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

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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.

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

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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

Prior stress promotes the generalization of contextual fear memories: Involvement of the gabaergic signaling within the basolateral amygdala complex.

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Bender, C L; Otamendi, A; Calfa, G D; Molina, V A

2018-04-20

Fear generalization occurs when a response, previously acquired with a threatening stimulus, is transferred to a similar one. However, it could be maladaptive when stimuli that do not represent a real threat are appraised as dangerous, which is a hallmark of several anxiety disorders. Stress exposure is a major risk factor for the occurrence of anxiety disorders and it is well established that it influences different phases of fear memory; nevertheless, its impact on the generalization of contextual fear memories has been less studied. In the present work, we have characterized the impact of acute restraint stress prior to contextual fear conditioning on the generalization of this fear memory, and the role of the GABAergic signaling within the basolateral amygdala complex (BLA) on the stress modulatory effects. We have found that a single stress exposure promoted the generalization of this memory trace to a different context that was well discriminated in unstressed conditioned animals. Moreover, this effect was dependent on the formation of a contextual associative memory and on the testing order (i.e., conditioning context first vs generalization context first). Furthermore, we observed that increasing GABA-A signaling by intra-BLA midazolam administration prior to the stressful session exposure prevented the generalization of fear memory, whereas intra-BLA administration of the GABA-A antagonist (Bicuculline), prior to fear conditioning, induced the generalization of fear memory in unstressed rats. We concluded that stress exposure, prior to contextual fear conditioning, promotes the generalization of fear memory and that the GABAergic transmission within the BLA has a critical role in this phenomenon. Copyright © 2017 Elsevier Inc. All rights reserved.

Acute nicotine disrupts consolidation of contextual fear extinction and alters long-term memory-associated hippocampal kinase activity.

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Kutlu, Munir Gunes; Garrett, Brendan; Gadiwalla, Sana; Tumolo, Jessica M; Gould, Thomas J

2017-11-01

Previous research has shown that acute nicotine, an agonist of nAChRs, impaired fear extinction. However, the effects of acute nicotine on consolidation of contextual fear extinction memories and associated cell signaling cascades are unknown. Therefore, we examined the effects of acute nicotine injections before (pre-extinction) and after (post-extinction) contextual fear extinction on behavior and the phosphorylation of dorsal and ventral hippocampal ERK1/2 and JNK1 and protein levels on the 1st and 3rd day of extinction. Our results showed that acute nicotine administered prior to extinction sessions downregulated the phosphorylated forms of ERK1/2 in the ventral hippocampus, but not dorsal hippocampus, and JNK1 in both dorsal and ventral hippocampus on the 3rd extinction day. These effects were absent on the 1st day of extinction. We also showed that acute nicotine administered immediately and 30 min, but not 6 h, following extinction impaired contextual fear extinction suggesting that acute nicotine disrupts consolidation of contextual fear extinction memories. Finally, acute nicotine injections immediately after extinction sessions upregulated the phosphorylated forms of ERK1/2 in the ventral hippocampus, but did not affect JNK1. These results show that acute nicotine impairs contextual fear extinction potentially by altering molecular processes responsible for the consolidation of extinction memories. Copyright © 2017 Elsevier Inc. All rights reserved.

Differential role of Rac in the basolateral amygdala and cornu ammonis 1 in the reconsolidation of auditory and contextual Pavlovian fear memory in rats.

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Wu, Ping; Ding, Zeng-Bo; Meng, Shi-Qiu; Shen, Hao-Wei; Sun, Shi-Chao; Luo, Yi-Xiao; Liu, Jian-Feng; Lu, Lin; Zhu, Wei-Li; Shi, Jie

2014-08-01

A conditioned stimulus (CS) is associated with a fearful unconditioned stimulus (US) in the traditional fear conditioning model. After fear conditioning, the CS-US association memory undergoes the consolidation process to become stable. Consolidated memory enters an unstable state after retrieval and requires the reconsolidation process to stabilize again. Evidence indicates the important role of Rac (Ras-related C3 botulinum toxin substrate) in the acquisition and extinction of fear memory. In the present study, we hypothesized that Rac in the amygdala is crucial for the reconsolidation of auditory and contextual Pavlovian fear memory. Auditory and contextual fear conditioning and microinjections of the Rac inhibitor NSC23766 were used to explore the role of Rac in the reconsolidation of auditory and contextual Pavlovian fear memory in rats. A microinjection of NSC23766 into the basolateral amygdala (BLA) but not central amygdala (CeA) or cornu ammonis 1 (CA1) immediately after memory retrieval disrupted the reconsolidation of auditory Pavlovian fear memory. A microinjection of NSC23766 into the CA1 but not BLA or CeA after memory retrieval disrupted the reconsolidation of contextual Pavlovian fear memory. Our experiments demonstrate that Rac in the BLA is crucial for the reconsolidation of auditory Pavlovian fear memory, whereas Rac in the CA1 is critical for the reconsolidation of contextual Pavlovian fear memory.

Loss of Ensemble Segregation in Dentate Gyrus, but Not in Somatosensory Cortex, during Contextual Fear Memory Generalization

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Marie Yokoyama

2016-11-01

Full Text Available The details of contextual or episodic memories are lost and generalized with the passage of time. Proper generalization may underlie the formation and assimilation of semantic memories and enable animals to adapt to ever-changing environments, whereas overgeneralization of fear memory evokes maladaptive fear responses to harmless stimuli, which is a symptom of anxiety disorders such as post-traumatic stress disorder (PTSD. To understand the neural basis of fear memory generalization, we investigated the patterns of neuronal ensemble reactivation during memory retrieval when contextual fear memory expression is generalized using transgenic mice that allowed us to visualize specific neuronal ensembles activated during memory encoding and retrieval. We found preferential reactivations of neuronal ensembles in the primary somatosensory cortex, when mice were returned to the conditioned context to retrieve their memory 1 day after conditioning. In the hippocampal dentate gyrus (DG, exclusively separated ensemble reactivation was observed when mice were exposed to a novel context. These results suggest that the DG as well as the somatosensory cortex were likely to distinguish the two different contexts at the ensemble activity level when memory is not generalized at the behavioral level. However, 9 days after conditioning when animals exhibited generalized fear, the unique reactivation pattern in the DG, but not in the somatosensory cortex, was lost. Our results suggest that the alternations in the ensemble representation within the DG, or in upstream structures that link the sensory cortex to the hippocampus, may underlie generalized contextual fear memory expression.

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

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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

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

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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

Acute immobilization stress following contextual fear conditioning reduces fear memory: timing is essential.

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Uwaya, Akemi; Lee, Hyunjin; Park, Jonghyuk; Lee, Hosung; Muto, Junko; Nakajima, Sanae; Ohta, Shigeo; Mikami, Toshio

2016-02-24

Histone acetylation is regulated in response to stress and plays an important role in learning and memory. Chronic stress is known to deteriorate cognition, whereas acute stress facilitates memory formation. However, whether acute stress facilitates memory formation when it is applied after fear stimulation is not yet known. Therefore, this study aimed to investigate the effect of acute stress applied after fear training on memory formation, mRNA expression of brain-derived neurotrophic factor (BDNF), epigenetic regulation of BDNF expression, and corticosterone level in mice in vivo. Mice were subjected to acute immobilization stress for 30 min at 60 or 90 min after contextual fear conditioning training, and acetylation of histone 3 at lysine 14 (H3K14) and level of corticosterone were measured using western blot analysis and enzyme-linked immunosorbent assay (ELISA), respectively. A freezing behavior test was performed 24 h after training, and mRNA expression of BDNF was measured using real-time polymerase chain reactions. Different groups of mice were used for each test. Freezing behavior significantly decreased with the down-regulation of BDNF mRNA expression caused by acute immobilization stress at 60 min after fear conditioning training owing to the reduction of H3K14 acetylation. However, BDNF mRNA expression and H3K14 acetylation were not reduced in animals subjected to immobilization stress at 90 min after the training. Further, the corticosterone level was significantly high in mice subjected to immobilization stress at 60 min after the training. Acute immobilization stress for 30 min at 60 min after fear conditioning training impaired memory formation and reduced BDNF mRNA expression and H3K14 acetylation in the hippocampus of mice owing to the high level of corticosterone.

Inhibition of Rac1 activity in the hippocampus impaired extinction of contextual fear.

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Jiang, Lizhu; Mao, Rongrong; Tong, Jianbin; Li, Jinnan; Chai, Anping; Zhou, Qixin; Yang, Yuexiong; Wang, Liping; Li, Lingjiang; Xu, Lin

2016-10-01

Promoting extinction of fear memory is the main treatment of fear disorders, especially post-traumatic stress disorder (PTSD). However, fear extinction is often incomplete in these patients. Our previous study had shown that Rac1 activity in hippocampus plays a crucial role in the learning of contextual fear memory in rats. Here, we further investigated whether Rac1 activity also modulated the extinction of contextual fear memory. We found that massed extinction obviously upregulated hippocampal Rac1 activity and induced long-term extinction of contextual fear in rats. Intrahippocampal injection of the Rac1 inhibitor NSC23766 prevents extinction of contextual fear in massed extinction training rats. In contrast, long-spaced extinction downregulated Rac1 activity and caused less extinction. And Rac1 activator CN04-A promotes extinction of contextual fear in long-spaced extinction rats. Our study demonstrates that inhibition of Rac1 activity in the hippocampus impaired extinction of contextual fear, suggesting that modulating Rac1 activity of the hippocampus may be promising therapy of fear disorders. Copyright © 2016 Elsevier Ltd. All rights reserved.

Blocking mineralocorticoid receptors prior to retrieval reduces contextual fear memory in mice.

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Ming Zhou

Full Text Available BACKGROUND: Corticosteroid hormones regulate appraisal and consolidation of information via mineralocorticoid receptors (MRs and glucocorticoid receptors (GRs respectively. How activation of these receptors modulates retrieval of fearful information and the subsequent expression of fear is largely unknown. We tested here whether blockade of MRs or GRs during retrieval also affects subsequent expression of fear memory. METHODOLOGY/PRINCIPAL FINDINGS: Mice were trained in contextual or tone cue fear conditioning paradigms, by pairing mild foot shocks with a particular context or tone respectively. Twenty-four hours after training, context-conditioned animals were re-exposed to the context for 3 or 30 minutes (day 2; tone-conditioned animals were placed in a different context and re-exposed to one or six tones. Twenty-four hours (day 3 and one month later, freezing behavior to the aversive context/tone was scored again. MR or GR blockade was achieved by giving spironolactone or RU486 subcutaneously one hour before retrieval on day 2. Spironolactone administered prior to brief context re-exposure reduced freezing behavior during retrieval and 24 hours later, but not one month later. Administration of spironolactone without retrieval of the context or immediately after retrieval on day 2 did not reduce freezing on day 3. Re-exposure to the context for 30 minutes on day 2 significantly reduced freezing on day 3 and one month later, but freezing was not further reduced by spironolactone. Administration of spironolactone prior to tone-cue re-exposure on day 2 did not affect freezing behavior. Treatment with RU486 prior to re-exposure did not affect context or tone-cue fear memories at any time point. CONCLUSIONS/SIGNIFICANCE: We conclude that MR blockade prior to retrieval strongly reduces the expression of contextual fear, implying that MRs, rather than GRs, play an important role in retrieval of emotional information and subsequent fear expression.

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

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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 (ploss. 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 responses without affecting their acquisition, and it is involved in time spent on social interaction, but not acquisition and short

Role of the hippocampus in contextual modulation of fear extinction

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Lingzhi Kong; Xihong Wu; Liang Li

2008-01-01

Fear extinction is an important form of emotional learning, and affects neural plasticity. Cue fear extinction is a classical form of inhibitory learning that can be used as an exposure-based treatment for phobia, because the long-term extinction memory produced during cue fear extinction can limit the over-expression of fear. The expression of this inhibitory memory partly depends on the context in which the extinction learning occurs. Studies such as transient inhibition, electrophysiology and brain imaging have proved that the hippocampus - an important structure in the limbic system - facilitates memory retrieval by contextual cues.Mediation of the hippocampus-medial prefrontal lobe circuit may be the neurobiological basis of this process.This article has reviewed the role of the hippocampus in the learning and retrieval of fear extinction.Contextual modulation of fear extinction may rely on a neural network consisting of the hippocampus, the medial prefrontal cortex and the amygdala.

Toll-like receptor 7-mediated enhancement of contextual fear memory in mice.

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Kubo, Yasunori; Yanagawa, Yoshiki; Matsumoto, Machiko; Hiraide, Sachiko; Kobayashi, Masanobu; Togashi, Hiroko

2012-10-01

Toll-like receptor (TLR) 7 recognizes viral single-stranded RNA and triggers production of the type I interferons (IFNs) IFN-α and IFN-β. Imiquimod, a synthetic TLR7 ligand, induces production of type I IFNs and is used clinically as an antiviral and antitumor drug. In the present study, we examined the effect of imiquimod on conditioned and innate fear behaviors in mice. Imiquimod was administered 2, 4, or 15 h before contextual fear conditioning. Imiquimod treatment 4 or 15 h before fear conditioning significantly enhanced context-dependent freezing behavior. This imiquimod-induced enhancement of fear-related behaviors was observed 120 h after fear conditioning. In contrast, imiquimod failed to enhance context-dependent freezing behavior in TLR7 knockout mice. Imiquimod had no significant effect on pain threshold or on innate fear-related behavior, as measured by the elevated plus-maze. The levels of type I IFN mRNA in the brain were significantly increased at 2 h after imiquimod treatment. Imiquimod also increased interleukin (IL)-1β mRNA expression in the brain at 4 h following administration, while mRNA expression of F4/80, a macrophage marker, was unaffected by imiquimod treatment. Our findings suggest that TLR7-mediated signaling enhances contextual fear memory in mice, possibly by inducing the expression of type I IFNs and IL-1β in the brain. Copyright © 2012 Elsevier Inc. All rights reserved.

Post-Training Unilateral Amygdala Lesions Selectively Impair Contextual Fear Memories

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

2012-01-01

The basolateral amygdala (BLA) and the dorsal hippocampus (dHPC) are both structures with key roles in contextual fear conditioning. During fear conditioning, it is postulated that contextual representations of the environment are formed in the hippocampus, which are then associated with foot shock in the amygdala. However, it is not known to what…

Extinction after retrieval: effects on the associative and nonassociative components of remote contextual fear memory.

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Costanzi, Marco; Cannas, Sara; Saraulli, Daniele; Rossi-Arnaud, Clelia; Cestari, Vincenzo

2011-01-01

Long-lasting memories of adverse experiences are essential for individuals' survival but are also involved, in the form of recurrent recollections of the traumatic experience, in the aetiology of anxiety diseases (e.g., post-traumatic stress disorder [PTSD]). Extinction-based erasure of fear memories has long been pursued as a behavioral way to treat anxiety disorders; yet, such a procedure turns out to be transient, context-dependent, and ineffective unless it is applied immediately after trauma. Recent evidence indicates that, in both rats and humans, extinction training can prevent the return of fear if administered within the reconsolidation window, when memories become temporarily labile and susceptible of being updated. Here, we show that the reconsolidation-extinction procedure fails to prevent the spontaneous recovery of a remote contextual fear memory in a mouse model of PTSD, as well as the long-lasting behavioral abnormalities induced by traumatic experience on anxiety and in both social and cognitive domains (i.e., social withdrawal and spatial learning deficits). Such a failure appears to be related to the ineffectiveness of the reconsolidation-extinction procedure in targeting the pathogenic process of fear sensitization, a nonassociative component of traumatic memory that causes animals to react aberrantly to harmless stimuli. This indicates fear sensitization as a major target for treatments aimed at mitigating anxiety and the behavioral outcomes of traumatic experiences.

Activity of the anterior cingulate cortex and ventral hippocampus underlie increases in contextual fear generalization.

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Cullen, Patrick K; Gilman, T Lee; Winiecki, Patrick; Riccio, David C; Jasnow, Aaron M

2015-10-01

Memories for context become less specific with time resulting in animals generalizing fear from training contexts to novel contexts. Though much attention has been given to the neural structures that underlie the long-term consolidation of a context fear memory, very little is known about the mechanisms responsible for the increase in fear generalization that occurs as the memory ages. Here, we examine the neural pattern of activation underlying the expression of a generalized context fear memory in male C57BL/6J mice. Animals were context fear conditioned and tested for fear in either the training context or a novel context at recent and remote time points. Animals were sacrificed and fluorescent in situ hybridization was performed to assay neural activation. Our results demonstrate activity of the prelimbic, infralimbic, and anterior cingulate (ACC) cortices as well as the ventral hippocampus (vHPC) underlie expression of a generalized fear memory. To verify the involvement of the ACC and vHPC in the expression of a generalized fear memory, animals were context fear conditioned and infused with 4% lidocaine into the ACC, dHPC, or vHPC prior to retrieval to temporarily inactivate these structures. The results demonstrate that activity of the ACC and vHPC is required for the expression of a generalized fear memory, as inactivation of these regions returned the memory to a contextually precise form. Current theories of time-dependent generalization of contextual memories do not predict involvement of the vHPC. Our data suggest a novel role of this region in generalized memory, which should be incorporated into current theories of time-dependent memory generalization. We also show that the dorsal hippocampus plays a prolonged role in contextually precise memories. Our findings suggest a possible interaction between the ACC and vHPC controls the expression of fear generalization. Copyright © 2015 Elsevier Inc. All rights reserved.

