Central

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

2016-01-01

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

Stress enables reinforcement-elicited serotonergic consolidation of fear memory

PubMed Central

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

2015-01-01

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

Amyloid-beta oligomers impair fear conditioned memory in a calcineurin-dependent fashion in mice.

PubMed

Dineley, Kelly T; Kayed, Rakez; Neugebauer, Volker; Fu, Yu; Zhang, Wenru; Reese, Lindsay C; Taglialatela, Giulio

2010-10-01

Soluble oligomeric aggregates of the amyloid-beta (A beta) peptide are believed to be the most neurotoxic A beta species affecting the brain in Alzheimer disease (AD), a terminal neurodegenerative disorder involving severe cognitive decline underscored by initial synaptic dysfunction and later extensive neuronal death in the CNS. Recent evidence indicates that A beta oligomers are recruited at the synapse, oppose expression of long-term potentiation (LTP), perturb intracellular calcium balance, disrupt dendritic spines, and induce memory deficits. However, the molecular mechanisms behind these outcomes are only partially understood; achieving such insight is necessary for the comprehension of A beta-mediated neuronal dysfunction. We have investigated the role of the phosphatase calcineurin (CaN) in these pathological processes of AD. CaN is especially abundant in the CNS, where it is involved in synaptic activity, LTP, and memory function. Here, we describe how oligomeric A beta treatment causes memory deficits and depresses LTP expression in a CaN-dependent fashion. Mice given a single intracerebroventricular injection of A beta oligomers exhibited increased CaN activity and decreased pCREB, a transcription factor involved in proper synaptic function, accompanied by decreased memory in a fear conditioning task. These effects were reversed by treatment with the CaN inhibitor FK506. We further found that expression of hippocampal LTP in acutely cultured rodent brain slices was opposed by A beta oligomers and that this effect was also reversed by FK506. Collectively, these results indicate that CaN activation may play a central role in mediating synaptic and memory disruption induced by acute oligomeric A beta treatment in mice. (c) 2010 Wiley-Liss, Inc.

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

PubMed

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

2014-12-01

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

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

PubMed Central

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

2014-01-01

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

Nonlinear Developmental trajectory of fear learning and memory

PubMed Central

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

2013-01-01

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

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. Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Computational search for hypotheses concerning the endocannabinoid contribution to the extinction of fear conditioning.

PubMed

Anastasio, Thomas J

2013-01-01

Fear conditioning, in which a cue is conditioned to elicit a fear response, and extinction, in which a previously conditioned cue no longer elicits a fear response, depend on neural plasticity occurring within the amygdala. Projection neurons in the basolateral amygdala (BLA) learn to respond to the cue during fear conditioning, and they mediate fear responding by transferring cue signals to the output stage of the amygdala. Some BLA projection neurons retain their cue responses after extinction. Recent work shows that activation of the endocannabinoid system is necessary for extinction, and it leads to long-term depression (LTD) of the GABAergic synapses that inhibitory interneurons make onto BLA projection neurons. Such GABAergic LTD would enhance the responses of the BLA projection neurons that mediate fear responding, so it would seem to oppose, rather than promote, extinction. To address this paradox, a computational analysis of two well-known conceptual models of amygdaloid plasticity was undertaken. The analysis employed exhaustive state-space search conducted within a declarative programming environment. The analysis reveals that GABAergic LTD actually increases the number of synaptic strength configurations that achieve extinction while preserving the cue responses of some BLA projection neurons in both models. The results suggest that GABAergic LTD helps the amygdala retain cue memory during extinction even as the amygdala learns to suppress the previously conditioned response. The analysis also reveals which features of both models are essential for their ability to achieve extinction with some cue memory preservation, and suggests experimental tests of those features.

Computational search for hypotheses concerning the endocannabinoid contribution to the extinction of fear conditioning

PubMed Central

Anastasio, Thomas J.

2013-01-01

Fear conditioning, in which a cue is conditioned to elicit a fear response, and extinction, in which a previously conditioned cue no longer elicits a fear response, depend on neural plasticity occurring within the amygdala. Projection neurons in the basolateral amygdala (BLA) learn to respond to the cue during fear conditioning, and they mediate fear responding by transferring cue signals to the output stage of the amygdala. Some BLA projection neurons retain their cue responses after extinction. Recent work shows that activation of the endocannabinoid system is necessary for extinction, and it leads to long-term depression (LTD) of the GABAergic synapses that inhibitory interneurons make onto BLA projection neurons. Such GABAergic LTD would enhance the responses of the BLA projection neurons that mediate fear responding, so it would seem to oppose, rather than promote, extinction. To address this paradox, a computational analysis of two well-known conceptual models of amygdaloid plasticity was undertaken. The analysis employed exhaustive state-space search conducted within a declarative programming environment. The analysis reveals that GABAergic LTD actually increases the number of synaptic strength configurations that achieve extinction while preserving the cue responses of some BLA projection neurons in both models. The results suggest that GABAergic LTD helps the amygdala retain cue memory during extinction even as the amygdala learns to suppress the previously conditioned response. The analysis also reveals which features of both models are essential for their ability to achieve extinction with some cue memory preservation, and suggests experimental tests of those features. PMID:23761759

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

Toxoplasma gondii Infection in Mice Impairs Long-Term Fear Memory Consolidation through Dysfunction of the Cortex and Amygdala.