Acute ethanol has biphasic effects on short- and long-term memory in both foreground and background contextual fear conditioning in C57BL/6 mice.

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Gulick, Danielle; Gould, Thomas J

2007-09-01

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. 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. 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). 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.

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

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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.

Repeated Recall and PKM? Maintain Fear Memories in Juvenile Rats

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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…

Impaired contextual fear extinction and hippocampal synaptic plasticity in adult rats induced by prenatal morphine exposure.

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Tan, Ji-Wei; Duan, Ting-Ting; Zhou, Qi-Xin; Ding, Ze-Yang; Jing, Liang; Cao, Jun; Wang, Li-Ping; Mao, Rong-Rong; Xu, Lin

2015-07-01

Prenatal opiate exposure causes a series of neurobehavioral disturbances by affecting brain development. However, the question of whether prenatal opiate exposure increases vulnerability to memory-related neuropsychiatric disorders in adult offspring remains largely unknown. Here, we found that rats prenatally exposed to morphine (PM) showed impaired acquisition but enhanced maintenance of contextual fear memory compared with control animals that were prenatally exposed to saline (PS). The impairment of acquisition was rescued by increasing the intensity of footshocks (1.2 mA rather than 0.8 mA). Meanwhile, we also found that PM rats exhibited impaired extinction of contextual fear, which is associated with enhanced maintenance of fear memory. The impaired extinction lasted for 1 week following extinction training. Furthermore, PM rats exhibited reduced anxiety-like behavior in the elevated plus-maze and light/dark box test without differences in locomotor activity. These alterations in PM rats were mirrored by abnormalities in synaptic plasticity in the Schaffer collateral-CA1 synapses of the hippocampus in vivo. PS rats showed blocked long-term potentiation and enabled long-term depression in CA1 synapses following contextual fear conditioning, while prenatal morphine exposure restricted synaptic plasticity in CA1 synapses. The smaller long-term potentiation in PM rats was not further blocked by contextual fear conditioning, and the long-term depression enabled by contextual fear conditioning was abolished. Taken together, our results provide the first evidence suggesting that prenatal morphine exposure may increase vulnerability to fear memory-related neuropsychiatric disorders in adulthood. © 2014 Society for the Study of Addiction.

Impairment in extinction of contextual and cued, fear following post-training whole body irradiation

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Reid HJ Olsen

2014-07-01

Full Text Available Because of the use of radiation in cancer therapy, the risk of nuclear contamination from power plants, military conflicts, and terrorism, there is a compelling scientific and public health interest in the effects of environmental radiation exposure on brain function, in particular hippocampal function and learning and memory. Previous studies have emphasized changes in learning and memory following radiation exposure. These approaches have ignored the question of how radiation exposure might impact recently acquired memories, which might be acquired under traumatic circumstances (cancer treatment, nuclear disaster, etc.. To address the question of how radiation exposure might affect the processing and recall of recently acquired memories, we employed a fear-conditioning paradigm wherein animals were trained, and subsequently irradiated (whole-body X-ray irradiation 24 hours later. Animals were given two weeks to recover, and were tested for retention and extinction of hippocampus-dependent contextual fear conditioning. Exposure to irradiation following training was associated with reduced daily increases in body weights over the 22 days of the study and resulted in greater freezing levels and aberrant extinction 2 weeks later. This was also observed when the intensity of the training protocol was increased. Cued freezing levels and measures of anxiety 2 weeks after training were also higher in irradiated than sham-irradiated mice. In contrast to contextual freezing levels, cued freezing levels were even higher in irradiated mice receiving 5 shocks during training than sham-irradiated mice receiving 10 shocks during training. In addition, the effects of radiation on extinction of contextual fear were more profound than those on the extinction of cued fear. Thus, whole body irradiation elevates contextual and cued fear memory recall.

Small-conductance Ca2+-activated potassium type 2 channels regulate the formation of contextual fear memory.

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Saravana R K Murthy

Full Text Available Small-conductance, Ca2+ activated K+ channels (SK channels are expressed at high levels in brain regions responsible for learning and memory. In the current study we characterized the contribution of SK2 channels to synaptic plasticity and to different phases of hippocampal memory formation. Selective SK2 antisense-treatment facilitated basal synaptic transmission and theta-burst induced LTP in hippocampal brain slices. Using the selective SK2 antagonist Lei-Dab7 or SK2 antisense probes, we found that hippocampal SK2 channels are critical during two different time windows: 1 blockade of SK2 channels before the training impaired fear memory, whereas, 2 blockade of SK2 channels immediately after the training enhanced contextual fear memory. We provided the evidence that the post-training cleavage of the SK2 channels was responsible for the observed bidirectional effect of SK2 channel blockade on memory consolidation. Thus, Lei-Dab7-injection before training impaired the C-terminal cleavage of SK2 channels, while Lei-Dab7 given immediately after training facilitated the C-terminal cleavage. Application of the synthetic peptide comprising a leucine-zipper domain of the C-terminal fragment to Jurkat cells impaired SK2 channel-mediated currents, indicating that the endogenously cleaved fragment might exert its effects on memory formation by blocking SK2 channel-mediated currents. Our present findings suggest that SK2 channel proteins contribute to synaptic plasticity and memory not only as ion channels but also by additionally generating a SK2 C-terminal fragment, involved in both processes. The modulation of fear memory by down-regulating SK2 C-terminal cleavage might have applicability in the treatment of anxiety disorders in which fear conditioning is enhanced.

Revealing context-specific conditioned fear memories with full immersion virtual reality

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Nicole eHuff

2011-11-01

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

Artificial theta stimulation impairs encoding of contextual fear memory.

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Arto Lipponen

Full Text Available Several experiments have demonstrated an intimate relationship between hippocampal theta rhythm (4-12 Hz and memory. Lesioning the medial septum or fimbria-fornix, a fiber track connecting the hippocampus and the medial septum, abolishes the theta rhythm and results in a severe impairment in declarative memory. To assess whether there is a causal relationship between hippocampal theta and memory formation we investigated whether restoration of hippocampal theta by electrical stimulation during the encoding phase also restores fimbria-fornix lesion induced memory deficit in rats in the fear conditioning paradigm. Male Wistar rats underwent sham or fimbria-fornix lesion operation. Stimulation electrodes were implanted in the ventral hippocampal commissure and recording electrodes in the septal hippocampus. Artificial theta stimulation of 8 Hz was delivered during 3-min free exploration of the test cage in half of the rats before aversive conditioning with three foot shocks during 2 min. Memory was assessed by total freezing time in the same environment 24 h and 28 h after fear conditioning, and in an intervening test session in a different context. As expected, fimbria-fornix lesion impaired fear memory and dramatically attenuated hippocampal theta power. Artificial theta stimulation produced continuous theta oscillations that were almost similar to endogenous theta rhythm in amplitude and frequency. However, contrary to our predictions, artificial theta stimulation impaired conditioned fear response in both sham and fimbria-fornix lesioned animals. These data suggest that restoration of theta oscillation per se is not sufficient to support memory encoding after fimbria-fornix lesion and that universal theta oscillation in the hippocampus with a fixed frequency may actually impair memory.

Behavioural memory reconsolidation of food and fear memories.

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

2011-10-18

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 analogue of memory reconsolidation, we show that prevention of contextual fear memory reactivation by the L-type voltage-gated calcium channel blocker nimodipine interferes with the amnestic outcome. Therefore, the reconsolidation process can be manipulated behaviourally to disrupt both aversive and appetitive memories. © 2011 Macmillan Publishers Limited. All rights reserved.

DREAM (Downstream Regulatory Element Antagonist Modulator contributes to synaptic depression and contextual fear memory

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Wu Long-Jun

2010-01-01

Full Text Available Abstract The downstream regulatory element antagonist modulator (DREAM, a multifunctional Ca2+-binding protein, binds specifically to DNA and several nucleoproteins regulating gene expression and with proteins outside the nucleus to regulate membrane excitability or calcium homeostasis. DREAM is highly expressed in the central nervous system including the hippocampus and cortex; however, the roles of DREAM in hippocampal synaptic transmission and plasticity have not been investigated. Taking advantage of transgenic mice overexpressing a Ca2+-insensitive DREAM mutant (TgDREAM, we used integrative methods including electrophysiology, biochemistry, immunostaining, and behavior tests to study the function of DREAM in synaptic transmission, long-term plasticity and fear memory in hippocampal CA1 region. We found that NMDA receptor but not AMPA receptor-mediated current was decreased in TgDREAM mice. Moreover, synaptic plasticity, such as long-term depression (LTD but not long-term potentiation (LTP, was impaired in TgDREAM mice. Biochemical experiments found that DREAM interacts with PSD-95 and may inhibit NMDA receptor function through this interaction. Contextual fear memory was significantly impaired in TgDREAM mice. By contrast, sensory responses to noxious stimuli were not affected. Our results demonstrate that DREAM plays a novel role in postsynaptic modulation of the NMDA receptor, and contributes to synaptic plasticity and behavioral memory.

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

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Jun Liu

Full Text Available 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.

Block of glucocorticoid synthesis during re-activation inhibits extinction of an established fear memory.

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Blundell, Jacqueline; Blaiss, Cory A; Lagace, Diane C; Eisch, Amelia J; Powell, Craig M

2011-05-01

The pharmacology of traumatic memory extinction has not been fully characterized despite its potential as a therapeutic target for established, acquired anxiety disorders, including post-traumatic stress disorder (PTSD). Here we examine the role of endogenous glucocorticoids in traumatic memory extinction. Male C57BL/6J mice were injected with corticosterone (10 mg/kg, i.p.) or metyrapone (50 mg/kg, s.c.) during re-activation of a contextual fear memory, and compared to vehicle groups (N=10-12 per group). To ensure that metyrapone was blocking corticosterone synthesis, we measured corticosterone levels following re-activation of a fear memory in metyrapone- and vehicle-treated animals. Corticosterone administration following extinction trials caused a long-lasting inhibition of the original fear memory trace. In contrast, blockade of corticosteroid synthesis with metyrapone prior to extinction trials enhanced retrieval and prevented extinction of context-dependent fear responses in mice. Further behavioral analysis suggested that the metyrapone enhancement of retrieval and prevention of extinction were not due to non-specific alterations in locomotor or anxiety-like behavior. In addition, the inhibition of extinction by metyrapone was rescued by exogenous administration of corticosterone following extinction trials. Finally, we confirmed that the rise in corticosterone during re-activation of a contextual fear memory was blocked by metyrapone. We demonstrate that extinction of a classical contextual fear memory is dependent on endogenous glucocorticoid synthesis during re-activation of a fear memory. Our data suggest that decreased glucocorticoids during fear memory re-activation may contribute to the inability to extinguish a fear memory, thus contributing to one of the core symptoms of PTSD. Copyright © 2011 Elsevier Inc. All rights reserved.

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

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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

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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

Mice lacking Ras-GRF1 show contextual fear conditioning but not spatial memory impairments: convergent evidence from two independently generated mouse mutant lines

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Raffaele ed'Isa

2011-12-01

Full Text Available Ras-GRF1 is a neuronal specific guanine exchange factor that, once activated by both ionotropic and metabotropic neurotransmitter receptors, can stimulate Ras proteins, leading to long-term phosphorylation of downstream signaling. The two available reports on the behavior of two independently generated Ras-GRF1 deficient mouse lines provide contrasting evidence on the role of Ras-GRF1 in spatial memory and contextual fear conditioning. These discrepancies may be due to the distinct alterations introduced in the mouse genome by gene targeting in the two lines that could differentially affect expression of nearby genes located in the imprinted region containing the Ras-grf1 locus. In order to determine the real contribution of Ras-GRF1 to spatial memory we compared in Morris Water Maze learning the Brambilla’s mice with a third mouse line (GENA53 in which a nonsense mutation was introduced in the Ras-GRF1 coding region without additional changes in the genome and we found that memory in this task is normal. Also, we measured both contextual and cued fear conditioning, which were previously reported to be affected in the Brambilla’s mice, and we confirmed that contextual learning but not cued conditioning is impaired in both mouse lines. In addition, we also tested both lines for the first time in conditioned place aversion in the Intellicage, an ecological and remotely controlled behavioral test, and we observed normal learning. Finally, based on previous reports of other mutant lines suggesting that Ras-GRF1 may control body weight, we also measured this non-cognitive phenotype and we confirmed that both Ras-GRF1 deficient mutants are smaller than their control littermates. In conclusion, we demonstrate that Ras-GRF1 has no unique role in spatial memory while its function in contextual fear conditioning is likely to be due not only to its involvement in amygdalar functions but possibly to some distinct hippocampal connections specific to

Chronic nicotine differentially alters spontaneous recovery of contextual fear in male and female mice.

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Tumolo, Jessica M; Kutlu, Munir Gunes; Gould, Thomas J

2018-04-02

Post-traumatic stress disorder (PTSD) is a devastating disorder with symptoms such as flashbacks, hyperarousal, and avoidance of reminders of the traumatic event. Exposure therapy, which attempts to extinguish fear responses, is a commonly used treatment for PTSD but relapse following successful exposure therapy is a frequent problem. In rodents, spontaneous recovery (SR), where extinguished fear responses resurface following extinction treatment, is used as a model of fear relapse. Previous studies from our lab showed that chronic nicotine impaired fear extinction and acute nicotine enhanced SR of contextual fear in adult male mice. In addition, we showed that acute nicotine's effects were specific to SR as acute nicotine did not affect recall of contextual fear conditioning in the absence of extinction. However, effects of chronic nicotine administration on SR are not known. Therefore, in the present study, we investigated if chronic nicotine administration altered SR or recall of contextual fear in adult male and female C57BL/6J mice. Our results showed that chronic nicotine significantly enhanced SR in female mice and significantly decreased SR in males. Chronic nicotine had no effect on recall of contextual fear in males or females. Female sham mice also had significantly less baseline SR than male sham mice. Overall, these results demonstrate sex differences in SR of fear memories and that chronic nicotine modulates these effects on SR but nicotine does not alter recall of contextual fear. Copyright © 2018 Elsevier B.V. All rights reserved.

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

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Poplawski, Shane G.; Schoch, Hannah; 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 recei...

Impairment in extinction of cued fear memory in syntenin-1 knockout mice.

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Talukdar, Gourango; Inoue, Ran; Yoshida, Tomoyuki; Mori, Hisashi

2018-03-01

Syntenin-1 is a PDZ domain-containing intracellular scaffold protein involved in exosome production, synapse formation, and synaptic plasticity. We tested whether syntenin-1 can regulate learning and memory through its effects on synaptic plasticity. Specifically, we investigated the role of syntenin-1 in contextual and cued fear conditioning and extinction of conditioned fear using syntenin-1 knockout (KO) mice. Genetic disruption of syntenin-1 had little effect on contextual and cued fear memory. However, syntenin-1 KO mice exhibited selective impairment in cued fear extinction retention. This extinction retention deficit in syntenin-1 KO mice was associated with reduced c-Fos-positive neurons in the basolateral amygdala (BLA) and infralimbic cortex (IL) after extinction training and increased c-Fos-positive neurons in the BLA after an extinction retention test. Our results suggest that syntenin-1 plays an important role in extinction of cued fear memory by modulating neuronal activity in the BLA and IL. Copyright © 2018 Elsevier Inc. All rights reserved.

Hippocampal dendritic spines remodeling and fear memory are modulated by GABAergic signaling within the basolateral amygdala complex.

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

2015-05-01

GABAergic signaling in the basolateral amygdala complex (BLA) plays a crucial role on the modulation of the stress influence on fear memory. Moreover, accumulating evidence suggests that the dorsal hippocampus (DH) is a downstream target of BLA neurons in contextual fear. Given that hippocampal structural plasticity is proposed to provide a substrate for the storage of long-term memories, the main aim of this study is to evaluate the modulation of GABA neurotransmission in the BLA on spine density in the DH following stress on contextual fear learning. The present findings show that prior stressful experience promoted contextual fear memory and enhanced spine density in the DH. Intra-BLA infusion of midazolam, a positive modulator of GABAa sites, prevented the facilitating influence of stress on both fear retention and hippocampal dendritic spine remodeling. Similarly to the stress-induced effects, the blockade of GABAa sites within the BLA ameliorated fear memory emergence and induced structural remodeling in the DH. These findings suggest that GABAergic transmission in BLA modulates the structural changes in DH associated to the influence of stress on fear memory. © 2015 Wiley Periodicals, Inc.

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

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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.

Time-dependent effects of cortisol on the contextualization of emotional memories

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van Ast, V.A.; Cornelisse, S.; Meeter, M.; Joëls, M.; Kindt, M.

2013-01-01

Background: The inability to store fearful memories into their original encoding context is considered to be an important vulnerability factor for the development of anxiety disorders like posttraumatic stress disorder. Altered memory contextualization most likely involves effects of the stress

Serotonergic Modulation of Conditioned Fear

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Judith R. Homberg

2012-01-01

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

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

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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.

Postreactivation glucocorticoids impair recall of established fear memory.

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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.