PubMed

Ihara, Fumiaki; Nishimura, Maki; Muroi, Yoshikage; Mahmoud, Motamed Elsayed; Yokoyama, Naoaki; Nagamune, Kisaburo; Nishikawa, Yoshifumi

2016-10-01

Chronic infection with Toxoplasma gondii becomes established in tissues of the central nervous system, where parasites may directly or indirectly modulate neuronal function. Epidemiological studies have revealed that chronic infection in humans is a risk factor for developing mental diseases. However, the mechanisms underlying parasite-induced neuronal dysfunction in the brain remain unclear. Here, we examined memory associated with conditioned fear in mice and found that T. gondii infection impairs consolidation of conditioned fear memory. To examine the brain pathology induced by T. gondii infection, we analyzed the parasite load and histopathological changes. T. gondii infects all brain areas, yet the cortex exhibits more severe tissue damage than other regions. We measured neurotransmitter levels in the cortex and amygdala because these regions are involved in fear memory expression. The levels of dopamine metabolites but not those of dopamine were increased in the cortex of infected mice compared with those in the cortex of uninfected mice. In contrast, serotonin levels were decreased in the amygdala and norepinephrine levels were decreased in the cortex and amygdala of infected mice. The levels of cortical dopamine metabolites were associated with the time spent freezing in the fear-conditioning test. These results suggest that T. gondii infection affects fear memory through dysfunction of the cortex and amygdala. Our findings provide insight into the mechanisms underlying the neurological changes seen during T. gondii infection. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

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

The effect of left frontal transcranial direct-current stimulation on propranolol-induced fear memory acquisition and consolidation deficits.

PubMed

Nasehi, Mohammad; Khani-Abyaneh, Mozhgan; Ebrahimi-Ghiri, Mohaddeseh; Zarrindast, Mohammad-Reza

2017-07-28

Accumulating evidence supports the efficacy of transcranial direct current stimulation (tDCS) in modulating numerous cognitive functions. Despite the fact that tDCS has been used for the enhancement of memory and cognition, very few animal studies have addressed its impact on the modulation of fear memory. This study was designed to determine whether pre/post-training frontal tDCS application would alter fear memory acquisition and/or consolidation deficits induced by propranolol in NMRI mice. Results indicated that administration of β1-adrenoceptor blocker propranolol (0.1mg/kg) impaired fear memory retrieval. Pre/post-training application of anodal tDCS when propranolol was administered prior to training reversed contextual memory retrieval whereas only the anodal application prior to training could induce the same result in the auditory test. Meanwhile, anodal stimulation had no effect on fear memories by itself. Moreover, regardless of when cathode was applied and propranolol administered, their combination restored contextual memory retrieval, while only cathodal stimulation prior to training facilitated the contextual memory retrieval. Also, auditory memory retrieval was restored when cathodal stimulation and propranolol occurred prior to training but it was abolished when stimulation occurred after training and propranolol was administered prior to training. Collectively, our findings show that tDCS applied on the left frontal cortex of mice affects fear memory performance. This alteration seems to be task-dependent and varies depending on the nature and timing of the stimulation. In certain conditions, tDCS reverses the effect of propranolol. These results provide initial evidence to support the timely use of tDCS for the modulation of fear-related memories. Copyright © 2017 Elsevier B.V. All rights reserved.

Circadian Rhythms in Fear Conditioning: An Overview of Behavioral, Brain System, and Molecular Interactions

PubMed Central

Stork, Oliver

2017-01-01

The formation of fear memories is a powerful and highly evolutionary conserved mechanism that serves the behavioral adaptation to environmental threats. Accordingly, classical fear conditioning paradigms have been employed to investigate fundamental molecular processes of memory formation. Evidence suggests that a circadian regulation mechanism allows for a timestamping of such fear memories and controlling memory salience during both their acquisition and their modification after retrieval. These mechanisms include an expression of molecular clocks in neurons of the amygdala, hippocampus, and medial prefrontal cortex and their tight interaction with the intracellular signaling pathways that mediate neural plasticity and information storage. The cellular activities are coordinated across different brain regions and neural circuits through the release of glucocorticoids and neuromodulators such as acetylcholine, which integrate circadian and memory-related activation. Disturbance of this interplay by circadian phase shifts or traumatic experience appears to be an important factor in the development of stress-related psychopathology, considering these circadian components are of critical importance for optimizing therapeutic approaches to these disorders. PMID:28698810

Changes in heart rate variability are associated with expression of short-term and long-term contextual and cued fear memories.

PubMed

Liu, Jun; Wei, Wei; Kuang, Hui; Zhao, Fang; Tsien, Joe Z

2013-01-01

Heart physiology is a highly useful indicator for measuring not only physical states, but also emotional changes in animals. Yet changes of heart rate variability during fear conditioning have not been systematically studied in mice. Here, we investigated changes in heart rate and heart rate variability in both short-term and long-term contextual and cued fear conditioning. We found that while fear conditioning could increase heart rate, the most significant change was the reduction in heart rate variability which could be further divided into two distinct stages: a highly rhythmic phase (stage-I) and a more variable phase (stage-II). We showed that the time duration of the stage-I rhythmic phase were sensitive enough to reflect the transition from short-term to long-term fear memories. Moreover, it could also detect fear extinction effect during the repeated tone recall. These results suggest that heart rate variability is a valuable physiological indicator for sensitively measuring the consolidation and expression of fear memories in mice.

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.)…

Context-Dependent Encoding of Fear and Extinction Memories in a Large-Scale Network Model of the Basal Amygdala

PubMed Central

Vlachos, Ioannis; Herry, Cyril; Lüthi, Andreas; Aertsen, Ad; Kumar, Arvind

2011-01-01

The basal nucleus of the amygdala (BA) is involved in the formation of context-dependent conditioned fear and extinction memories. To understand the underlying neural mechanisms we developed a large-scale neuron network model of the BA, composed of excitatory and inhibitory leaky-integrate-and-fire neurons. Excitatory BA neurons received conditioned stimulus (CS)-related input from the adjacent lateral nucleus (LA) and contextual input from the hippocampus or medial prefrontal cortex (mPFC). We implemented a plasticity mechanism according to which CS and contextual synapses were potentiated if CS and contextual inputs temporally coincided on the afferents of the excitatory neurons. Our simulations revealed a differential recruitment of two distinct subpopulations of BA neurons during conditioning and extinction, mimicking the activation of experimentally observed cell populations. We propose that these two subgroups encode contextual specificity of fear and extinction memories, respectively. Mutual competition between them, mediated by feedback inhibition and driven by contextual inputs, regulates the activity in the central amygdala (CEA) thereby controlling amygdala output and fear behavior. The model makes multiple testable predictions that may advance our understanding of fear and extinction memories. PMID:21437238

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

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

PubMed

Burghardt, N S; Bauer, E P

2013-09-05

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

Hippocampal Processing of Ambiguity Enhances Fear Memory

PubMed Central

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

2016-01-01

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

Hippocampal Processing of Ambiguity Enhances Fear Memory.

PubMed

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

2017-02-01

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

Fear memory for cue and context: opposite and time-dependent effects of a physiological dose of corticosterone in male BALB/c and C57BL/6J mice.

PubMed

Diamantopoulou, Anastasia; Oitzl, Melly S; Grauer, Ettie

2012-07-23

Highly emotional, stress reactive BALB/c mice secrete more corticosterone in response to fear conditioning than the low stress reactive C57BL/6J mice. Fear memory to cue and context differs between the strains. We injected corticosterone at physiological concentrations (250 μg/kg i.p.) 30 min before fear conditioning. Fear memory was tested 48 and 72 h later. Although corticosterone had little effect on acquisition, it differentially affected fear memories in strain dependent manner: while BALB/c mice decreased freezing during cue and context episodes, C57BL/6J mice showed an overall increase in freezing. BALB/c mice showed extinction over days while no such extinction was seen in C57BL/6J mice. Evaluation of these data in the perspective of previous studies using the same fear conditioning paradigm with corticosterone injections 5 min before or immediately after acquisition, revealed the impact of corticosterone during conditioning on the strength of fear memories. In C57BL/6J mice the overall increase in fear memories was higher if corticosterone was injected 30 min pre acquisition than if injected 5 min pre. In contrast, BALB/c mice showed reduced fear memories when injected 30 min pre compared to that seen 5 min pre acquisition. Both strains showed decreased fear memories compared to vehicle if corticosterone was administered immediately after acquisition. We conclude that the timing of physiologically relevant, stress levels increase in corticosterone is essential for the processing of aversive events and the formation of fear memories. However, the quality of the effect depends on the genetic background. These findings contribute to the understanding of the etiology of stress-related disorders. Copyright © 2012 Elsevier B.V. All rights reserved.

Human Fear Conditioning Conducted in Full Immersion 3-Dimensional Virtual Reality

PubMed Central

Huff, Nicole C.; Zielinski, 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 2 . Skin conductance response served as the dependent measure of fear acquisition, memory retention and extinction. PMID:20736913

Seeking a Spotless Mind: Extinction, Deconsolidation, and Erasure of Fear Memory

PubMed Central

Maren, Stephen

2011-01-01

Learning to contend with threats in the environment is essential to survival, but dysregulation of memories for traumatic events can lead to disabling psychopathology. Recent years have witnessed an impressive growth in our understanding of the neural systems and synaptic mechanisms underlying emotional memory formation. As a consequence, interest has emerged in developing strategies for suppressing, if not eliminating, fear memories. Here I review recent work employing sophisticated behavioral, pharmacological, and molecular tools to target fear memories, placing these memories firmly behind the crosshairs of neurobiologically informed interventions. PMID:21658578

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

PubMed

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

2010-11-01

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

Prefrontal consolidation supports the attainment of fear memory accuracy.

PubMed

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

2014-08-01

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. © 2014 Vieira et al.; Published by Cold Spring Harbor Laboratory Press.

From Contextual Fear to a Dynamic View of Memory Systems

PubMed Central

Fanselow, Michael S

2009-01-01

The brain does not learn and remember in a unitary fashion. Rather, different circuits specialize in certain classes of problems and encode different types of information. Damage to one of these systems typically results in amnesia only for the form of memory that is the affected region's specialty. How does the brain allocate a specific category of memory to a particular circuit? This question has received little attention. The currently dominant view, Multiple Memory Systems Theory, assumes that such abilities are hard-wired. Using fear conditioning as a paradigmatic case, I propose an alternative model in which mnemonic processing is allocated to specific circuits through a dynamic process. Potential circuits compete to form memories with the most efficient circuits emerging as winners. However, alternate circuits compensate when these “primary” circuits are compromised. PMID:19939724

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

2016-08-04

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.

Selective neuronal degeneration in the retrosplenial cortex impairs the recall of contextual fear memory.

PubMed

Sigwald, Eric L; Genoud, Manuel E; Giachero, Marcelo; de Olmos, Soledad; Molina, Víctor A; Lorenzo, Alfredo

2016-05-01

The retrosplenial cortex (RSC) is one of the largest cortical areas in rodents, and is subdivided in two main regions, A29 and A30, according to their cytoarchitectural organization and connectivities. However, very little is known about the functional activity of each RSC subdivision during the execution of complex cognitive tasks. Here, we used a well-established fear learning protocol that induced long-lasting contextual fear memory and showed that during evocation of the fear memory, the expression of early growth response gene 1 was up-regulated in A30, and in other brain areas implicated in fear and spatial memory, however, was down-regulated in A29, including layers IV and V. To search for the participation of A29 on fear memory, we triggered selective degeneration of neurons within cortical layers IV and V of A29 by using a non-invasive protocol that takes advantage of the vulnerability that these neurons have MK801-toxicity and the modulation of this neurodegeneration by testosterone. Application of 5 mg/kg MK801 in intact males induced negligible neuronal degeneration of A29 neurons and had no impact on fear memory retrieval. However, in orchiectomized rats, 5 mg/kg MK801 induced overt degeneration of layers IV-V neurons of A29, significantly impairing fear memory recall. Degeneration of A29 neurons did not affect exploratory or anxiety-related behavior nor altered unconditioned freezing. Importantly, protecting A29 neurons from MK801-toxicity by testosterone preserved fear memory recall in orchiectomized rats. Thus, neurons within cortical layers IV-V of A29 are critically required for efficient retrieval of contextual fear memory.