Contextual control over expression of fear is affected by cortisol

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Vanessa Anna Van Ast

2012-10-01

Full Text Available At the core of anxiety disorders is the inability to use contextual information to modulate behavioral responses to potentially threatening events. Models of the pathogenesis of anxiety disorders incorporate stress and concomitant stress hormones as important vulnerability factors, while others emphasize sex as an important factor. However, translational basic research has not yet investigated the effects of stress hormones and sex on the ability to use contextual information to modulate responses to threat. Therefore, the purpose of the present study was threefold: first, we aimed at developing an experimental paradigm specifically capable of capturing contextual modulation of the expression of fear. Second, we tested whether cortisol would alter the contextualization of fear expression. Third, we aimed at assessing whether alterations in contextualization due to cortisol were different for men and women. Healthy participants (n = 42 received placebo or hydrocortisone (20 mg prior to undergoing a newly developed differential contextual fear conditioning paradigm. The results indicated that people rapidly acquire differential contextual modulation of the expression of fear, as measured by fear potentiated startle and skin conductance responses. In addition, cortisol impaired the contextualization of fear expression leading to increased fear generalization on fear potentiated startle data in women. The opposite pattern was found in men. Finally, as assessed by skin conductance responses, cortisol impaired differential conditioning in men. The results are in line with models suggesting heightened vulnerability in women for developing anxiety disorders after stressful events.

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

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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.

Overexpression of Protein Kinase Mζ in the Hippocampus Enhances Long-Term Potentiation and Long-Term Contextual But Not Cued Fear Memory in Rats.

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Schuette, Sven R M; Fernández-Fernández, Diego; Lamla, Thorsten; Rosenbrock, Holger; Hobson, Scott

2016-04-13

The persistently active protein kinase Mζ (PKMζ) has been found to be involved in the formation and maintenance of long-term memory. Most of the studies investigating PKMζ, however, have used either putatively unselective inhibitors or conventional knock-out animal models in which compensatory mechanisms may occur. Here, we overexpressed an active form of PKMζ in rat hippocampus, a structure highly involved in memory formation, and embedded in several neural networks. We investigated PKMζ's influence on synaptic plasticity using electrophysiological recordings of basal transmission, paired pulse facilitation, and LTP and combined this with behavioral cognitive experiments addressing formation and retention of both contextual memory during aversive conditioning and spatial memory during spontaneous exploration. We demonstrate that hippocampal slices overexpressing PKMζ show enhanced basal transmission, suggesting a potential role of PKMζ in postsynaptic AMPAR trafficking. Moreover, the PKMζ-overexpressing slices augmented LTP and this effect was not abolished by protein-synthesis blockers, indicating that PKMζ induces enhanced LTP formation in a protein-synthesis-independent manner. In addition, we found selectively enhanced long-term memory for contextual but not cued fear memory, underlining the theory of the hippocampus' involvement in the contextual aspect of aversive reinforced tasks. Memory for spatial orientation during spontaneous exploration remained unaltered, suggesting that PKMζ may not affect the neural circuits underlying spontaneous tasks that are different from aversive tasks. In this study, using an overexpression strategy as opposed to an inhibitor-based approach, we demonstrate an important modulatory role of PKMζ in synaptic plasticity and selective memory processing. Most of the literature investigating protein kinase Mζ (PKMζ) used inhibitors with selectivity that has been called into question or conventional knock-out animal

Effects of postretrieval-extinction learning on return of contextually controlled cued fear.

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Meir Drexler, Shira; Merz, Christian J; Hamacher-Dang, Tanja C; Marquardt, Veronica; Fritsch, Nathalie; Otto, Tobias; Wolf, Oliver T

2014-08-01

Reactivation of an already consolidated memory makes it labile for a period of several hrs, which are required for its reconsolidation. Evidence suggests that the return of conditioned fear through spontaneous recovery, reinstatement, or renewal can be prevented by blockading this reconsolidation process using pharmacological or behavioral interventions. Postretrieval-extinction learning has been shown to prevent the return of cued fear in humans using fear-irrelevant stimuli, as well as cued and contextual fear in rodents. The effects of postretrieval extinction on human contextually controlled cued fear to fear-relevant stimuli remain unknown, and are the focus of the present study. The experimental design was based on 3 consecutive days: acquisition, reactivation and extinction, and re-extinction. For the fear conditioning, 2 zoo frames served as different contexts, 5 fear-relevant stimuli (aversive animal pictures) served as conditioned stimuli (CS), electric shocks served as unconditioned stimuli (UCS). Expectancy ratings and skin-conductance response (SCR) were used as measures of fear responses; spontaneous recovery and renewal were used as indicators of the return of fear. The expectancy ratings and SCR results indicated spontaneous recovery on the third day, regardless of retrieval prior to extinction. No robust renewal effect was seen. It is suggested that the use of fear-relevant stimuli, the context salience, or reactivation context may explain the lack of reconsolidation effect. Our study indicates that the beneficial effects of postretrieval-extinction learning are sensitive to subtle methodological changes.

Differential Effects of Cannabinoid Receptor Agonist on Social Discrimination and Contextual Fear in Amygdala and Hippocampus

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Segev, Amir; Akirav, Irit

2011-01-01

We examined whether the cannabinoid receptor agonist WIN55,212-2 (WIN; 5 [mu]g/side) microinjected into the hippocampus or the amygdala would differentially affect memory processes in a neutral vs. an aversive task. In the aversive contextual fear task, WIN into the basolateral amygdala impaired fear acquisition/consolidation, but not retrieval.…

Context-dependent encoding of fear and extinction memories in a large-scale network model of the basal amygdala.

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

2011-03-01

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.

Context-dependent encoding of fear and extinction memories in a large-scale network model of the basal amygdala.

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Ioannis Vlachos

2011-03-01

Full Text Available 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.

Time-dependent effects of cortisol on the contextualization of emotional memories.

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

2013-12-01

The inability to store fearful memories into their original encoding context is considered to be an important vulnerability factor for the development of anxiety disorders like posttraumatic stress disorder. Altered memory contextualization most likely involves effects of the stress hormone cortisol, acting via receptors located in the memory neurocircuitry. Cortisol via these receptors induces rapid nongenomic effects followed by slower genomic effects, which are thought to modulate cognitive function in opposite, complementary ways. Here, we targeted these time-dependent effects of cortisol during memory encoding and tested subsequent contextualization of emotional and neutral memories. In a double-blind, placebo-controlled design, 64 men were randomly assigned to one of three groups: 1) received 10 mg hydrocortisone 30 minutes (rapid cortisol effects) before a memory encoding task; 2) received 10 mg hydrocortisone 210 minutes (slow cortisol) before a memory encoding task; or 3) received placebo at both times. During encoding, participants were presented with neutral and emotional words in unique background pictures. Approximately 24 hours later, context dependency of their memories was assessed. Recognition data revealed that cortisol's rapid effects impair emotional memory contextualization, while cortisol's slow effects enhance it. Neutral memory contextualization remained unaltered by cortisol, irrespective of the timing of the drug. This study shows distinct time-dependent effects of cortisol on the contextualization of specifically emotional memories. The results suggest that rapid effects of cortisol may lead to impaired emotional memory contextualization, while slow effects of cortisol may confer protection against emotional memory generalization. © 2013 Society of Biological Psychiatry.

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

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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…

Role of NPY Y1 receptor on acquisition, consolidation and extinction on contextual fear conditioning: dissociation between anxiety, locomotion and non-emotional memory behavior.

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Lach, Gilliard; de Lima, Thereza Christina Monteiro

2013-07-01

Neuropeptide Y (NPY) is the most abundant peptide in the central nervous system (CNS) and is densely localized in the brain regions involved in stress, memory, fear and anxiety. Although previous research supports a role for NPY in the mediation of rodent and human emotional behavior, there is currently a lack of information on the effects of low doses of NPY that could have a potential therapeutic advantage, minimizing side-effects such as cognition impairment or sedation. Herein, we assessed the effects of intracerebroventricular (i.c.v.) administration of low doses of NPY, and of the Y1-agonist Leu31Pro34-NPY (LP-NPY) on contextual fear conditioning (CFC), as they have no effect on unconditioned anxiety-like, locomotor activity and non-emotional memory. NPY (3 pmol) and LP-NPY (1 pmol) inhibited freezing behavior when administered in the acquisition or consolidation stages, indicating a reduction of fear. When injected in the extinction phase, only NPY inhibited freezing behavior on CFC. Pre-treatment with the Y1-antagonist BIBO3304 before NPY and LP-NPY was able to prevent the inhibition of fear responses induced by both NPY agonists. Taken together, our results demonstrate robust fear-inhibiting effects of i.c.v. injection of NPY on contextual fear conditioning in rats, a response that is mediated, at least in part, by the Y1 receptor. Moreover, these treatments were unable to change locomotor activity or to show an anxiolytic-like effect, as evaluated in an open-field and an elevated plus-maze. This specific fear reduction effect may underlie resilience systems in the CNS and has potential therapeutic relevance in PTSD. Copyright © 2013 Elsevier Inc. All rights reserved.

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

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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.

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

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

2015-01-01

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

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

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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.

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

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

2002-01-01

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

Contextual change after fear acquisition affects conditioned responding and the time course of extinction learning – Implications for renewal research

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Rachel eSjouwerman

2015-12-01

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

Methylphenidate enhances extinction of contextual fear

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Abraham, Antony D.; Cunningham, Christopher L.; Lattal, K. Matthew

2012-01-01

Methylphenidate (MPH, Ritalin) is a norepinephrine and dopamine transporter blocker that is widely used in humans for treatment of attention deficit disorder and narcolepsy. Although there is some evidence that targeted microinjections of MPH may enhance fear acquisition, little is known about the effect of MPH on fear extinction. Here, we show that MPH, administered before or immediately following extinction of contextual fear, will enhance extinction retention in C57BL/6 mice. Animals that ...

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

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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

Fear memory consolidation in sleep requires protein kinase A.

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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.

Suppression of neurotoxic lesion-induced seizure activity: evidence for a permanent role for the hippocampus in contextual memory.

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Fraser T Sparks

Full Text Available Damage to the hippocampus (HPC using the excitotoxin N-methyl-D-aspartate (NMDA can cause retrograde amnesia for contextual fear memory. This amnesia is typically attributed to loss of cells in the HPC. However, NMDA is also known to cause intense neuronal discharge (seizure activity during the hours that follow its injection. These seizures may have detrimental effects on retrieval of memories. Here we evaluate the possibility that retrograde amnesia is due to NMDA-induced seizure activity or cell damage per se. To assess the effects of NMDA induced activity on contextual memory, we developed a lesion technique that utilizes the neurotoxic effects of NMDA while at the same time suppressing possible associated seizure activity. NMDA and tetrodotoxin (TTX, a sodium channel blocker, are simultaneously infused into the rat HPC, resulting in extensive bilateral damage to the HPC. TTX, co-infused with NMDA, suppresses propagation of seizure activity. Rats received pairings of a novel context with foot shock, after which they received NMDA-induced, TTX+NMDA-induced, or no damage to the HPC at a recent (24 hours or remote (5 weeks time point. After recovery, the rats were placed into the shock context and freezing was scored as an index of fear memory. Rats with an intact HPC exhibited robust memory for the aversive context at both time points, whereas rats that received NMDA or NMDA+TTX lesions showed a significant reduction in learned fear of equal magnitude at both the recent and remote time points. Therefore, it is unlikely that observed retrograde amnesia in contextual fear conditioning are due to disruption of non-HPC networks by propagated seizure activity. Moreover, the memory deficit observed at both time points offers additional evidence supporting the proposition that the HPC has a continuing role in maintaining contextual memories.

Abnormal Fear Memory as a Model for Posttraumatic Stress Disorder.

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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.

Impaired spatial and contextual memory formation in galectin-1 deficient mice

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Sakaguchi Masanori

2011-09-01

Full Text Available Abstract Galectins are a 15 member family of carbohydrate-binding proteins that have been implicated in cancer, immunity, inflammation and development. While galectins are expressed in the central nervous system, little is known about their function in the adult brain. Previously we have shown that galectin-1 (gal-1 is expressed in the adult hippocampus, and, in particular, in putative neural stem cells in the subgranular zone. To evaluate how gal-1 might contribute to hippocampal memory function here we studied galectin-1 null mutant (gal-1-/- mice. Compared to their wildtype littermate controls, gal-1-/- mice exhibited impaired spatial learning in the water maze and contextual fear learning. Interestingly, tone fear conditioning was normal in gal-1-/- mice suggesting that loss of gal-1 might especially impact hippocampal learning and memory. Furthermore, gal-1-/- mice exhibited normal motor function, emotion and sensory processing in a battery of other behavioral tests, suggesting that non-mnemonic performance deficits are unlikely to account for the spatial and contextual learning deficits. Together, these data reveal a role for galectin-carbohydrate signalling in hippocampal memory function.

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

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

2014-12-01

Recent accounts of Posttraumatic Stress Disorder (PTSD) suggest that the encoding of an episode within a fearful context generates different implicit and explicit memory representations. Whilst implicit memory traces include the associated emotional states, explicit traces include a recoding into an abstract or gist-based structural context of the episode. Theoretically, the long-term preservation of implicit memory traces may facilitate the often untreatable memory intrusions in PTSD. Here, we tracked in two experiments how implicit and explicit memory traces for fearful episodes dissociate and evolve over time. Subjects (N=86) were presented with semantically-related word-lists in a contextual fear paradigm and tested for explicit memories either immediately (i.e., 30 min) or after a delay (i.e., 1 or 2 weeks) with a verbal recognition task. Skin Conductance Response (SCR) was used to assess implicit memory responses. Subjects showed high memory accuracy for words when tested immediately after encoding. At test, SCR was higher during the presentation of verbatim but not gist-based words encoded in a fearful context, and remained unchanged after 2 weeks, despite subjects being unaware of words' encoding context. We found no clear evidence of accurate explicit memory traces for the fearful or neutral contexts of words presented during encoding, either 30 min or 2 weeks afterwards. These findings indicate that the implicit, but not the explicit, memory trace of a fearful context of an episode can be detected at long-term through SCR and is dissociated from the gist-based memory. They may have implicationstowards the understanding of how the processing of fearful memoriescould lead to PTSD. Copyright © 2014 Elsevier Inc. All rights reserved.

Multimodal assessment of long-term memory recall and reinstatement in a combined cue and context fear conditioning and extinction paradigm in humans.

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Jan Haaker

Full Text Available Learning to predict danger via associative learning processes is critical for adaptive behaviour. After successful extinction, persisting fear memories often emerge as returning fear. Investigation of return of fear phenomena, e.g. reinstatement, have only recently began and to date, many critical questions with respect to reinstatement in human populations remain unresolved. Few studies have separated experimental phases in time even though increasing evidence shows that allowing for passage of time (and consolidation between experimental phases has a major impact on the results. In addition, studies have relied on a single psychophysiological dimension only (SCRs/SCL or FPS which hampers comparability between different studies that showed both differential or generalized return of fear following a reinstatement manipulation. In 93 participants, we used a multimodal approach (fear-potentiated startle, skin conductance responses, fear ratings to asses fear conditioning (day 1, extinction (day 2 as well as delayed memory recall and reinstatement (day 8 in a paradigm that probed contextual and cued fear intra-individually. Our findings show persistence of conditioning and extinction memory over time and demonstrate that reinstated fear responses were qualitatively different between dependent variables (subjective fear ratings, FPS, SCRs as well as between cued and contextual CSs. While only the arousal-related measurement (SCRs showed increasing reactions following reinstatement to the cued CSs, no evidence of reinstatement was observed for the subjective ratings and fear-related measurement (FPS. In contrast, for contextual CSs, reinstatement was evident as differential and generalized reinstatement in fear ratings as well as generally elevated physiological fear (FPS and arousal (SCRs related measurements to all contextual CSs (generalized non-differential reinstatement. Returning fear after reinstatement likely depends on a variety of variables

p300/CBP Histone Acetyltransferase Activity Is Required for Newly Acquired and Reactivated Fear Memories in the Lateral Amygdala

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

2013-01-01

Modifications in chromatin structure have been widely implicated in memory and cognition, most notably using hippocampal-dependent memory paradigms including object recognition, spatial memory, and contextual fear memory. Relatively little is known, however, about the role of chromatin-modifying enzymes in amygdala-dependent memory formation.…

Facilitating influence of stress on the consolidation of fear memory induced by a weak training: reversal by midazolam pretreatment.

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Maldonado, Noelia Martina; Martijena, Irene Delia; Molina, Víctor Alejandro

2011-11-20

It is well known that an emotionally arousing experience usually results in a robust and persistent memory trace. The present study explored the potential mechanisms involved in the influence of stress on the consolidation of a contextual fear memory in animals subjected to a weak fear training protocol, and whether pretreatment with intra-basolateral amygdala or systemic administration of midazolam (MDZ) prevents the potential stress-induced influence on fear memory formation. A previous restraint session facilitated fear retention, this effect was not due to a sensitized effect of restraint on the footshock experience. MDZ, both systemically or intra-basolateral amygdala infusion prior to the restraint, attenuated the stress-induced promoting influence on fear memory formation. In addition, stress exposure activated the ERK1/2 pathway in basolateral amygdala (BLA) after the weak training procedure but not after the immediate footshock protocol. Similar to our behavioral findings, MDZ attenuated stress-induced elevation of phospho-ERK2 (p-ERK2) in BLA following the acquisition session. Given that the activation of ERK1/2 pathway is essential for associative learning, we propose that stress-induced facilitation of p-ERK2 in BLA is an important mechanism for the promoting influence of stress on the consolidation of contextual fear memory. Copyright © 2011 Elsevier B.V. All rights reserved.