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…

NF-κB mediates Gadd45β expression and DNA demethylation in the hippocampus during fear memory formation.

PubMed

Jarome, Timothy J; Butler, Anderson A; Nichols, Jessica N; Pacheco, Natasha L; Lubin, Farah D

2015-01-01

Gadd45-mediated DNA demethylation mechanisms have been implicated in the process of memory formation. However, the transcriptional mechanisms involved in the regulation of Gadd45 gene expression during memory formation remain unexplored. NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) controls transcription of genes in neurons and is a critical regulator of synaptic plasticity and memory formation. In silico analysis revealed several NF-κB (p65/RelA and cRel) consensus sequences within the Gadd45β gene promoter. Whether NF-κB activity regulates Gadd45 expression and associated DNA demethylation in neurons during memory formation is unknown. Here, we found that learning in a fear conditioning paradigm increased Gadd45β gene expression and brain-derivedneurotrophic factor (BDNF) DNA demethylation in area CA1 of the hippocampus, both of which were prevented with pharmacological inhibition of NF-κB activity. Further experiments found that conditional mutations in p65/RelA impaired fear memory formation but did not alter changes in Gadd45β expression. The learning-induced increases in Gadd45β mRNA levels, Gadd45β binding at the BDNF gene and BDNF DNA demethylation were blocked in area CA1 of the c-rel knockout mice. Additionally, local siRNA-mediated knockdown of c-rel in area CA1 prevented fear conditioning-induced increases in Gadd45β expression and BDNF DNA demethylation, suggesting that c-Rel containing NF-κB transcription factor complex is responsible for Gadd45β regulation during memory formation. Together, these results support a novel transcriptional role for NF-κB in regulation of Gadd45β expression and DNA demethylation in hippocampal neurons during fear memory.

An Additional Prior Retrieval Alters the Effects of a Retrieval-Extinction Procedure on Recent and Remote Fear Memory

PubMed Central

An, Xianli; Yang, Ping; Chen, Siguang; Zhang, Fenfen; Yu, Duonan

2018-01-01

Several studies have shown that the isolated retrieval of a consolidated fear memory can induce a labile phase, during which extinction training can prevent the reinstatement, a form of relapse in which fear response to a fear-provoking context returns when a mild shock is presented. However, fear memory retrieval may also have another opposing result: the enhancement of fear memory. This implies that the fear memory trace can be modified by a brief retrieval. Unclear is whether the fear-impairing effect of retrieval-extinction (RE) is altered by a prior brief retrieval. The present study investigated the responses of recent and remote fear memories to the RE procedure after the presentation of an additional prior retrieval (priRet). We found that a single RE procedure effectively blocked the reinstatement of 2-day recent contextual fear memory. The memory-impairing effect of the RE procedure on recent fear was not observed when priRet was presented 6 or 24 h before the RE procedure. In contrast to the 2-day recent memory, the RE procedure failed to block the reinstatement of 36-day remote fear memory but successfully disrupted the return of remote fear memory after priRet. This memory-disruptive effect on remote memory did not occur when priRet was performed in a novel context. Nimodipine administration revealed that the blockade of priRet-induced processes recovered the effects of the RE procedure on both recent and remote fear memories. Our findings suggest that the susceptibility of recent and remote fear memories to RE procedures can be altered by an additional retrieval. PMID:29358910

An Additional Prior Retrieval Alters the Effects of a Retrieval-Extinction Procedure on Recent and Remote Fear Memory.

PubMed

An, Xianli; Yang, Ping; Chen, Siguang; Zhang, Fenfen; Yu, Duonan

2017-01-01

Several studies have shown that the isolated retrieval of a consolidated fear memory can induce a labile phase, during which extinction training can prevent the reinstatement, a form of relapse in which fear response to a fear-provoking context returns when a mild shock is presented. However, fear memory retrieval may also have another opposing result: the enhancement of fear memory. This implies that the fear memory trace can be modified by a brief retrieval. Unclear is whether the fear-impairing effect of retrieval-extinction (RE) is altered by a prior brief retrieval. The present study investigated the responses of recent and remote fear memories to the RE procedure after the presentation of an additional prior retrieval (priRet). We found that a single RE procedure effectively blocked the reinstatement of 2-day recent contextual fear memory. The memory-impairing effect of the RE procedure on recent fear was not observed when priRet was presented 6 or 24 h before the RE procedure. In contrast to the 2-day recent memory, the RE procedure failed to block the reinstatement of 36-day remote fear memory but successfully disrupted the return of remote fear memory after priRet. This memory-disruptive effect on remote memory did not occur when priRet was performed in a novel context. Nimodipine administration revealed that the blockade of priRet-induced processes recovered the effects of the RE procedure on both recent and remote fear memories. Our findings suggest that the susceptibility of recent and remote fear memories to RE procedures can be altered by an additional retrieval.