A Time for Learning and a Time for Sleep : The Effect of Sleep Deprivation on Contextual Fear Conditioning at Different Times of the Day

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Hagewoud, Roelina; Whitcomb, Shamiso N.; Heeringa, Amarins N.; Havekes, Robbert; Koolhaas, Jaap M.; Meerlo, Peter

2010-01-01

Study Objectives: Sleep deprivation negatively affects memory consolidation, especially in the case of hippocampus-dependent memories. Studies in rodents have shown that 5 hours of sleep deprivation immediately following footshock exposure selectively impairs the formation of a contextual fear

Differential effects of α4β2 nicotinic receptor antagonists and partial-agonists on contextual fear extinction in male C57BL/6 mice.

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Kutlu, Munir Gunes; Tumolo, Jessica M; Cann, Courtney; Gould, Thomas J

2018-04-01

Numerous studies have attributed the psychopathology of post-traumatic stress disorder (PTSD) to maladaptive behavioral responses such as an inability to extinguish fear. While exposure therapies are mostly effective in treating these disorders by enhancing extinction learning, relapse of PTSD symptoms is common. Although several studies indicated a role for cholinergic transmission and nicotinic acetylcholine receptors (nAChRs) in anxiety and stress disorder symptomatology, very little is known about the specific contribution of nAChRs to fear extinction OBJECTIVES: In the present study, we examined the effects of inhibition and desensitization of α4β2 nAChRs via a full antagonist (Dihydro-beta-erythroidine (DhβE)) and two α4β2 nAChR partial-agonists (varenicline and sazetidine-A) on contextual fear extinction, locomotor activity, and spontaneous recovery of contextual fear in mice. We trained and tested the subjects in a contextual fear extinction as well as an open field paradigm and spontaneous recovery following injections of DhβE, varenicline, and sazetidine-A. Our results demonstrated that lower doses of DhβE (1 mg/kg) and sazetidine-A (0.01 mg/kg) enhanced contextual fear extinction whereas higher doses of varenicline (0.1 mg/kg) and sazetidine-A (0.1 mg/kg) resulted in impaired contextual fear extinction. However, the higher dose of sazetidine-A (0.1 mg/kg) decreased locomotor activity, which may contribute to increased freezing response observed during fear extinction. Finally, we found that the low dose of DhβE, but not sazetidine-A, also decreased spontaneous recovery of contextual fear following fear extinction. Overall, these results suggest that inhibition and desensitization of α4β2 nAChRs enhance extinction of contextual fear memories. This suggests that modulation of α4β2 nAChRs may be employed as an alternative pharmacological strategy to aid exposure therapies associated with PTSD by augmenting contextual fear extinction

Segregated populations of hippocampal principal CA1 neurons mediating conditioning and extinction of contextual fear.

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Tronson, Natalie C; Schrick, Christina; Guzman, Yomayra F; Huh, Kyu Hwan; Srivastava, Deepak P; Penzes, Peter; Guedea, Anita L; Gao, Can; Radulovic, Jelena

2009-03-18

Learning processes mediating conditioning and extinction of contextual fear require activation of several key signaling pathways in the hippocampus. Principal hippocampal CA1 neurons respond to fear conditioning by a coordinated activation of multiple protein kinases and immediate early genes, such as cFos, enabling rapid and lasting consolidation of contextual fear memory. The extracellular signal-regulated kinase (Erk) additionally acts as a central mediator of fear extinction. It is not known however, whether these molecular events take place in overlapping or nonoverlapping neuronal populations. By using mouse models of conditioning and extinction of fear, we set out to determine the time course of cFos and Erk activity, their cellular overlap, and regulation by afferent cholinergic input from the medial septum. Analyses of cFos(+) and pErk(+) cells by immunofluorescence revealed predominant nuclear activation of either protein during conditioning and extinction of fear, respectively. Transgenic cFos-LacZ mice were further used to label in vivo Fos(+) hippocampal cells during conditioning followed by pErk immunostaining after extinction. The results showed that these signaling molecules were activated in segregated populations of hippocampal principal neurons. Furthermore, immunotoxin-induced lesions of medial septal neurons, providing cholinergic input into the hippocampus, selectively abolished Erk activation and extinction of fear without affecting cFos responses and conditioning. These results demonstrate that extinction mechanisms based on Erk signaling involve a specific population of CA1 principal neurons distinctively regulated by afferent cholinergic input from the medial septum.

Inhaled Lavandula angustifolia essential oil inhibits consolidation of contextual- but not tone-fear conditioning in rats.

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Coelho, Laura Segismundo; Correa-Netto, Nelson Francisco; Masukawa, Marcia Yuriko; Lima, Ariadiny Caetano; Maluf, Samia; Linardi, Alessandra; Santos-Junior, Jair Guilherme

2018-04-06

Although the current treatment for anxiety is effective, it promotes a number of adverse reactions and medical interactions. Inhaled essential oils have a prominent action on the central nervous system, with minimal systemic effects, primarily because of reduced systemic bioavailability. The effects of drugs on the consolidation of fear conditioning reflects its clinical efficacy in preventing a vicious cycle of anticipatory anxiety leading to fearful cognition and anxiety symptoms. In this study, we investigated the effects of inhaled Lavandula angustifolia essential oil on the consolidation of aversive memories and its influence on c-Fos expression. Adult male Wistar rats were subjected to a fear conditioning protocol. Immediately after the training session, the rats were exposed to vaporized water or essential oil (1%, 2.5% and 5% solutions) for 4h. The next day, the rats underwent contextual- or tone-fear tests and 90min after the test they were euthanized and their brains processed for c-Fos immunohistochemistry. In the contextual-fear test, essential oil at 2.5% and 5% (but not 1%) reduced the freezing response and its respective c-Fos expression in the ventral hippocampus and amygdala. In the tone-fear test, essential oil did not reduce the freezing response during tone presentation. However, rats that inhaled essential oil at 2.5% and 5% (but not 1%) showed decreased freezing in the three minutes after tone presentation, as well as reduced c-Fos expression in the prefrontal cortex and amygdala. These results show that the inhalation of L. angustifolia essential oil inhibited the consolidation of contextual- but not tone-fear conditioning and had an anxiolytic effect in a conditioned animal model of anxiety. Copyright © 2018 Elsevier B.V. All rights reserved.

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

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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

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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

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

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Edward G Meloni

Full Text Available 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.

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

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

2017-10-21

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

Direct Neuronal Glucose Uptake Is Required for Contextual Fear Acquisition in the Dorsal Hippocampus

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Liang Kong

2017-11-01

Full Text Available The metabolism of glucose is a nearly exclusive source of energy for maintaining neuronal survival, synaptic transmission and information processing in the brain. Two glucose metabolism pathways have been reported, direct neuronal glucose uptake and the astrocyte-neuron lactate shuttle (ANLS, which can be involved in these functions simultaneously or separately. Although ANLS in the dorsal hippocampus (DH has been proved to be required for memory consolidation, the specific metabolic pathway involved during memory acquisition remains unclear. The DH and amygdala are two key brain regions for acquisition of contextual fear conditioning (CFC. In 2-NBDG experiments, we observed that 2-NBDG-positive neurons were significantly increased during the acquisition of CFC in the DH. However, in the amygdala and cerebellum, 2-NBDG-positive neurons were not changed during CFC training. Strikingly, microinjection of a glucose transporter (GLUT inhibitor into the DH decreased freezing values during CFC training and 1 h later, while injection of a monocarboxylate transporter (MCT inhibitor into the amygdala also reduced freezing values. Therefore, we demonstrated that direct neuronal glucose uptake was the primary means of energy supply in the DH, while ANLS might supply energy in the amygdala during acquisition. Furthermore, knockdown of GLUT3 by a lentivirus in the DH impaired the acquisition of CFC. Taken together, the results indicated that there were two different glucose metabolism pathways in the DH and amygdala during acquisition of contextual fear memory and that direct neuronal glucose uptake in the DH may be regulated by GLUT3.

Infralimbic Neurotrophin-3 Infusion Rescues Fear Extinction Impairment in a Mouse Model of Pathological Fear.

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D'Amico, Davide; Gener, Thomas; de Lagrán, Maria Martínez; Sanchez-Vives, Maria V; Santos, Mónica; Dierssen, Mara

2017-01-01

The inability to properly extinguish fear memories constitutes the foundation of several anxiety disorders, including panic disorder. Recent findings show that boosting prefrontal cortex synaptic plasticity potentiates fear extinction, suggesting that therapies that augment synaptic plasticity could prove useful in rescue of fear extinction impairments in this group of disorders. Previously, we reported that mice with selective deregulation of neurotrophic tyrosine kinase receptor, type 3 expression (TgNTRK3) exhibit increased fear memories accompanied by impaired extinction, congruent with an altered activation pattern of the amygdala-hippocampus-medial prefrontal cortex fear circuit. Here we explore the specific role of neurotrophin 3 and its cognate receptor in the medial prefrontal cortex, and its involvement in fear extinction in a pathological context. In this study we combined molecular, behavioral, in vivo pharmacology and ex vivo electrophysiological recordings in TgNTRK3 animals during contextual fear extinction processes. We show that neurotrophin 3 protein levels are increased upon contextual fear extinction in wild-type animals but not in TgNTRK3 mice, which present deficits in infralimbic long-term potentiation. Importantly, infusion of neurotrophin 3 to the medial prefrontal cortex of TgNTRK3 mice rescues contextual fear extinction and ex vivo local application improves medial prefrontal cortex synaptic plasticity. This effect is blocked by inhibition of extracellular signal-regulated kinase phosphorylation through peripheral administration of SL327, suggesting that rescue occurs via this pathway. Our results suggest that stimulating neurotrophin 3-dependent medial prefrontal cortex plasticity could restore contextual fear extinction deficit in pathological fear and could constitute an effective treatment for fear-related disorders.

Facilitation of Contextual Fear Extinction by Orexin-1 Receptor Antagonism Is Associated with the Activation of Specific Amygdala Cell Subpopulations.

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Flores, África; Herry, Cyril; Maldonado, Rafael; Berrendero, Fernando

2017-08-01

Orexins are hypothalamic neuropeptides recently involved in the regulation of emotional memory. The basolateral amygdala, an area orchestrating fear memory processes, appears to be modulated by orexin transmission during fear extinction. However, the neuronal types within the basolateral amygdala involved in this modulation remain to be elucidated. We used retrograde tracing combined with immunofluorescence techniques in mice to identify basolateral amygdala projection neurons and cell subpopulations in this brain region influenced by orexin transmission during contextual fear extinction consolidation. Treatment with the orexin-1 receptor antagonist SB334867 increased the activity of basolateral amygdala neurons projecting to infralimbic medial prefrontal cortex during fear extinction. GABAergic interneurons expressing calbindin, but not parvalbumin, were also activated by orexin-1 receptor antagonism in the basolateral amygdala. These data identify neuronal circuits and cell populations of the amygdala associated with the facilitation of fear extinction consolidation induced by the orexin-1 receptor antagonist SB334867. © The Author 2017. Published by Oxford University Press on behalf of CINP.

Inhibiting the Activity of CA1 Hippocampal Neurons Prevents the Recall of Contextual Fear Memory in Inducible ArchT Transgenic Mice.

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Masanori Sakaguchi

Full Text Available The optogenetic manipulation of light-activated ion-channels/pumps (i.e., opsins can reversibly activate or suppress neuronal activity with precise temporal control. Therefore, optogenetic techniques hold great potential to establish causal relationships between specific neuronal circuits and their function in freely moving animals. Due to the critical role of the hippocampal CA1 region in memory function, we explored the possibility of targeting an inhibitory opsin, ArchT, to CA1 pyramidal neurons in mice. We established a transgenic mouse line in which tetracycline trans-activator induces ArchT expression. By crossing this line with a CaMKIIα-tTA transgenic line, the delivery of light via an implanted optrode inhibits the activity of excitatory CA1 neurons. We found that light delivery to the hippocampus inhibited the recall of a contextual fear memory. Our results demonstrate that this optogenetic mouse line can be used to investigate the neuronal circuits underlying behavior.

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

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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.

Involvement of the prelimbic cortex in contextual fear conditioning with temporal and spatial discontinuity.

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Santos, Thays Brenner; Kramer-Soares, Juliana Carlota; Favaro, Vanessa Manchim; Oliveira, Maria Gabriela Menezes

2017-10-01

Time plays an important role in conditioning, it is not only possible to associate stimuli with events that overlap, as in delay fear conditioning, but it is also possible to associate stimuli that are discontinuous in time, as shown in trace conditioning for a discrete stimuli. The environment itself can be a powerful conditioned stimulus (CS) and be associated to unconditioned stimulus (US). Thus, the aim of the present study was to determine the parameters in which contextual fear conditioning occurs by the maintenance of a contextual representation over short and long time intervals. The results showed that a contextual representation can be maintained and associated after 5s, even in the absence of a 15s re-exposure to the training context before US delivery. The same effect was not observed with a 24h interval of discontinuity. Furthermore, optimal conditioned response with a 5s interval is produced only when the contexts (of pre-exposure and shock) match. As the pre-limbic cortex (PL) is necessary for the maintenance of a continuous representation of a stimulus, the involvement of the PL in this temporal and contextual processing was investigated. The reversible inactivation of the PL by muscimol infusion impaired the acquisition of contextual fear conditioning with a 5s interval, but not with a 24h interval, and did not impair delay fear conditioning. The data provided evidence that short and long intervals of discontinuity have different mechanisms, thus contributing to a better understanding of PL involvement in contextual fear conditioning and providing a model that considers both temporal and contextual factors in fear conditioning. Copyright © 2017 Elsevier Inc. All rights reserved.

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

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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.

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

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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.

Pre-exposure and retrieval effects on generalization of contextual fear

NARCIS (Netherlands)

Sevenster, D.; de Oliveira Alvares, L.; D'Hooge, R.

2018-01-01

The degree of generalization from a fearful context to other contexts is determined by precision of the original fear memory. Experiences before and after fear learning affect memory precision. Pre-exposure to a similar context before context conditioning results in increased generalization to the

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

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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.

Memory reconsolidation mediates the updating of hippocampal memory content

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Jonathan L C Lee

2010-11-01

Full Text Available The retrieval or reactivation of a memory places it into a labile state, requiring a process of reconsolidation to restabilize it. This retrieval-induced plasticity is a potential mechanism for the modification of the existing memory. Following previous data supportive of a functional role for memory reconsolidation in the modification of memory strength, here I show that hippocampal memory reconsolidation also supports the updating of contextual memory content. Using a procedure that separates the learning of pure context from footshock-motivated contextual fear learning, I demonstrate doubly dissociable hippocampal mechanisms of initial context learning and subsequent updating of the neutral contextual representation to incorporate the footshock. Contextual memory consolidation was dependent upon BDNF expression in the dorsal hippocampus, whereas the footshock modification of the contextual representation required the expression of Zif268. These mechanisms match those previously shown to be selectively involved in hippocampal memory consolidation and reconsolidation, respectively. Moreover, memory reactivation is a necessary step in modifying memory content, as inhibition of hippocampal synaptic protein degradation also prevented the footshock-mediated memory modification. Finally, dorsal hippocampal knockdown of Zif268 impaired the reconsolidation of the pure contextual memory only under conditions of weak context memory training, as well as failing to disrupt contextual freezing when a strong contextual fear memory is reactivated by further conditioning. Therefore, an adaptive function of the reactivation and reconsolidation process is to enable the updating of memory content.

Inhibition of PKA anchoring to A-kinase anchoring proteins impairs consolidation and facilitates extinction of contextual fear memories

NARCIS (Netherlands)

Nijholt, Ingrid M.; Ostroveanu, Anghelus; Scheper, Wouter A.; Penke, Botond; Luiten, Paul G. M.; Van der Zee, Eddy A.; Eisel, Ulrich L. M.

Both genetic and pharmacological studies demonstrated that contextual fear conditioning is critically regulated by cyclic AMP-dependent protein kinase (PKA). Since PKA is a broad range protein kinase, a mechanism for confining its activity is required. It has been shown that intracellular spatial

Effects of sleep on memory for conditioned fear and fear extinction

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

2015-01-01

Learning and memory for extinction of conditioned fear is a basic mammalian mechanism for regulating negative emotion. Sleep promotes both the consolidation of memory and the regulation of emotion. Sleep can influence consolidation and modification of memories associated with both fear and its extinction. After brief overviews of the behavior and neural circuitry associated with fear conditioning, extinction learning and extinction memory in the rodent and human, interactions of sleep with th...

Effects of sleep on memory for conditioned fear and fear extinction

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

2015-01-01

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

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

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

2015-07-01

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

High-affinity α4β2 nicotinic receptors mediate the impairing effects of acute nicotine on contextual fear extinction.