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

PubMed

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

2016-10-01

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

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…

Dissociation between Complete Hippocampal Context Memory Formation and Context Fear Acquisition

ERIC Educational Resources Information Center

Leake, Jessica; Zinn, Raphael; Corbit, Laura; Vissel, Bryce

2017-01-01

Rodents require a minimal time period to explore a context prior to footshock to display plateau-level context fear at test. To investigate whether this rapid fear plateau reflects complete memory formation within that short time-frame, we used the immediate-early gene product Arc as an indicator of hippocampal context memory formation-related…

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

PubMed

Katz, Ira K; Lamprecht, Raphael

2015-02-01

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

The endocannabinoid system in anxiety, fear memory and habituation

PubMed Central

Ruehle, S; Rey, A Aparisi; Remmers, F

2012-01-01

Evidence for the involvement of the endocannabinoid system (ECS) in anxiety and fear has been accumulated, providing leads for novel therapeutic approaches. In anxiety, a bidirectional influence of the ECS has been reported, whereby anxiolytic and anxiogenic responses have been obtained after both increases and decreases of the endocannabinoid tone. The recently developed genetic tools have revealed different but complementary roles for the cannabinoid type 1 (CB1) receptor on GABAergic and glutamatergic neuronal populations. This dual functionality, together with the plasticity of CB1 receptor expression, particularly on GABAergic neurons, as induced by stressful and rewarding experiences, gives the ECS a unique regulatory capacity for maintaining emotional homeostasis. However, the promiscuity of the endogenous ligands of the CB1 receptor complicates the interpretation of experimental data concerning ECS and anxiety. In fear memory paradigms, the ECS is mostly involved in the two opposing processes of reconsolidation and extinction of the fear memory. Whereas ECS activation deteriorates reconsolidation, proper extinction depends on intact CB1 receptor signalling. Thus, both for anxiety and fear memory processing, endocannabinoid signalling may ensure an appropriate reaction to stressful events. Therefore, the ECS can be considered as a regulatory buffer system for emotional responses. PMID:21768162

Brief fear preexposure facilitates subsequent fear conditioning.

PubMed

Iwasaki, Satoshi; Sakaguchi, Tetsuya; Ikegaya, Yuji

2015-06-01

Post-traumatic stress disorder (PTSD) is an anxiety disorder that occurs following an unexpected exposure to a severe psychological event. A history of a brief trauma is reported to affect a risk for future PTSD development; however, little is known about the mechanisms by which a previous trauma exposure drives the sensitivity to a late-coming trauma. Using a mouse PTSD model, we found that a prior foot shock enhances contextual fear conditioning. This shock-induced facilitation of fear conditioning (i.e., priming effect) persisted for 7 days and was prevented by MK801, an N-methyl-D-aspartate receptor antagonist. Other types of trauma, such as forced swimming or tail pinch, did not induce a priming effect on fear conditioning. Thus, a trauma is unlikely generalized to modify the sensitivity to other traumatic experiences. The behavioral procedure employed in this study may be a useful tool to elucidate the etiology of PTSD. Copyright © 2015 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

Inhibition of serotonin transporters disrupts the enhancement of fear memory extinction by 3,4-methylenedioxymethamphetamine (MDMA).

PubMed

Young, Matthew B; Norrholm, Seth D; Khoury, Lara M; Jovanovic, Tanja; Rauch, Sheila A M; Reiff, Collin M; Dunlop, Boadie W; Rothbaum, Barbara O; Howell, Leonard L

2017-10-01

3,4-Methylenedioxymethamphetamine (MDMA) persistently improves symptoms of post-traumatic stress disorder (PTSD) when combined with psychotherapy. Studies in rodents suggest that these effects can be attributed to enhancement of fear memory extinction. Therefore, MDMA may improve the effects of exposure-based therapy for PTSD, particularly in treatment-resistant patients. However, given MDMA's broad pharmacological profile, further investigation is warranted before moving to a complex clinical population. We aimed to inform clinical research by providing a translational model of MDMA's effect, and elucidating monoaminergic mechanisms through which MDMA enhances fear extinction. We explored the importance of monoamine transporters targeted by MDMA to fear memory extinction, as measured by reductions in conditioned freezing and fear-potentiated startle (FPS) in mice. Mice were treated with selective inhibitors of individual monoamine transporters prior to combined MDMA treatment and fear extinction training. MDMA enhanced the lasting extinction of FPS. Acute and chronic treatment with a 5-HT transporter (5-HTT) inhibitor blocked MDMA's effect on fear memory extinction. Acute inhibition of dopamine (DA) and norepinephrine (NE) transporters had no effect. 5-HT release alone did not enhance extinction. Blockade of MDMA's effect by 5-HTT inhibition also downregulated 5-HT 2A -mediated behavior, and 5-HT 2A antagonism disrupted MDMA's effect on extinction. We validate enhancement of fear memory extinction by MDMA in a translational behavioral model, and reveal the importance of 5-HTT and 5-HT 2A receptors to this effect. These observations support future clinical research of MDMA as an adjunct to exposure therapy, and provide important pharmacological considerations for clinical use in a population frequently treated with 5-HTT inhibitors.

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

Cholinergic transmission in the dorsal hippocampus modulates trace but not delay fear conditioning.

PubMed

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

2010-09-01

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

Cholinergic effects on fear conditioning I: the degraded contingency effect is disrupted by atropine but reinstated by physostigmine.

PubMed

Carnicella, Sebastien; Pain, Laure; Oberling, Philippe

2005-04-01

The cholinergic system has been shown to modulate contextual fear conditioning. However, with the exception of trace conditioning studies, most of the available data have focussed on independent context, i.e., context that do not compete with the conditioned stimulus to control for the conditioned response (interactive context). In the present series of experiments, the effects of the muscarinic antagonist, atropine, were assessed when contextual fear memory interacts with cued fear memory to regulate conditioned response, using a Pavlovian degraded contingency preparation in rats. This preparation not only afforded an insight into simple Pavlovian associations but also enabled us to test for the processes of competition that made use of these associations to make an appropriate response to a stimulus [degraded contingency effect (DCE)]. In experiment 1, three doses of atropine [2.5, 5.0, and 10.0 mg/kg, intraperitoneally (i.p.)] were evaluated on male Sprague-Dawley rats. In experiment 2, physostigmine (0.037-0.3 mg/kg, i.p.) was injected after the administration of 5 mg/kg of atropine. Experiment 1A and its partial replication (experiment 1B) showed that at asymptotic level of training, atropine did not alter contextual and cued fear memories when the subjects were directly tested for them, whereas it suppressed the DCE for a 5 mg/kg dose. Indeed, atropine-induced suppression of the DCE was found to be an inverted U-shaped dose-response curve. Experiment 2 showed that physostigmine caused a dose-dependent reversal of the atropine-induced alleviation of the DCE, without altering the expression of simple cued and contextual fear memories. These results evidence at asymptotic level of training a cholinergic modulation of the processing of interactive context, but not of independent ones. They are discussed in the framework of the mechanisms that are involved in both types of contextual processing.

Developing and validating trace fear conditioning protocols in C57BL/6 mice.

PubMed

Burman, Michael A; Simmons, Cassandra A; Hughes, Miles; Lei, Lei

2014-01-30

Classical fear conditioning is commonly used to study the biology of fear, anxiety and memory. Previous research demonstrated that delay conditioning requires a neural circuit involving the amygdala, but not usually the hippocampus. Trace and contextual fear conditioning require the amygdala and hippocampus. While these paradigms were developed primarily using rat models, they are increasingly being used in mice. The current studies develop trace fear conditioning and control paradigms to allow for the assessment of trace and delay fear conditioning in C57BL/6N mice. Our initial protocol yielded clear delay and contextual conditioning. However, trace conditioning failed to differentiate from an unpaired group and was not hippocampus-dependent. These results suggested that the protocol needed to be modified to specifically accommodate trace conditioning the mice. In order to reduce unconditioned freezing and increase learning, the final protocol was developed by decreasing the intensity of the tone and by increasing the inter-trial interval. Our final protocol produced trace conditioned freezing that was significantly greater than that followed unpaired stimulus exposure and was disrupted by hippocampus lesions. A review of the literature produced 90 articles using trace conditioning in mice. Few of those articles used any kind of behavioral control group, which is required to rule out non-associative factors causing fearful behavior. Fewer used unpaired groups involving tones and shocks within a session, which is the optimal control group. Our final trace conditioning protocol can be used in future studies examining genetically modified C57BL/6N mice. Copyright © 2013 Elsevier B.V. All rights reserved.

Developing and Validating Trace Fear Conditioning Protocols in C57BL/6 Mice

PubMed Central

Burman, Michael A; Simmons, Cassandra A; Hughes, Miles; Lei, Lei

2013-01-01

Background Classical fear conditioning is commonly used to study the biology of fear, anxiety and memory. Previous research demonstrated that delay conditioning requires a neural circuit involving the amygdala, but not usually the hippocampus. Trace and contextual fear conditioning require the amygdala and hippocampus. While these paradigms were developed primarily using rat models, they are increasingly being used in mice. New Method The current studies develop trace fear conditioning and control paradigms to allow for the assessment of trace and delay fear conditioning in C57BL/6N mice. Our initial protocol yielded clear delay and contextual conditioning. However, trace conditioning failed to differentiate from an unpaired group and was not hippocampus-dependent. These results suggested that the protocol needed to be modified to specifically accommodate trace conditioning the mice. In order to reduce unconditioned freezing and increase learning, the final protocol was developed by decreasing the intensity of the tone and by increasing the inter-trial interval. Results Our final protocol produced trace conditioned freezing that was significantly greater than that followed unpaired stimulus exposure and was disrupted by hippocampus lesions. Comparison with Existing Methods A review of the literature produced 90 articles using trace conditioning in mice. Few of those articles used any kind of behavioral control group, which is required to rule out non-associative factors causing fearful behavior. Fewer used unpaired groups involving tones and shocks within a session, which is the optimal control group. Conclusions Our final trace conditioning protocol can be used in future studies examining genetically modified C57BL/6N mice. PMID:24269252

16Oxygen irradiation enhances cued fear memory in B6D2F1 mice

NASA Astrophysics Data System (ADS)

Raber, Jacob; Marzulla, Tessa; Kronenberg, Amy; Turker, Mitchell S.

2015-11-01

The space radiation environment includes energetic charged particles that may impact cognitive performance. We assessed the effects of 16O ion irradiation on cognitive performance of C57BL/6J × DBA/2J F1 (B6D2F1) mice at OHSU (Portland, OR) one month following irradiation at Brookhaven National Laboratory (BNL, Upton, NY). Hippocampus-dependent contextual fear memory and hippocampus-independent cued fear memory of B6D2F1 mice were tested. 16O ion exposure enhanced cued fear memory. This effect showed a bell-shaped dose response curve. Cued fear memory was significantly stronger in mice irradiated with 16O ions at a dose of 0.4 or 0.8 Gy than in sham-irradiated mice or following irradiation at 1.6 Gy. In contrast to cued fear memory, contextual fear memory was not affected following 16O ion irradiation at the doses used in this study. These data indicate that the amygdala might be particularly susceptible to effects of 16O ion exposure.

Calpain modulates fear memory consolidation, retrieval and reconsolidation in the hippocampus.