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Kutlu, Munir Gunes; Holliday, Erica; Gould, Thomas J

2016-02-01

Previously, studies from our lab have shown that while acute nicotine administered prior to training and testing enhances contextual fear conditioning, acute nicotine injections prior to extinction sessions impair extinction of contextual fear. Although there is also strong evidence showing that the acute nicotine's enhancing effects on contextual fear conditioning require high-affinity α4β2 nicotinic acetylcholine receptors (nAChRs), it is unknown which nAChR subtypes are involved in the acute nicotine-induced impairment of contextual fear extinction. In this study, we investigated the effects of acute nicotine administration on contextual fear extinction in knock-out (KO) mice lacking α4, β2 or α7 subtypes of nAChRs and their wild-type (WT) littermates. Both KO and WT mice were first trained and tested for contextual fear conditioning and received a daily contextual extinction session for 4 days. Subjects received intraperitoneal injections of nicotine (0.18 mg/kg) or saline 2-4 min prior to each extinction session. Our results showed that the mice that lack α4 and β2 subtypes of nAChRs showed normal contextual fear extinction but not the acute nicotine-induced impairment while the mice that lack the α7 subtype showed both normal contextual extinction and nicotine-induced impairment of contextual extinction. In addition, control experiments showed that acute nicotine-induced impairment of contextual fear extinction persisted when nicotine administration was ceased and repeated acute nicotine administrations alone did not induce freezing behavior in the absence of context-shock learning. These results clearly demonstrate that high-affinity α4β2 nAChRs are necessary for the effects of acute nicotine on contextual fear extinction. Copyright © 2015 Elsevier Inc. All rights reserved.

Fearful contextual expression impairs the encoding and recognition of target faces: an ERP study

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Huiyan eLin

2015-09-01

Full Text Available Previous event-related potential (ERP studies have shown that the N170 to faces is modulated by the emotion of the face and its context. However, it is unclear how the encoding of emotional target faces as reflected in the N170 is modulated by the preceding contextual facial expression when temporal onset and identity of target faces are unpredictable. In addition, no study as yet has investigated whether contextual facial expression modulates later recognition of target faces. To address these issues, participants in the present study were asked to identify target faces (fearful or neutral that were presented after a sequence of fearful or neutral contextual faces. The number of sequential contextual faces was random and contextual and target faces were of different identities so that temporal onset and identity of target faces were unpredictable. Electroencephalography (EEG data was recorded during the encoding phase. Subsequently, participants had to perform an unexpected old/new recognition task in which target face identities were presented in either the encoded or the non-encoded expression. ERP data showed a reduced N170 to target faces in fearful as compared to neutral context regardless of target facial expression. In the later recognition phase, recognition rates were reduced for target faces in the encoded expression when they had been encountered in fearful as compared to neutral context. The present findings suggest that fearful compared to neutral contextual faces reduce the allocation of attentional resources towards target faces, which results in limited encoding and recognition of target faces.

Dissociating response systems: erasing fear from memory.

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Soeter, Marieke; Kindt, Merel

2010-07-01

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

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

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

2015-01-01

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

Extinction partially reverts structural changes associated with remote fear memory

DEFF Research Database (Denmark)

Vetere, Gisella; Restivo, Leonardo; Novembre, Giovanni

2011-01-01

Structural synaptic changes occur in medial prefrontal cortex circuits during remote memory formation. Whether extinction reverts or further reshapes these circuits is, however, unknown. Here we show that the number and the size of spines were enhanced in anterior cingulate (aCC) and infralimbic...... (ILC) cortices 36 d following contextual fear conditioning. Upon extinction, aCC spine density returned to baseline, but the enhanced proportion of large spines did not. Differently, ILC spine density remained elevated, but the size of spines decreased dramatically. Thus, extinction partially erases...

The neural dynamics of fear memory

NARCIS (Netherlands)

Visser, R.M.

2016-01-01

While much of what we learn will be forgotten over time, fear memory appears to be particularly resilient to forgetting. Our understanding of how fearful events are transformed into durable memory, and how this memory subsequently influences the processing of (novel) stimuli, is limited. Studying

Early life stress in rats sex-dependently affects remote endocrine rather than behavioral consequences of adult exposure to contextual fear conditioning.

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Fuentes, Sílvia; Daviu, Núria; Gagliano, Humberto; Belda, Xavier; Armario, Antonio; Nadal, Roser

2018-05-30

Exposure to electric foot-shocks can induce in rodents contextual fear conditioning, generalization of fear to other contexts and sensitization of the hypothalamic-pituitary-adrenal (HPA) axis to further stressors. All these aspects are relevant for the study of post-traumatic stress disorder. In the present work we evaluated in rats the sex differences and the role of early life stress (ELS) in fear memories, generalization and sensitization. During the first postnatal days subjects were exposed to restriction of nesting material along with exposure to a "substitute" mother. In the adulthood they were exposed to (i) a contextual fear conditioning to evaluate long-term memory and extinction and (ii) to a novel environment to study cognitive fear generalization and HPA axis heterotypic sensitization. ELS did not alter acquisition, expression or extinction of context fear conditioned behavior (freezing) in either sex, but reduced activity in novel environments only in males. Fear conditioning associated hypoactivity in novel environments (cognitive generalization) was greater in males than females but was not specifically affected by ELS. Although overall females showed greater basal and stress-induced levels of ACTH and corticosterone, an interaction between ELS, shock exposure and sex was found regarding HPA hormones. In males, ELS did not affect ACTH response in any situation, whereas in females, ELS reduced both shock-induced sensitization of ACTH and its conditioned response to the shock context. Also, shock-induced sensitization of corticosterone was only observed in males and ELS specifically reduced corticosterone response to stressors in males but not females. In conclusion, ELS seems to have only a minor impact on shock-induced behavioral conditioning, while affecting the unconditioned and conditioned responses of HPA hormones in a sex-dependent manner. Copyright © 2018. Published by Elsevier Inc.

Retrieving fear memories, as time goes by…

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Do Monte, Fabricio H.; Quirk, Gregory J.; Li, Bo; Penzo, Mario A.

2016-01-01

Fear conditioning researches have led to a comprehensive picture of the neuronal circuit underlying the formation of fear memories. In contrast, knowledge about the retrieval of fear memories is much more limited. This disparity may stem from the fact that fear memories are not rigid, but reorganize over time. To bring clarity and raise awareness on the time-dependent dynamics of retrieval circuits, we review current evidence on the neuronal circuitry participating in fear memory retrieval at both early and late time points after conditioning. We focus on the temporal recruitment of the paraventricular nucleus of the thalamus, and its BDNFergic efferents to the central nucleus of the amygdala, for the retrieval and maintenance of fear memories. Finally, we speculate as to why retrieval circuits change across time, and the functional benefits of recruiting structures such as the paraventricular nucleus into the retrieval circuit. PMID:27217148

Estradiol replacement enhances fear memory formation, impairs extinction and reduces COMT expression levels in the hippocampus of ovariectomized female mice.

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McDermott, Carmel M; Liu, Dan; Ade, Catherine; Schrader, Laura A

2015-02-01

Females experience depression, posttraumatic stress disorder (PTSD), and anxiety disorders at approximately twice the rate of males, but the mechanisms underlying this difference remain undefined. The effect of sex hormones on neural substrates presents a possible mechanism. We investigated the effect of ovariectomy at two ages, before puberty and in adulthood, and 17β-estradiol (E2) replacement administered chronically in drinking water on anxiety level, fear memory formation, and extinction. Based on previous studies, we hypothesized that estradiol replacement would impair fear memory formation and enhance extinction rate. Females, age 4 weeks and 10 weeks, were divided randomly into 4 groups; sham surgery, OVX, OVX+low E2 (200nM), and OVX+high E2 (1000nM). Chronic treatment with high levels of E2 significantly increased anxiety levels measured in the elevated plus maze. In both age groups, high levels of E2 significantly increased contextual fear memory but had no effect on cued fear memory. In addition, high E2 decreased the rate of extinction in both ages. Finally, catechol-O-methyltransferase (COMT) is important for regulation of catecholamine levels, which play a role in fear memory formation and extinction. COMT expression in the hippocampus was significantly reduced by high E2 replacement, implying increased catecholamine levels in the hippocampus of high E2 mice. These results suggest that estradiol enhanced fear memory formation, and inhibited fear memory extinction, possibly stabilizing the fear memory in female mice. This study has implications for a neurobiological mechanism for PTSD and anxiety disorders. Copyright © 2014 Elsevier Inc. All rights reserved.

Generation and memory for contextual detail.

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Mulligan, Neil W

2004-07-01

Generation enhances item memory but may not enhance other aspects of memory. In 12 experiments, the author investigated the effect of generation on context memory, motivated in part by the hypothesis that generation produces a trade-off in encoding item and contextual information. Participants generated some study words (e.g., hot-c__) and read others (e.g., hot-cold). Generation consistently enhanced item memory but did not enhance context memory. More specifically, generation disrupted context memory for the color of the target word but did not affect context memory for location, background color, and cue-word color. The specificity of the negative generation effect in context memory argues against a general item-context trade-off. A processing account of generation meets greater success. In addition, the results provide no evidence that generation enhances recollection of contextual details. Copyright 2004 APA, all rights reserved

Concentration- and age-dependent effects of chronic caffeine on contextual fear conditioning in C57BL/6J mice

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Poole, Rachel L.; Braak, David; Gould, Thomas J.

2015-01-01

Chronic caffeine exerts negligible effects on learning and memory in normal adults, but it is unknown whether this is also true for children and adolescents. The hippocampus, a brain region important for learning and memory, undergoes extensive structural and functional modifications during pre-adolescence and adolescence. As a result, chronic caffeine may have differential effects on hippocampus-dependent learning in pre-adolescents and adolescents compared with adults. Here, we characterized the effects of chronic caffeine and withdrawal from chronic caffeine on hippocampus-dependent (contextual) and hippocampus-independent (cued) fear conditioning in pre-adolescent, adolescent, and adult mice. The results indicate that chronic exposure to caffeine during pre-adolescence and adolescence enhances or impairs contextual conditioning depending on concentration, yet has no effect on cued conditioning. In contrast, withdrawal from chronic caffeine impairs contextual conditioning in pre-adolescent mice only. No changes in learning were seen for adult mice for either the chronic caffeine or withdrawal conditions. These findings support the hypothesis that chronic exposure to caffeine during pre-adolescence and adolescence can alter learning and memory and as changes were only seen in hippocampus-dependent learning, this suggests that the developing hippocampus may be sensitive to the effects of caffeine. PMID:25827925

Concentration- and age-dependent effects of chronic caffeine on contextual fear conditioning in C57BL/6J mice.

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Poole, Rachel L; Braak, David; Gould, Thomas J

2016-02-01

Chronic caffeine exerts negligible effects on learning and memory in normal adults, but it is unknown whether this is also true for children and adolescents. The hippocampus, a brain region important for learning and memory, undergoes extensive structural and functional modifications during pre-adolescence and adolescence. As a result, chronic caffeine may have differential effects on hippocampus-dependent learning in pre-adolescents and adolescents compared with adults. Here, we characterized the effects of chronic caffeine and withdrawal from chronic caffeine on hippocampus-dependent (contextual) and hippocampus-independent (cued) fear conditioning in pre-adolescent, adolescent, and adult mice. The results indicate that chronic exposure to caffeine during pre-adolescence and adolescence enhances or impairs contextual conditioning depending on concentration, yet has no effect on cued conditioning. In contrast, withdrawal from chronic caffeine impairs contextual conditioning in pre-adolescent mice only. No changes in learning were seen for adult mice for either the chronic caffeine or withdrawal conditions. These findings support the hypothesis that chronic exposure to caffeine during pre-adolescence and adolescence can alter learning and memory and as changes were only seen in hippocampus-dependent learning, which suggests that the developing hippocampus may be sensitive to the effects of caffeine. Copyright © 2015 Elsevier B.V. All rights reserved.

Tyrosine receptor kinase B receptor activation reverses the impairing effects of acute nicotine on contextual fear extinction.

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Kutlu, Munir Gunes; Cole, Robert D; Connor, David A; Natwora, Brendan; Gould, Thomas J

2018-03-01

Anxiety and stress disorders have been linked to deficits in fear extinction. Our laboratory and others have demonstrated that acute nicotine impairs contextual fear extinction, suggesting that nicotine exposure may have negative effects on anxiety and stress disorder symptomatology. However, the neurobiological mechanisms underlying the acute nicotine-induced impairment of contextual fear extinction are unknown. Therefore, based on the previous studies showing that brain-derived neurotrophic factor is central for fear extinction learning and acute nicotine dysregulates brain-derived neurotrophic factor signaling, we hypothesized that the nicotine-induced impairment of contextual fear extinction may involve changes in tyrosine receptor kinase B signaling. To test this hypothesis, we systemically, intraperitoneally, injected C57BL/6J mice sub-threshold doses (2.5 and 4.0 mg/kg) of 7,8-dihydroxyflavone, a small-molecule tyrosine receptor kinase B agonist that fully mimics the effects of brain-derived neurotrophic factor, or vehicle an hour before each contextual fear extinction session. Mice also received injections, intraperitoneally, of acute nicotine (0.18 mg/kg) or saline 2-4 min before extinction sessions. While the animals that received only 7,8-dihydroxyflavone did not show any changes in contextual fear extinction, 4.0 mg/kg of 7,8-dihydroxyflavone ameliorated the extinction deficits in mice administered acute nicotine. Overall, these results suggest that acute nicotine-induced impairment of context extinction may be related to a disrupted brain-derived neurotrophic factor signaling.

Vicarious extinction learning during reconsolidation neutralizes fear memory.

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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.

Noradrenergic Modulation of Fear Conditioning and Extinction.

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Giustino, Thomas F; Maren, Stephen

2018-01-01

The locus coeruleus norepinephrine (LC-NE) system plays a broad role in learning and memory. Here we begin with an overview of the LC-NE system. We then consider how both direct and indirect manipulations of the LC-NE system affect cued and contextual aversive learning and memory. We propose that NE dynamically modulates Pavlovian conditioning and extinction, either promoting or impairing learning aversive processes under different levels of behavioral arousal. We suggest that under high levels of stress (e.g., during/soon after fear conditioning) the locus coeruleus (LC) promotes cued fear learning by enhancing amygdala function while simultaneously blunting prefrontal function. Under low levels of arousal, the LC promotes PFC function to promote downstream inhibition of the amygdala and foster the extinction of cued fear. Thus, LC-NE action on the medial prefrontal cortex (mPFC) might be described by an inverted-U function such that it can either enhance or hinder learning depending on arousal states. In addition, LC-NE seems to be particularly important for the acquisition, consolidation and extinction of contextual fear memories. This may be due to dense adrenoceptor expression in the hippocampus (HPC) which encodes contextual information, and the ability of NE to regulate long-term potentiation (LTP). Moreover, recent work reveals that the diversity of LC-NE functions in aversive learning and memory are mediated by functionally heterogeneous populations of LC neurons that are defined by their projection targets. Hence, LC-NE function in learning and memory is determined by projection-specific neuromodulation that accompanies various states of behavioral arousal.

Noradrenergic Modulation of Fear Conditioning and Extinction

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Thomas F. Giustino

2018-03-01

Full Text Available The locus coeruleus norepinephrine (LC-NE system plays a broad role in learning and memory. Here we begin with an overview of the LC-NE system. We then consider how both direct and indirect manipulations of the LC-NE system affect cued and contextual aversive learning and memory. We propose that NE dynamically modulates Pavlovian conditioning and extinction, either promoting or impairing learning aversive processes under different levels of behavioral arousal. We suggest that under high levels of stress (e.g., during/soon after fear conditioning the locus coeruleus (LC promotes cued fear learning by enhancing amygdala function while simultaneously blunting prefrontal function. Under low levels of arousal, the LC promotes PFC function to promote downstream inhibition of the amygdala and foster the extinction of cued fear. Thus, LC-NE action on the medial prefrontal cortex (mPFC might be described by an inverted-U function such that it can either enhance or hinder learning depending on arousal states. In addition, LC-NE seems to be particularly important for the acquisition, consolidation and extinction of contextual fear memories. This may be due to dense adrenoceptor expression in the hippocampus (HPC which encodes contextual information, and the ability of NE to regulate long-term potentiation (LTP. Moreover, recent work reveals that the diversity of LC-NE functions in aversive learning and memory are mediated by functionally heterogeneous populations of LC neurons that are defined by their projection targets. Hence, LC-NE function in learning and memory is determined by projection-specific neuromodulation that accompanies various states of behavioral arousal.

Contextual fear conditioning in virtual reality is affected by 5HTTLPR and NPSR1 polymorphisms: effects on fear-potentiated startle

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Evelyn eGlotzbach-Schoon

2013-04-01

Full Text Available The serotonin (5-HT and neuropeptide S (NPS systems are discussed as important genetic modulators of fear and sustained anxiety contributing to the etiology of anxiety disorders. Sustained anxiety is a crucial characteristic of most anxiety disorders which likely develops through context conditioning. This study investigated if and how genetic alterations of the 5-HT and the NPS systems as well as their interaction modulate contextual fear conditioning; specifically, function polymorphic variants in the genes coding for the 5-HT transporter (5HTT and the NPS receptor (NPSR1 were studied. A large group of healthy volunteers was therefore stratified for 5HTTLPR (S+ vs. LL carriers and NPSR1 rs324981 (T+ vs. AA carriers polymorphisms resulting in four genotype groups (S+/T+, S+/AA, LL/T+, LL/AA of 20 participants each. All participants underwent contextual fear conditioning and extinction using a virtual reality paradigm. During acquisition, one virtual office room (anxiety context, CXT+ was paired with an unpredictable electric stimulus (unconditioned stimulus, US, whereas another virtual office room was not paired with any US (safety context, CXT-. During extinction no US was administered. Anxiety responses were quantified by fear-potentiated startle and ratings. Most importantly, we found a gene × gene interaction on fear-potentiated startle. Only carriers of both risk alleles (S+/T+ exhibited higher startle responses in CXT+ compared to CXT-. In contrast, anxiety ratings were only influenced by the NPSR1 polymorphism with AA carriers showing higher anxiety ratings in CXT+ as compared to CXT-. Our results speak in favor of a two level account of fear conditioning with diverging effects on implicit vs. explicit fear responses. Contextual fear reflected in potentiated startle responses may be an endophenotype for anxiety disorders.