PubMed

Popik, Bruno; Crestani, Ana Paula; Silva, Mateus Oliveira; Quillfeldt, Jorge Alberto; de Oliveira Alvares, Lucas

2018-05-01

It has been proposed that long-lasting changes in dendritic spines provide a physical correlate for memory formation and maintenance. Spine size and shape are highly plastic, controlled by actin polymerization/depolymerization cycles. This actin dynamics are regulated by proteins such as calpain, a calcium-dependent cysteine protease that cleaves the structural cytoskeleton proteins and other targets involved in synaptic plasticity. Here, we tested whether the pharmacological inhibition of calpain in the dorsal hippocampus affects memory consolidation, retrieval and reconsolidation in rats trained in contextual fear conditioning. We first found that post-training infusion of the calpain inhibitor PD150606 impaired long-term memory consolidation, but not short-term memory. Next, we showed that pre-test infusion of the calpain inhibitor hindered memory retrieval. Finally, blocking calpain activity after memory reactivation disrupted reconsolidation. Taken together, our results show that calpain play an essential role in the hippocampus by enabling memory formation, expression and reconsolidation. Copyright © 2018 Elsevier Inc. All rights reserved.

The interhemispheric CA1 circuit governs rapid generalisation but not fear memory.

PubMed

Zhou, Heng; Xiong, Gui-Jing; Jing, Liang; Song, Ning-Ning; Pu, De-Lin; Tang, Xun; He, Xiao-Bing; Xu, Fu-Qiang; Huang, Jing-Fei; Li, Ling-Jiang; Richter-Levin, Gal; Mao, Rong-Rong; Zhou, Qi-Xin; Ding, Yu-Qiang; Xu, Lin

2017-12-19

Encoding specificity theory predicts most effective recall by the original conditions at encoding, while generalization endows recall flexibly under circumstances which deviate from the originals. The CA1 regions have been implicated in memory and generalization but whether and which locally separated mechanisms are involved is not clear. We report here that fear memory is quickly formed, but generalization develops gradually over 24 h. Generalization but not fear memory is impaired by inhibiting ipsilateral (ips) or contralateral (con) CA1, and by optogenetic silencing of the ipsCA1 projections onto conCA1. By contrast, in vivo fEPSP recordings reveal that ipsCA1-conCA1 synaptic efficacy is increased with delay over 24 h when generalization is formed but it is unchanged if generalization is disrupted. Direct excitation of ipsCA1-conCA1 synapses using chemogenetic hM3Dq facilitates generalization formation. Thus, rapid generalization is an active process dependent on bilateral CA1 regions, and encoded by gradual synaptic learning in ipsCA1-conCA1 circuit.

Extinction training during the reconsolidation window prevents recovery of fear.

PubMed

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

2012-08-24

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

M1-muscarinic receptors promote fear memory consolidation via phospholipase C and the M-current.

PubMed

Young, Matthew B; Thomas, Steven A

2014-01-29

Neuromodulators released during and after a fearful experience promote the consolidation of long-term memory for that experience. Because overconsolidation may contribute to the recurrent and intrusive memories of post-traumatic stress disorder, neuromodulatory receptors provide a potential pharmacological target for prevention. Stimulation of muscarinic receptors promotes memory consolidation in several conditioning paradigms, an effect primarily associated with the M1 receptor (M1R). However, neither inhibiting nor genetically disrupting M1R impairs the consolidation of cued fear memory. Using the M1R agonist cevimeline and antagonist telenzepine, as well as M1R knock-out mice, we show here that M1R, along with β2-adrenergic (β2AR) and D5-dopaminergic (D5R) receptors, regulates the consolidation of cued fear memory by redundantly activating phospholipase C (PLC) in the basolateral amygdala (BLA). We also demonstrate that fear memory consolidation in the BLA is mediated in part by neuromodulatory inhibition of the M-current, which is conducted by KCNQ channels and is known to be inhibited by muscarinic receptors. Manipulating the M-current by administering the KCNQ channel blocker XE991 or the KCNQ channel opener retigabine reverses the effects on consolidation caused by manipulating β2AR, D5R, M1R, and PLC. Finally, we show that cAMP and protein kinase A (cAMP/PKA) signaling relevant to this stage of consolidation is upstream of these neuromodulators and PLC, suggesting an important presynaptic role for cAMP/PKA in consolidation. These results support the idea that neuromodulatory regulation of ion channel activity and neuronal excitability is a critical mechanism for promoting consolidation well after acquisition has occurred.

Monetary effects on fear conditioning.

PubMed

Qu, Chen; Zhang, Aiyi; Chen, Qishan

2013-04-01

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

Delta-9-Tetrahydrocannabinol Potentiates Fear Memory Salience Through Functional Modulation of Mesolimbic Dopaminergic Activity States.

PubMed

Fitoussi, Aurelie; Zunder, Jordan; Tan, Huibing; Laviolette, Steven R

2018-05-18

Chronic or acute exposure to delta-9-tetrahydrocannabinol (THC), the main psychoactive compound in cannabis, has been associated with numerous neuropsychiatric side-effects, including dysregulation of emotional processing and associative memory formation. Clinical and pre-clinical evidence suggests that the effects of THC are due to the ability to modulate mesolimbic dopamine (DA) activity states in the nucleus accumbens (NAc) and ventral tegmental area (VTA). Nevertheless, the mechanisms by which THC modulates mesolimbic DA function and emotional processing are not well understood. Using an olfactory associative fear memory procedure combined with in vivo neuronal electrophysiology, we examined the effects of direct THC microinfusions targeting the shell region of the NAc (NASh) and examined how THC may modulate the processing of fear-related emotional memory and concomitant activity states of the mesolimbic DA system. We report that intra-NASh THC dose-dependently potentiates the emotional salience of normally sub-threshold fear-conditioning cues. These effects were dependent upon intra-VTA transmission through GABAergic receptor mechanisms and intra-NASh DAergic transmission. Furthermore, doses of intra-NASh THC that potentiated fear memory salience were found to modulate intra-VTA neuronal network activity by increasing the spontaneous firing and bursting frequency of DAergic neurons whilst decreasing the activity levels of a subpopulation of putative GABAergic VTA neurons. These findings demonstrate that THC can act directly in the NASh to modulate mesolimbic activity states and induce disturbances in emotional salience and memory formation through modulation of VTA DAergic transmission. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Sleep-Dependent Oscillatory Synchronization: A Role in Fear Memory Consolidation.