The roles of the actin cytoskeleton in fear memory formation

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Raphael eLamprecht

2011-07-01

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

A BDNF sensitive mechanism is involved in the fear memory resulting from the interaction between stress and the retrieval of an established trace.

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Giachero, Marcelo; Bustos, Silvia G; Calfa, Gaston; Molina, Victor A

2013-04-15

The present study investigates the fear memory resulting from the interaction of a stressful experience and the retrieval of an established fear memory trace. Such a combination enhanced both fear expression and fear retention in adult Wistar rats. Likewise, midazolam intra-basolateral amygdala (BLA) infusion prior to stress attenuated the enhancement of fear memory thus suggesting the involvement of a stress-induced reduction of the GABAergic transmission in BLA in the stress-induced enhancing effect. It has been suggested that, unlike the immediate-early gene Zif268 which is related to the reconsolidation process, the expression of hippocampal brain-derived neurotrophic factor (BDNF) is highly correlated with consolidation. We therefore evaluate the relative contribution of these two neurobiological processes to the fear memory resulting from the above-mentioned interaction. Intra-dorsal hippocampus (DH) infusions of either the antisense Zif268 or the inhibitor of the protein degradation (Clasto-Lactacystin β-Lactone), suggested to be involved in the retrieval-dependent destabilization process, did not affect the resulting contextual memory. In contrast, the knockdown of hippocampal BDNF mitigated the stress-induced facilitating influence on fear retention. In addition, the retrieval experience elevated BDNF level in DH at 60 min after recall exclusively in stressed animals. These findings suggest the involvement of a hippocampal BDNF sensitive mechanism in the stress-promoting influence on the fear memory following retrieval.

Glycyrrhizin Treatment Facilitates Extinction of Conditioned Fear Responses After a Single Prolonged Stress Exposure in Rats

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Shuhua Lai

2018-03-01

Full Text Available Background/Aims: Impaired fear memory extinction is widely considered a key mechanism of post-traumatic stress disorder (PTSD. Recent studies have suggested that neuroinflammation after a single prolonged stress (SPS exposure may play a critical role in the impaired fear memory extinction. Studies have shown that high mobility group box chromosomal protein 1 (HMGB-1 is critically involved in neuroinflammation. However, the role of HMGB-1 underlying the development of impairment of fear memory extinction is still not known. Methods: Thus, we examined the levels of HMGB-1 in the basolateral amygdala (BLA following SPS using Western blot and evaluated the levels of microglia and astrocytes activation in the BLA after SPS using immunohistochemical staining. We then examined the effects of pre-SPS intra-BLA administration of glycyrrhizin, an HMGB1 inhibitor, or LPS-RS, a competitive TLR4 antagonist, on subsequent post-SPS fear extinction. Results: We found that SPS treatment prolonged the extinction of contextual fear memory after the SPS. The impairment of SPS-induced extinction of contextual fear memory was associated with increased HMGB1 and Toll-like receptor 4 (TLR4 levels in the BLA. Additionally, the impairment of SPS-induced extinction of contextual fear memory was associated with increased activation of microglia and astrocyte in the BLA. Intra-BLA administrations of glycyrrhizin (HMGB-1 inhibitor or LPS-RS (TLR4 antagonist can prevent the development of SPS-induced fear extinction impairment. Conclusion: Taken together, these results suggested that SPS treatment may not only produce short term effects on the HMGB1/TLR4-mediated pro-inflammation, but alter the response of microglia and astrocytes to the exposure to fear associated contextual stimuli.

Glycyrrhizin Treatment Facilitates Extinction of Conditioned Fear Responses After a Single Prolonged Stress Exposure in Rats.

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Lai, Shuhua; Wu, Gangwei; Jiang, Zhixian

2018-01-01

Impaired fear memory extinction is widely considered a key mechanism of post-traumatic stress disorder (PTSD). Recent studies have suggested that neuroinflammation after a single prolonged stress (SPS) exposure may play a critical role in the impaired fear memory extinction. Studies have shown that high mobility group box chromosomal protein 1 (HMGB-1) is critically involved in neuroinflammation. However, the role of HMGB-1 underlying the development of impairment of fear memory extinction is still not known. Thus, we examined the levels of HMGB-1 in the basolateral amygdala (BLA) following SPS using Western blot and evaluated the levels of microglia and astrocytes activation in the BLA after SPS using immunohistochemical staining. We then examined the effects of pre-SPS intra-BLA administration of glycyrrhizin, an HMGB1 inhibitor, or LPS-RS, a competitive TLR4 antagonist, on subsequent post-SPS fear extinction. We found that SPS treatment prolonged the extinction of contextual fear memory after the SPS. The impairment of SPS-induced extinction of contextual fear memory was associated with increased HMGB1 and Toll-like receptor 4 (TLR4) levels in the BLA. Additionally, the impairment of SPS-induced extinction of contextual fear memory was associated with increased activation of microglia and astrocyte in the BLA. Intra-BLA administrations of glycyrrhizin (HMGB-1 inhibitor) or LPS-RS (TLR4 antagonist) can prevent the development of SPS-induced fear extinction impairment. Taken together, these results suggested that SPS treatment may not only produce short term effects on the HMGB1/TLR4-mediated pro-inflammation, but alter the response of microglia and astrocytes to the exposure to fear associated contextual stimuli. © 2018 The Author(s). Published by S. Karger AG, Basel.

Juvenile neurogenesis makes essential contributions to adult brain structure and plays a sex-dependent role in fear memories

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Jesse Daniel Cushman

2012-02-01

Full Text Available Postnatal-neurogenesis (PNN contributes neurons to olfactory bulb (OB and dentate gyrus (DG throughout juvenile development, but the quantitative amount, temporal dynamics and functional roles of this contribution have not been defined. By using transgenic mouse models for cell lineage tracing and conditional cell ablation, we found that juvenile neurogenesis gradually increased the total number of granule neurons by approximately 40% in OB, and by 25% in DG, between two weeks and two months of age, and that total numbers remained stable thereafter. These findings indicate that the overwhelming majority of net postnatal neuronal addition in these regions occurs during the juvenile period and that adult neurogenesis contributes primarily to replacement of granule cells in both regions. Behavioral analysis in our conditional cell ablation mouse model showed that complete loss of PNN throughout both the juvenile and adult period produced a specific set of sex-dependent cognitive changes. We observed normal hippocampus-independent delay fear conditioning, but excessive generalization of fear to a novel auditory stimulus, which is consistent with a role for PNN in psychopathology. Standard contextual fear conditioning was intact, however, pre-exposure dependent contextual fear was impaired suggesting a specific role for PNN in incidental contextual learning. Contextual discrimination between two highly similar contexts was enhanced; suggesting either enhanced contextual pattern separation or impaired temporal integration. We also observed a reduced reliance on olfactory cues, consistent with a role for OB PNN in the efficient processing of olfactory information. Thus, juvenile neurogenesis adds substantively to the total numbers of granule neurons in OB and DG during periods of critical juvenile behavioral development, including weaning, early social interactions and sexual maturation, and plays a sex-dependent role in fear memories.

Fear Conditioning Downregulates Rac1 Activity in the Basolateral Amygdala Astrocytes to Facilitate the Formation of Fear Memory.

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Liao, Zhaohui; Tao, Yezheng; Guo, Xiaomu; Cheng, Deqin; Wang, Feifei; Liu, Xing; Ma, Lan

2017-01-01

Astrocytes are well known to scale synaptic structural and functional plasticity, while the role in learning and memory, such as conditioned fear memory, is poorly elucidated. Here, using pharmacological approach, we find that fluorocitrate (FC) significantly inhibits the acquisition of fear memory, suggesting that astrocyte activity is required for fear memory formation. We further demonstrate that fear conditioning downregulates astrocytic Rac1 activity in basolateral amygdala (BLA) in mice and promotes astrocyte structural plasticity. Ablation of astrocytic Rac1 in BLA promotes fear memory acquisition, while overexpression or constitutive activation of astrocytic Rac1 attenuates fear memory acquisition. Furthermore, temporal activation of Rac1 by photoactivatable Rac1 (Rac1-PA) induces structural alterations in astrocytes and in vivo activation of Rac1 in BLA astrocytes during fear conditioning attenuates the formation of fear memory. Taken together, our study demonstrates that fear conditioning-induced suppression of BLA astrocytic Rac1 activity, associated with astrocyte structural plasticity, is required for the formation of conditioned fear memory.

The influence of stress on fear memory processes

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I.D. Martijena

2012-04-01

Full Text Available It is well recognized that stressful experiences promote robust emotional memories, which are well remembered. The amygdaloid complex, principally the basolateral complex (BLA, plays a pivotal role in fear memory and in the modulation of stress-induced emotional responses. A large number of reports have revealed that GABAergic interneurons provide a powerful inhibitory control of the activity of projecting glutamatergic neurons in the BLA. Indeed, a reduced GABAergic control in the BLA is essential for the stress-induced influence on the emergence of associative fear memory and on the generation of long-term potentiation (LTP in BLA neurons. The extracellular signal-regulated kinase (ERK subfamily of the mitogen-activated protein kinase (MAPK signaling pathway in the BLA plays a central role in the consolidation process and synaptic plasticity. In support of the view that stress facilitates long-term fear memory, stressed animals exhibited a phospho-ERK2 (pERK2 increase in the BLA, suggesting the involvement of this mechanism in the promoting influence of threatening stimuli on the consolidation fear memory. Moreover, the occurrence of reactivation-induced lability is prevented when fear memory is encoded under intense stressful conditions since the memory trace remains immune to disruption after recall in previously stressed animals. Thus, the underlying mechanism in retrieval-induced instability seems not to be functional in memories formed under stress. All these findings are indicative that stress influences both the consolidation and reconsolidation fear memory processes. Thus, it seems reasonable to propose that the emotional state generated by an environmental challenge critically modulates the formation and maintenance of long-term fear memory.

Central Ghrelin Resistance Permits the Overconsolidation of Fear Memory.

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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.

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

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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.

Contextual memory, psychosis-proneness, and the experience of intrusive imagery.

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Glazer, Daniel A; Mason, Oliver; King, John A; Brewin, Chris R

2013-01-01

This study tested the hypothesis that the presence and characteristics of naturally occurring involuntary imagery would be related to poorer context-dependent spatial memory and higher levels of proneness to psychotic experiences. Poorer contextual memory was also predicted to be associated with a greater sense of "nowness". Participants completed a virtual environment task that assessed contextual memory through responses that required allocentric and egocentric processing of virtual stimuli. Two questionnaires assessing predisposition to psychotic experiences were employed. Finally, participants completed an interview that required details of recent, naturally occurring involuntary images. Reports of involuntary imagery were associated with greater proneness to psychotic experiences but not with memory. In those participants who reported imagery, however, poorer memory performance was associated with more vivid and detailed intrusive imagery. Poorer contextual memory was specifically associated with a greater sense of "nowness". Possible links between contextual memory and proneness to psychosis are discussed.

Pre-Training Reversible Inactivation of the Basal Amygdala (BA Disrupts Contextual, but Not Auditory, Fear Conditioning, in Rats.

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Elisa Mari Akagi Jordão

Full Text Available The basolateral amygdala complex (BLA, including the lateral (LA, basal (BA and accessory basal (AB nuclei, is involved in acquisition of contextual and auditory fear conditioning. The BA is one of the main targets for hippocampal information, a brain structure critical for contextual learning, which integrates several discrete stimuli into a single configural representation. Congruent with the hodology, selective neurotoxic damage to the BA results in impairments in contextual, but not auditory, fear conditioning, similarly to the behavioral impairments found after hippocampal damage. This study evaluated the effects of muscimol-induced reversible inactivation of the BA during a simultaneous contextual and auditory fear conditioning training on later fear responses to both the context and the tone, tested separately, without muscimol administration. As compared to control rats micro-infused with vehicle, subjects micro-infused with muscimol before training exhibited, during testing without muscimol, significant reduction of freezing responses to the conditioned context, but not to the conditioned tone. Therefore, reversible inactivation of the BA during training impaired contextual, but not auditory fear conditioning, thus confirming and extending similar behavioral observations following selective neurotoxic damage to the BA and, in addition, revealing that this effect is not related to the lack of a functional BA during testing.

Dopamine D1-like receptor in lateral habenula nucleus affects contextual fear memory and long-term potentiation in hippocampal CA1 in rats.

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Chan, Jiangping; Guan, Xin; Ni, Yiling; Luo, Lilu; Yang, Liqiang; Zhang, Pengyue; Zhang, Jichuan; Chen, Yanmei

2017-03-15

The Lateral Habenula (LHb) plays an important role in emotion and cognition. Recent experiments suggest that LHb has functional interaction with the hippocampus and plays an important role in spatial learning. LHb is reciprocally connected with midbrain monoaminergic brain areas such as the ventral tegmental area (VTA). However, the role of dopamine type 1 receptor (D1R) in LHb in learning and memory is not clear yet. In the present study, D1R agonist or antagonist were administered bilaterally into the LHb in rats. We found that both D1R agonist and antagonist impaired the acquisition of contextual fear memory in rats. D1R agonist or antagonist also impaired long term potentiation (LTP) in hippocampal CA3-CA1 synapses in freely moving rats and attenuated learning induced phosphorylation of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR) subunit 1 (GluA1) at Ser831 and Ser845 in hippocampus. Taken together, our results suggested that dysfunction of D1R in LHb affected the function of hippocampus. Copyright © 2016 Elsevier B.V. All rights reserved.

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

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Marco eCostanzi

2014-08-01

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

Inhibition of projections from the basolateral amygdala to the entorhinal cortex disrupts the acquisition of contextual fear

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Dennis R. Sparta

2014-05-01

Full Text Available The development of excessive fear and/or stress responses to environmental cues such as contexts associated with a traumatic event is a hallmark of post-traumatic stress disorder (PTSD. The basolateral amygdala (BLA has been implicated as a key structure mediating contextual fear conditioning. In addition, the hippocampus has an integral role in the encoding and processing of contexts associated with strong, salient stimuli such as fear. Given that both the BLA and hippocampus play an important role in the regulation of contextual fear conditioning, examining the functional connectivity between these two structures may elucidate a role for this pathway in the development of PTSD. Here, we used optogenetic strategies to demonstrate that the BLA sends a strong glutamatergic projection to the hippocampal formation through the entorhinal cortex (EC. Next, we photoinhibited glutamatergic fibers from the BLA terminating in the EC during the acquisition or expression of contextual fear conditioning. In mice that received optical inhibition of the BLA-to-EC pathway during the acquisition session, we observed a significant decrease in freezing behavior in a context re-exposure session. In contrast, we observed no differences in freezing behavior in mice that were only photoinhibited during the context re-exposure session. These data demonstrate an important role for the BLA-to-EC glutamatergic pathway in the acquisition of contextual fear conditioning.

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

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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.

Sex differences in the behavioural and hypothalamic-pituitary-adrenal response to contextual fear conditioning in rats.

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Daviu, Núria; Andero, Raül; Armario, Antonio; Nadal, Roser

2014-11-01

In recent years, special attention is being paid to sex differences in susceptibility to disease. In this regard, there is evidence that male rats present higher levels of both cued and contextual fear conditioning than females. However, little is known about the concomitant hypothalamic-pituitary-adrenal (HPA) axis response to those situations which are critical in emotional memories. Here, we studied the behavioural and HPA responses of male and female Wistar rats to context fear conditioning using electric footshock as the aversive stimulus. Fear-conditioned rats showed a much greater ACTH and corticosterone response than those merely exposed to the fear conditioning chamber without receiving shocks. Moreover, males presented higher levels of freezing whereas HPA axis response was greater in females. Accordingly, during the fear extinction tests, female rats consistently showed less freezing and higher extinction rate, but greater HPA activation than males. Exposure to an open-field resulted in lower activity/exploration in fear-conditioned males, but not in females, suggesting greater conditioned cognitive generalization in males than females. It can be concluded that important sex differences in fear conditioning are observed in both freezing and HPA activation, but the two sets of variables are affected in the opposite direction: enhanced behavioural impact in males, but enhanced HPA responsiveness in females. Thus, the role of sex differences on fear-related stimuli may depend on the variables chosen to evaluate it, the greater responsiveness of the HPA axis in females perhaps being an important factor to be further explored. Copyright © 2014 Elsevier Inc. All rights reserved.

Adiponectin regulates contextual fear extinction and intrinsic excitability of dentate gyrus granule neurons through AdipoR2 receptors.

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

2017-07-01

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

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

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

2005-01-01

The effects of acute nicotine administration (0.09 mg/kg nicotine), chronic nicotine administration (6.3 mg/kg/d nicotine for 14 d), and withdrawal from chronic nicotine administration on fear conditioning in C57BL/6 mice were examined. Mice were trained using two coterminating conditioned stimulus (30 s; 85 dB white noise)– unconditioned stimulus (2 s; 0.57 mA foot shock) pairings and tested 24 h later for contextual and cued fear conditioning. Acute nicotine administration enhanced contextu...

Long-term contextual memory in infant rats as evidenced by an ethanol conditioned tolerance procedure.

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Castelló, Stefanía; Molina, Juan Carlos; Arias, Carlos

2017-08-14

Conditioned tolerance can be conceptualized as a particular case of Pavlovian conditioning in which contextual cues play the role of the conditioned stimulus. Although the evidence is contradictory, it is frequently assumed that long-term contextual conditioning in pre-weanling rats is weak or even absent. This hypothesis comes from and is sustained mainly by behavioral studies that explored different contextual effects in 16-18day-old rats using a fear-conditioning paradigm, but their conclusions are stated in terms of an immature (hippocampal-dependent) declarative memory system. The main goal of the present manuscript was based on a recent antecedent from our laboratory, to analyze whether context-dependent tolerance induced by ethanol during the pre-weanling period persists over time. Results showed that the context was able to modulate ethanol-induced tolerance in 2- and 3-week-old rats. Interestingly, contextual conditioned tolerance was stronger (in terms of persistence) during the third than during the second postnatal week. When subjects were tested 8days after training, when the context presumably lost its influence over tolerance, the opposite effect emerged (sensitization). These results are important for the ethanol literature, adding new evidence of long-term retention of ethanol effects acquired during infancy, whilst also showing striking ontogenetic differences in the sensitivity to ethanol between the 2nd and 3rd postnatal weeks. Importantly, contextual information modulates the expression of these ethanol effects even eight days after training, a result that is particularly relevant to the discussion of the ontogeny of contextual memory. Copyright © 2017 Elsevier B.V. All rights reserved.

Encoding of Fear Memory in High and Low Fear Mice

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2013-11-18

contextual fear conditioning and retrieval. Brain structure & function   15.  Black AH, Young GA. 1972.  Electrical  activity of the hippocampus and cortex...0 Cara Olsen Statistician 0.12 0 SUBTOTALS 0

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

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Marieke Soeter

Full Text Available 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.

Intranasal Cotinine Plus Krill Oil Facilitates Fear Extinction, Decreases Depressive-Like Behavior, and Increases Hippocampal Calcineurin A Levels in Mice.

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Alvarez-Ricartes, Nathalie; Oliveros-Matus, Patricia; Mendoza, Cristhian; Perez-Urrutia, Nelson; Echeverria, Florencia; Iarkov, Alexandre; Barreto, George E; Echeverria, Valentina

2018-02-27

Failure in fear extinction is one of the more troublesome characteristics of posttraumatic stress disorder (PTSD). Cotinine facilitates fear memory extinction and reduces depressive-like behavior when administered 24 h after fear conditioning in mice. In this study, it was investigated the behavioral and molecular effects of cotinine, and other antidepressant preparations infused intranasally. Intranasal (IN) cotinine, IN krill oil, IN cotinine plus krill oil, and oral sertraline were evaluated on depressive-like behavior and fear retention and extinction after fear conditioning in C57BL/6 mice. Since calcineurin A has been involved in facilitating fear extinction in rodents, we also investigated changes of calcineurin in the hippocampus, a region key on contextual fear extinction. Short-term treatment with cotinine formulations was superior to krill oil and oral sertraline in reducing depressive-like behavior and fear consolidation and enhancing contextual fear memory extinction in mice. IN krill oil slowed the extinction of fear. IN cotinine preparations increased the levels of calcineurin A in the hippocampus of conditioned mice. In the light of the results, the future investigation of the use of IN cotinine preparations for the extinction of contextual fear memory and treatment of treatment-resistant depression (TRD) in PTSD is discussed.

Differential patterns of contextual organization of memory in first-episode psychosis.

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Murty, Vishnu P; McKinney, Rachel A; DuBrow, Sarah; Jalbrzikowski, Maria; Haas, Gretchen L; Luna, Beatriz

2018-02-15

Contextual information is used to support and organize episodic memory. Prior research has reliably shown memory deficits in psychosis; however, little research has characterized how this population uses contextual information during memory recall. We employed an approach founded in a computational framework of free recall to quantify how individuals with first episode of psychosis (FEP, N = 97) and controls (CON, N = 55) use temporal and semantic context to organize memory recall. Free recall was characterized using the Hopkins Verbal Learning Test-Revised (HVLT-R). We compared FEP and CON on three measures of free recall: proportion recalled, temporal clustering, and semantic clustering. Measures of temporal/semantic clustering quantified how individuals use contextual information to organize memory recall. We also assessed to what extent these measures relate to antipsychotic use and differentiated between different types of psychosis. We also explored the relationship between these measures and intelligence. In comparison to CON, FEP had reduced recall and less temporal clustering during free recall (p contextual organization of memory. IQ was related to free recall accuracy, but not the use of contextual information during recall in either group (p < 0.05, Bonferroni-corrected). These results show that in addition to deficits in memory recall, FEP differed in how they organize memories compared to CON.

Vicarious extinction learning during reconsolidation neutralizes fear memory

NARCIS (Netherlands)

Golkar, A.; Tjaden, C.; Kindt, M.

Background: 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

Optogenetic stimulation of a hippocampal engram activates fear memory recall.

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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.

Cocaine and Pavlovian fear conditioning: dose-effect analysis.

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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.

MOLECULAR MECHANISMS OF FEAR LEARNING AND MEMORY

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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.

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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.

Targeting memory reconsolidation to prevent the return of fear in patients with fear of flying.

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Maples-Keller, Jessica L; Price, Matthew; Jovanovic, Tanja; Norrholm, Seth D; Odenat, Lydia; Post, Loren; Zwiebach, Liza; Breazeale, Kathryn; Gross, Robin; Kim, Sae-Jin; Rothbaum, Barbara Olasov

2017-07-01

When a memory is recalled, it may again exist in a labile state and stored information becomes amenable to change, a psychobiological process known as reconsolidation. Exposure therapy for anxiety disorders involves accessing a fear memory and modifying it with less fearful information. A preclinical study reported that providing a reminder of a fear memory 10 min prior to extinction training in humans decreased fear up to 1 year later (Schiller et al., 2010). For this pilot clinical study, we used virtual reality exposure therapy (VRE) for fear of flying (FoF) to determine if using a cue to reactivate the memory of the feared stimulus 10 min prior to exposure sessions leads to fewer anxiety-related behaviors and a more durable response compared to a neutral cue. FoF participants (N = 89) received four sessions of anxiety management training followed by four sessions of VRE. Participants were randomly assigned to receive an FoF cue (reactivation group) or a neutral cue (control group) prior to the VRE sessions. Heart rate (HR) and skin conductance levels (SCLs) were collected during posttreatment and 3-month follow-up assessments as objective markers of fear responding. Treatment was effective and all clinical measures improved equally between groups at posttreatment with maintained gains through follow-ups. Significant differences were identified with regard to HR and SCL indices. These results suggest that memory reactivation prior to exposure therapy did not have an impact on clinical measures but may enhance the effect of exposure therapy at the physiological level. © 2017 Wiley Periodicals, Inc.

Sleep modulates the neural substrates of both spatial and contextual memory consolidation.

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Géraldine Rauchs

Full Text Available It is known that sleep reshapes the neural representations that subtend the memories acquired while navigating in a virtual environment. However, navigation is not process-pure, as manifold learning components contribute to performance, notably the spatial and contextual memory constituents. In this context, it remains unclear whether post-training sleep globally promotes consolidation of all of the memory components embedded in virtual navigation, or rather favors the development of specific representations. Here, we investigated the effect of post-training sleep on the neural substrates of the consolidation of spatial and contextual memories acquired while navigating in a complex 3D, naturalistic virtual town. Using fMRI, we mapped regional cerebral activity during various tasks designed to tap either the spatial or the contextual memory component, or both, 72 h after encoding with or without sleep deprivation during the first post-training night. Behavioral performance was not dependent upon post-training sleep deprivation, neither in a natural setting that engages both spatial and contextual memory processes nor when looking more specifically at each of these memory representations. At the neuronal level however, analyses that focused on contextual memory revealed distinct correlations between performance and neuronal activity in frontal areas associated with recollection processes after post-training sleep, and in the parahippocampal gyrus associated with familiarity processes in sleep-deprived participants. Likewise, efficient spatial memory was associated with posterior cortical activity after sleep whereas it correlated with parahippocampal/medial temporal activity after sleep deprivation. Finally, variations in place-finding efficiency in a natural setting encompassing spatial and contextual elements were associated with caudate activity after post-training sleep, suggesting the automation of navigation. These data indicate that post

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

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Johannes Björkstrand

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

The prelimbic cortex uses contextual cues to modulate responding towards predictive stimuli during fear renewal.

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Sharpe, Melissa; Killcross, Simon

2015-02-01

Previous research suggests the prelimbic (PL) cortex is involved in expression of conditioned fear (Burgos-Robles, Vidal-Gonzalez, & Quirk, 2009; Corcoran & Quirk, 2007). However, there is a long history of research in the appetitive domain which implicates this region in using higher-order cues to modulate a behavioural response (Birrell & Brown, 2000; Floresco, Block, & Tse, 2008; Marquis, Killcross, & Haddon, 2007; Sharpe & Killcross, 2014). For example, the PL cortex is necessary to allow animals to use contextual cues to disambiguate response conflict in ambiguous circumstances (Marquis et al., 2007). Using an ABA fear renewal procedure, we assessed the role of the PL cortex in using contextual cues to modulate a response towards a conditioned stimulus (CS) in an aversive setting. We found that pre-training lesions of the PL cortex did not impact on the expression or extinction of conditioned fear. Rather, they selectively abolished renewal. Functional inactivation of the PL cortex during extinction did not disrupt the subsequent renewal of conditioned fear or the ability of animals to exhibit fear towards a CS during the extinction session. However, PL inactivation during the renewal test session disrupted the ability of animals to demonstrate a reinstatement of responding in the renewal context. An analysis of orienting responses showed that renewal deficits were accompanied by a lack of change in attentional responding towards the CS. These data suggest the PL cortex uses contextual cues to modulate both a behavioural and an attentional response during aversive procedures. We argue that the role of the PL cortex in the expression of conditioned fear is to use higher-order information to modulate responding towards predictive cues in ambiguous circumstance. Copyright © 2014 Elsevier Inc. All rights reserved.

Cat odor causes long-lasting contextual fear conditioning and increased pituitary-adrenal activation, without modifying anxiety.

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Muñoz-Abellán, Cristina; Daviu, Nuria; Rabasa, Cristina; Nadal, Roser; Armario, Antonio

2009-10-01

A single exposure to a cat or cat odors has been reported by some groups to induce contextual and auditory fear conditioning and long-lasting changes in anxiety-like behaviour, but there is no evidence for parallel changes in biological stress markers. In the present study we demonstrated in male rats that exposure to a novel environment containing a cloth impregnated with cat fur odor resulted in avoidance of the odor, lower levels of activity and higher pituitary-adrenal (PA) response as compared to those exposed to the novel environment containing a clean cloth, suggesting increased levels of stress in the former animals. When re-exposed 9 days later to the same environment with a clean cloth, previously cat fur exposed rats again showed avoidance of the cloth area and lower levels of activity, suggesting development of contextual fear conditioning, which again was associated with a higher PA activation. In contrast, unaltered both anxiety-like behaviour and PA responsiveness to an elevated plus-maze were found 7 days after cat odor exposure. It is concluded that: (i) PA activation is able to reflect both the stressful properties of cat fur odor and odor-induced contextual fear conditioning; (ii) development of cat odor-induced contextual fear conditioning is independent of the induction of long-lasting changes in anxiety-like behaviour; and (iii) greater PA activation during exposure to the odor context is not explained by non-specific sensitization of the PA axis caused by previous exposure to cat fur odor.

Functional imaging of stimulus convergence in amygdalar neurons during Pavlovian fear conditioning.

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Sabiha K Barot

2009-07-01

Full Text Available Associative conditioning is a ubiquitous form of learning throughout the animal kingdom and fear conditioning is one of the most widely researched models for studying its neurobiological basis. Fear conditioning is also considered a model system for understanding phobias and anxiety disorders. A fundamental issue in fear conditioning regards the existence and location of neurons in the brain that receive convergent information about the conditioned stimulus (CS and unconditioned stimulus (US during the acquisition of conditioned fear memory. Convergent activation of neurons is generally viewed as a key event for fear learning, yet there has been almost no direct evidence of this critical event in the mammalian brain.Here, we used Arc cellular compartmental analysis of temporal gene transcription by fluorescence in situ hybridization (catFISH to identify neurons activated during single trial contextual fear conditioning in rats. To conform to temporal requirements of catFISH analysis we used a novel delayed contextual fear conditioning protocol which yields significant single- trial fear conditioning with temporal parameters amenable to catFISH analysis. Analysis yielded clear evidence that a population of BLA neurons receives convergent CS and US information at the time of the learning, that this only occurs when the CS-US arrangement is supportive of the learning, and that this process requires N-methyl-D-aspartate receptor activation. In contrast, CS-US convergence was not observed in dorsal hippocampus.Based on the pattern of Arc activation seen in conditioning and control groups, we propose that a key requirement for CS-US convergence onto BLA neurons is the potentiation of US responding by prior exposure to a novel CS. Our results also support the view that contextual fear memories are encoded in the amygdala and that the role of dorsal hippocampus is to process and transmit contextual CS information.

Individual variation in working memory is associated with fear extinction performance.

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Stout, Daniel M; Acheson, Dean T; Moore, Tyler M; Gur, Ruben C; Baker, Dewleen G; Geyer, Mark A; Risbrough, Victoria B

2018-03-01

PTSD has been associated consistently with abnormalities in fear acquisition and extinction learning and retention. Fear acquisition refers to learning to discriminate between threat and safety cues. Extinction learning reflects the formation of a new inhibitory-memory that competes with a previously learned threat-related memory. Adjudicating the competition between threat memory and the new inhibitory memory during extinction may rely, in part, on cognitive processes such as working memory (WM). Despite significant shared neural circuits and signaling pathways the relationship between WM, fear acquisition, and extinction is poorly understood. Here, we analyzed data from a large sample of healthy Marines who underwent an assessment battery including tests of fear acquisition, extinction learning, and WM (N-back). Fear potentiated startle (FPS), fear expectancy ratings, and self-reported anxiety served as the primary dependent variables. High WM ability (N = 192) was associated with greater CS + fear inhibition during the late block of extinction and greater US expectancy change during extinction learning compared to individuals with low WM ability (N = 204). WM ability was not associated with magnitude of fear conditioning/expression. Attention ability was unrelated to fear acquisition or extinction supporting specificity of WM associations with extinction. These results support the conclusion that individual differences in WM may contribute to regulating fear responses. Copyright © 2018. Published by Elsevier Ltd.

Extinction of Learned Fear Induces Hippocampal Place Cell Remapping

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

2015-01-01

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

Memory cost of quantum contextuality

International Nuclear Information System (INIS)

Kleinmann, Matthias; Gühne, Otfried; Portillo, José R; Larsson, Jan-Åke; Cabello, Adán

2011-01-01

The simulation of quantum effects requires certain classical resources, and quantifying them is an important step to characterize the difference between quantum and classical physics. For a simulation of the phenomenon of state-independent quantum contextuality, we show that the minimum amount of memory used by the simulation is the critical resource. We derive optimal simulation strategies for important cases and prove that reproducing the results of sequential measurements on a two-qubit system requires more memory than the information-carrying capacity of the system. (paper)

Contextualization: Memory Formation and Retrieval in a Nested Environment

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Piefke, Martina; Markowitsch, Hans J.

Episodic memory functions are highly context-dependent. This is true for both experimental and autobiographical episodic memory. We here review neuropsychological and neuroimaging evidence for effects of differential encoding and retrieval contexts on episodic memory performance as well as the underlying neurofunctional mechanisms. In studies of laboratory episodic memory, the influence of context parameters can be assessed by experimental manipulations. Such experiments suggest that contextual variables mainly affect prefrontal functions supporting executive processes involved in episodic learning and retrieval. Context parameters affecting episodic autobiographical memory are far more complex and cannot easily be controlled. Data support the view that not only prefrontal, but also further medial temporal and posterior parietal regions mediating the re-experience and emotional evaluation of personal memories are highly influenced by changing contextual variables of memory encoding and retrieval. Based on our review of available data, we thus suggest that experimental and autobiographical episodic memories are influenced by both overlapping and differential context parameters.

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

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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.

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

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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.

Effects of Mineralocorticoid Receptors Blockade on FearMemory Reconsolidation in Rats

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Abbas Ali Vafaei

2011-08-01

Full Text Available Reconsolidation memory is defined as a process in which the retrieval of a previously consolidated memory returns to a labile state which is then subject to stabilization. Previous studies have shown that mineralocorticoid receptors (MRs modulate distinct phases of learning and memory, which display a high concentration and distinct distribution in the hippocampus. Moreover, we found no studies that examined the role of hippocampal MRs in fear memory reconsolidation. Here, we investigated the effect of MRs blockade on fear memory reconsolidation in rats. Additionally, to test whether blockade of protein synthesis would disrupt fear memory reconsolidation in our paradigm, we tested the effect of cycloheximide, an inhibitor of protein synthesis after memory reactivation. Results indicated that systemic as well as intra-hippocampal administrations of the MR antagonist spironolactone immediately following memory reactivation did not affect on post-retrieval long-term memory. Cycloheximide given after the reactivation treatment produced a strong impairment that persisted over test sessions. These findings indicate that MRs are not required for reconsolidation of fear-based memory.