PubMed

Totty, Michael S; Chesney, Logan A; Geist, Phillip A; Datta, Subimal

2017-01-01

Sleep plays an important role in memory consolidation through the facilitation of neuronal plasticity; however, how sleep accomplishes this remains to be completely understood. It has previously been demonstrated that neural oscillations are an intrinsic mechanism by which the brain precisely controls neural ensembles. Inter-regional synchronization of these oscillations is also known to facilitate long-range communication and long-term potentiation (LTP). In the present study, we investigated how the characteristic rhythms found in local field potentials (LFPs) during non-REM and REM sleep play a role in emotional memory consolidation. Chronically implanted bipolar electrodes in the lateral amygdala (LA), dorsal and ventral hippocampus (DH, VH), and the infra-limbic (IL), and pre-limbic (PL) prefrontal cortex were used to record LFPs across sleep-wake activity following each day of a Pavlovian cued fear conditioning paradigm. This resulted in three principle findings: (1) theta rhythms during REM sleep are highly synchronized between regions; (2) the extent of inter-regional synchronization during REM and non-REM sleep is altered by FC and EX; (3) the mean phase difference of synchronization between the LA and VH during REM sleep predicts changes in freezing after cued fear extinction. These results both oppose a currently proposed model of sleep-dependent memory consolidation and provide a novel finding which suggests that the role of REM sleep theta rhythms in memory consolidation may rely more on the relative phase-shift between neural oscillations, rather than the extent of phase synchronization.

Identification of Parvalbumin Interneurons as Cellular Substrate of Fear Memory Persistence.

PubMed

Çaliskan, Gürsel; Müller, Iris; Semtner, Marcus; Winkelmann, Aline; Raza, Ahsan S; Hollnagel, Jan O; Rösler, Anton; Heinemann, Uwe; Stork, Oliver; Meier, Jochen C

2016-05-01

Parvalbumin-positive (PV) basket cells provide perisomatic inhibition in the cortex and hippocampus and control generation of memory-related network activity patterns, such as sharp wave ripples (SPW-R). Deterioration of this class of fast-spiking interneurons has been observed in neuropsychiatric disorders and evidence from animal models suggests their involvement in the acquisition and extinction of fear memories. Here, we used mice with neuron type-targeted expression of the presynaptic gain-of-function glycine receptor RNA variant GlyR α3L(185L)to genetically enhance the network activity of PV interneurons. These mice showed reduced extinction of contextual fear memory but normal auditory cued fear memory. They furthermore displayed increase of SPW-R activity in area CA3 and CA1 and facilitated propagation of this particular network activity pattern, as determined in ventral hippocampal slice preparations. Individual freezing levels during extinction and SPW-R propagation were correlated across genotypes. The same was true for parvalbumin immunoreactivity in the ventral hippocampus, which was generally augmented in the GlyR mutant mice and correlated with individual freezing levels. Together, these results identify PV interneurons as critical cellular substrate of fear memory persistence and associated SPW-R activity in the hippocampus. Our findings may be relevant for the identification and characterization of physiological correlates for posttraumatic stress and anxiety disorders. © The Author 2016. Published by Oxford University Press.

Identification of Parvalbumin Interneurons as Cellular Substrate of Fear Memory Persistence

PubMed Central

Çalışkan, Gürsel; Müller, Iris; Semtner, Marcus; Winkelmann, Aline; Raza, Ahsan S.; Hollnagel, Jan O.; Rösler, Anton; Heinemann, Uwe; Stork, Oliver; Meier, Jochen C.

2016-01-01

Parvalbumin-positive (PV) basket cells provide perisomatic inhibition in the cortex and hippocampus and control generation of memory-related network activity patterns, such as sharp wave ripples (SPW-R). Deterioration of this class of fast-spiking interneurons has been observed in neuropsychiatric disorders and evidence from animal models suggests their involvement in the acquisition and extinction of fear memories. Here, we used mice with neuron type-targeted expression of the presynaptic gain-of-function glycine receptor RNA variant GlyR α3L185L to genetically enhance the network activity of PV interneurons. These mice showed reduced extinction of contextual fear memory but normal auditory cued fear memory. They furthermore displayed increase of SPW-R activity in area CA3 and CA1 and facilitated propagation of this particular network activity pattern, as determined in ventral hippocampal slice preparations. Individual freezing levels during extinction and SPW-R propagation were correlated across genotypes. The same was true for parvalbumin immunoreactivity in the ventral hippocampus, which was generally augmented in the GlyR mutant mice and correlated with individual freezing levels. Together, these results identify PV interneurons as critical cellular substrate of fear memory persistence and associated SPW-R activity in the hippocampus. Our findings may be relevant for the identification and characterization of physiological correlates for posttraumatic stress and anxiety disorders. PMID:26908632

Phosphodiesterase 10A inhibition attenuates sleep deprivation-induced deficits in long-term fear memory.

PubMed

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

2016-12-02

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