Fragmentation of Rapid Eye Movement and Nonrapid Eye Movement Sleep without Total Sleep Loss Impairs Hippocampus-Dependent Fear Memory Consolidation.

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Lee, Michael L; Katsuyama, Ângela M; Duge, Leanne S; Sriram, Chaitra; Krushelnytskyy, Mykhaylo; Kim, Jeansok J; de la Iglesia, Horacio O

2016-11-01

Sleep is important for consolidation of hippocampus-dependent memories. It is hypothesized that the temporal sequence of nonrapid eye movement (NREM) sleep and rapid eye movement (REM) sleep is critical for the weakening of nonadaptive memories and the subsequent transfer of memories temporarily stored in the hippocampus to more permanent memories in the neocortex. A great body of evidence supporting this hypothesis relies on behavioral, pharmacological, neural, and/or genetic manipulations that induce sleep deprivation or stage-specific sleep deprivation. We exploit an experimental model of circadian desynchrony in which intact animals are not deprived of any sleep stage but show fragmentation of REM and NREM sleep within nonfragmented sleep bouts. We test the hypothesis that the shortening of NREM and REM sleep durations post-training will impair memory consolidation irrespective of total sleep duration. When circadian-desynchronized animals are trained in a hippocampus-dependent contextual fear-conditioning task they show normal short-term memory but impaired long-term memory consolidation. This impairment in memory consolidation is positively associated with the post-training fragmentation of REM and NREM sleep but is not significantly associated with the fragmentation of total sleep or the total amount of delta activity. We also show that the sleep stage fragmentation resulting from circadian desynchrony has no effect on hippocampus-dependent spatial memory and no effect on hippocampus-independent cued fear-conditioning memory. Our findings in an intact animal model, in which sleep deprivation is not a confounding factor, support the hypothesis that the stereotypic sequence and duration of sleep stages play a specific role in long-term hippocampus-dependent fear memory consolidation. © 2016 Associated Professional Sleep Societies, LLC.

Influence of affective meaning on memory for contextual information.

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D'Argembeau, Arnaud; Van der Linden, Martial

2004-06-01

In 4 experiments, the authors investigated the influence of the affective meaning of words on memory for 2 kinds of contextual features that differ in the amount of effortful processes they require to be encoded in memory (i.e., color and spatial location). The main results showed that memory for color, in which words were typed, was better for emotional than for neutral words, but only when color information was learned incidentally. In contrast, spatial location of the words was better remembered for emotional than for neutral words whatever the encoding conditions (intentional vs. incidental). It is suggested that the influence of affective meaning on context memory may involve an automatic attraction of attention to contextual features associated with emotional words. Copyright 2004 American Psychological Association

Distinct Hippocampal Pathways Mediate Dissociable Roles of Context in Memory Retrieval.

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Xu, Chun; Krabbe, Sabine; Gründemann, Jan; Botta, Paolo; Fadok, Jonathan P; Osakada, Fumitaka; Saur, Dieter; Grewe, Benjamin F; Schnitzer, Mark J; Callaway, Edward M; Lüthi, Andreas

2016-11-03

Memories about sensory experiences are tightly linked to the context in which they were formed. Memory contextualization is fundamental for the selection of appropriate behavioral reactions needed for survival, yet the underlying neuronal circuits are poorly understood. By combining trans-synaptic viral tracing and optogenetic manipulation, we found that the ventral hippocampus (vHC) and the amygdala, two key brain structures encoding context and emotional experiences, interact via multiple parallel pathways. A projection from the vHC to the basal amygdala mediates fear behavior elicited by a conditioned context, whereas a parallel projection from a distinct subset of vHC neurons onto midbrain-projecting neurons in the central amygdala is necessary for context-dependent retrieval of cued fear memories. Our findings demonstrate that two fundamentally distinct roles of context in fear memory retrieval are processed by distinct vHC output pathways, thereby allowing for the formation of robust contextual fear memories while preserving context-dependent behavioral flexibility. Copyright © 2016 Elsevier Inc. All rights reserved.

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

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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

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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

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

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Wilson, Yvette M.; Murphy, Mark

2009-01-01

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

The Formation and Extinction of Fear Memory in Tree Shrews

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Shujiang eShang

2015-07-01

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

Early-life exposure to fibroblast growth factor-2 facilitates context-dependent long-term memory in developing rats.

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Graham, Bronwyn M; Richardson, Rick

2010-06-01

Fibroblast growth factor-2 (FGF2) is a potent neurotrophic factor that is involved in brain development and the formation of long-term memory. It has recently been shown that acute FGF2, administered at the time of learning, enhances long-term memory for contextual fear conditioning as well as extinction of conditioned fear in developing rats. As other research has shown that administering FGF2 on the first day of life leads to long-term morphological changes in the hippocampus, in the present study we investigated whether early life exposure to FGF2 affects contextual fear conditioning, and renewal following extinction, later in life. Experiment 1 demonstrated that a single injection of FGF2 on Postnatal Day (PND) 1 did not lead to any detectable changes in contextual fear conditioning in PND 16 or PND 23 rats. Experiments 2 and 3 demonstrated that 5 days of injections of FGF2 (from PND 1-5) facilitated contextual fear conditioning in PND 16 and PND 23 rats. Experiment 4 demonstrated that the observed facilitation of memory was not due to FGF2 increasing rats' sensitivity to foot shock. Experiment 5 showed that early life exposure to FGF2 did not affect learning about a discrete conditioned stimulus, but did allow PND 16 rats to use contextual information in more complex ways, leading to context-dependent extinction of conditioned fear. These results further implicate FGF2 as a critical signal involved in the development of learning and memory.

Integration of contextual cues into memory depends on "prefrontal" N-methyl-D-aspartate receptors.

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Starosta, Sarah; Bartetzko, Isabelle; Stüttgen, Maik C; Güntürkün, Onur

2017-10-01

Every learning event is embedded in a context, but not always does the context become an integral part of the memory; however, for extinction learning it usually does, resulting in context-specific conditioned responding. The neuronal mechanisms underlying contextual control have been mainly investigated for Pavlovian fear extinction with a focus on hippocampal structures. However, the initial acquisition of novel responses can be subject to contextual control as well, although the neuronal mechanisms are mostly unknown. Here, we tested the hypothesis that contextual control of acquisition depends on glutamatergic transmission underlying executive functions in forebrain areas, e.g. by shifting attention to critical cues. Thus, we antagonized N-methyl-D-aspartate (NMDA) receptors with 2-amino-5-phosphonovaleric acid (AP5) in the pigeon nidopallium caudolaterale, the functional analogue of mammalian prefrontal cortex, during the concomitant acquisition and extinction of conditioned responding to two different stimuli. This paradigm has previously been shown to lead to contextual control over extinguished as well as non-extinguished responding. NMDA receptor blockade resulted in an impairment of extinction learning, but left the acquisition of responses to a novel stimulus unaffected. Critically, when responses were tested in a different context in the retrieval phase, we observed that NMDA receptor blockade led to the abolishment of contextual control over acquisition performance. This result is predicted by a model describing response inclination as the product of associative strength and contextual gain. In this model, learning under AP5 leads to a change in the contextual gain on the learned association, possibly via the modulation of attentional mechanisms. Copyright © 2017 Elsevier Inc. All rights reserved.

Memory and metamemory performance in Alzheimer's disease and healthy elderly: the Contextual Memory Test (CMT).

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Gil, N; Josman, N

2001-08-01

The purpose of the present study was to examine the ability of the Contextual Memory Test (CMT) to differentiate between elderly people suffering from Alzheimer's disease (AD) in comparison to healthy elderly people. Specifically, the objectives were to compare for differences between and within the groups on components of memory, including immediate and delayed recall as well as recognition. In addition, parameters of metamemory skills, such as general awareness, self-prediction of memory capacity, self-estimation, strategy use and use of contextual information, as well as the correlation between self-awareness and actual performance in both groups, were investigated. The sample consisted of 60 elderly participants, including 30 people diagnosed with AD who were assigned to the research group and 30 people matched for age, gender and educational level who were assigned to the control group. The results provide support for the hypothesis positing differences in memory performance between healthy elderly participants and those suffering from AD, particularly in immediate and delayed recall as well as in recognition. Moreover, findings indicate an improvement in memory performance under the cued condition (contextual), whereas improvement in the AD group proved to be significant only for immediate recall. The findings point to a distinct overestimation of memory ability predicted by both the AD and control groups. Following the memory task, however, the participants accurately estimated the number of items they remembered. In addition, significant correlations between the use of contextual and association strategies and the number of items remembered by both groups were obtained, in immediate as well as in delayed recall. Therefore, these findings support the CMT as a valuable memory and metamemory assessment tool for use with the AD population.

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

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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.

SAD-B kinase regulates pre-synaptic vesicular dynamics at hippocampal Schaffer collateral synapses and affects contextual fear memory.

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Watabe, Ayako M; Nagase, Masashi; Hagiwara, Akari; Hida, Yamato; Tsuji, Megumi; Ochiai, Toshitaka; Kato, Fusao; Ohtsuka, Toshihisa

2016-01-01

Synapses of amphids defective (SAD)-A/B kinases control various steps in neuronal development and differentiation, such as axon specifications and maturation in central and peripheral nervous systems. At mature pre-synaptic terminals, SAD-B is associated with synaptic vesicles and the active zone cytomatrix; however, how SAD-B regulates neurotransmission and synaptic plasticity in vivo remains unclear. Thus, we used SAD-B knockout (KO) mice to study the function of this pre-synaptic kinase in the brain. We found that the paired-pulse ratio was significantly enhanced at Shaffer collateral synapses in the hippocampal CA1 region in SAD-B KO mice compared with wild-type littermates. We also found that the frequency of the miniature excitatory post-synaptic current was decreased in SAD-B KO mice. Moreover, synaptic depression following prolonged low-frequency synaptic stimulation was significantly enhanced in SAD-B KO mice. These results suggest that SAD-B kinase regulates vesicular release probability at pre-synaptic terminals and is involved in vesicular trafficking and/or regulation of the readily releasable pool size. Finally, we found that hippocampus-dependent contextual fear learning was significantly impaired in SAD-B KO mice. These observations suggest that SAD-B kinase plays pivotal roles in controlling vesicular release properties and regulating hippocampal function in the mature brain. Synapses of amphids defective (SAD)-A/B kinases control various steps in neuronal development and differentiation, but their roles in mature brains were only partially known. Here, we demonstrated, at mature pre-synaptic terminals, that SAD-B regulates vesicular release probability and synaptic plasticity. Moreover, hippocampus-dependent contextual fear learning was significantly impaired in SAD-B KO mice, suggesting that SAD-B kinase plays pivotal roles in controlling vesicular release properties and regulating hippocampal function in the mature brain. © 2015 International

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

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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

Allopregnanolone in the bed nucleus of the stria terminalis modulates contextual fear in rats.

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Nagaya, Naomi; Acca, Gillian M; Maren, Stephen

2015-01-01

Trauma- and stress-related disorders are among the most common types of mental illness affecting the U.S. population. For many of these disorders, there is a striking sex difference in lifetime prevalence; for instance, women are twice as likely as men to be affected by posttraumatic stress disorder (PTSD). Gonadal steroids and their metabolites have been implicated in sex differences in fear and anxiety. One example, allopregnanolone (ALLO), is a neuroactive metabolite of progesterone that allosterically enhances GABAA receptor activity and has anxiolytic effects. Like other ovarian hormones, it not only occurs at different levels in males and females but also fluctuates over the female reproductive cycle. One brain structure that may be involved in neuroactive steroid regulation of fear and anxiety is the bed nucleus of the stria terminalis (BNST). To explore this question, we examined the consequences of augmenting or reducing ALLO activity in the BNST on the expression of Pavlovian fear conditioning in rats. In Experiment 1, intra-BNST infusions of ALLO in male rats suppressed freezing behavior (a fear response) to the conditioned context, but did not influence freezing to a discrete tone conditioned stimulus (CS). In Experiment 2, intra-BNST infusion of either finasteride (FIN), an inhibitor of ALLO synthesis, or 17-phenyl-(3α,5α)-androst-16-en-3-ol, an ALLO antagonist, in female rats enhanced contextual freezing; neither treatment affected freezing to the tone CS. These findings support a role for ALLO in modulating contextual fear via the BNST and suggest that sex differences in fear and anxiety could arise from differential steroid regulation of BNST function. The susceptibility of women to disorders such as PTSD may be linked to cyclic declines in neuroactive steroid activity within fear circuitry.

Allopregnanolone in the bed nucleus of the stria terminalis modulates contextual fear in rats

Directory of Open Access Journals (Sweden)

Naomi eNagaya

2015-08-01

Full Text Available Trauma- and stress-related disorders are among the most common types of mental illness affecting the U.S. population. For many of these disorders, there is a striking sex difference in lifetime prevalence; for instance, women are twice as likely as men to be affected by posttraumatic stress disorder (PTSD. Gonadal steroids and their metabolites have been implicated in sex differences in fear and anxiety. One example, allopregnanolone (ALLO, is a neuroactive metabolite of progesterone that allosterically enhances GABAA receptor activity and has anxiolytic effects. Like other ovarian hormones, it not only occurs at different levels in males and females but also fluctuates over the female reproductive cycle. One brain structure that may be involved in neuroactive steroid regulation of fear and anxiety is the bed nucleus of the stria terminalis (BNST. To explore this question, we examined the consequences of augmenting or reducing ALLO activity in the BNST on the expression of Pavlovian fear conditioning in rats. In Experiment 1, intra-BNST infusions of ALLO in male rats suppressed freezing behavior (a fear response to the conditioned context, but did not influence freezing to a discrete tone conditioned stimulus (CS. In Experiment 2, intra-BNST infusion of either finasteride, an inhibitor of ALLO synthesis, or 17-phenyl-(3α,5α-androst-16-en-3-ol, an ALLO antagonist, in female rats enhanced contextual freezing; neither treatment affected freezing to the tone CS. These findings support a role for ALLO in modulating contextual fear via the BNST and suggest that sex differences in fear and anxiety could arise from differential steroid regulation of BNST function. The susceptibility of women to disorders such as PTSD may be linked to cyclic declines in neuroactive steroid activity within fear circuitry.

Flavones from Erythrina falcata are modulators of fear memory.

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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

Inception of a false memory by optogenetic manipulation of a hippocampal memory engram.

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Liu, Xu; Ramirez, Steve; Tonegawa, Susumu

2014-01-05

Memories can be easily distorted, and a lack of relevant animal models has largely hindered our understanding of false-memory formation. Here, we first identified a population of cells in the dentate gyrus (DG) of the hippocampus that bear the engrams for a specific context; these cells were naturally activated during the encoding phase of fear conditioning and their artificial reactivation using optogenetics in an unrelated context was sufficient for inducing the fear memory specific to the conditioned context. In a further study, DG or CA1 neurons activated by exposure to a particular context were labelled with channelrhodopsin-2 (ChR2). These neurons were later optically reactivated during fear conditioning in a different context. The DG experimental group showed increased freezing in the original context in which a foot shock was never delivered. The recall of this false memory was context specific, activated similar downstream regions engaged during natural fear-memory recall, and was also capable of driving an active fear response. Together, our data demonstrate that by substituting a natural conditioned stimulus with optogenetically reactivated DG cells that bear contextual memory engrams, it is possible to incept an internally and behaviourally represented false fear memory.

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

DEFF Research Database (Denmark)

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

2017-01-01

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. Methods 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. Results 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. Conclusions...

Independence of long-term contextual memory and short-term perceptual hypotheses: Evidence from contextual cueing of interrupted search.

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Schlagbauer, Bernhard; Mink, Maurice; Müller, Hermann J; Geyer, Thomas

2017-02-01

Observers are able to resume an interrupted search trial faster relative to responding to a new, unseen display. This finding of rapid resumption is attributed to short-term perceptual hypotheses generated on the current look and confirmed upon subsequent looks at the same display. It has been suggested that the contents of perceptual hypotheses are similar to those of other forms of memory acquired long-term through repeated exposure to the same search displays over the course of several trials, that is, the memory supporting "contextual cueing." In three experiments, we investigated the relationship between short-term perceptual hypotheses and long-term contextual memory. The results indicated that long-term, contextual memory of repeated displays neither affected the generation nor the confirmation of short-term perceptual hypotheses for these displays. Furthermore, the analysis of eye movements suggests that long-term memory provides an initial benefit in guiding attention to the target, whereas in subsequent looks guidance is entirely based on short-term perceptual hypotheses. Overall, the results reveal a picture of both long- and short-term memory contributing to reliable performance gains in interrupted search, while exerting their effects in an independent manner.

Contextual knowledge reduces demands on working memory during reading.

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Miller, Lisa M Soederberg; Cohen, Jason A; Wingfield, Arthur

2006-09-01

An experiment is reported in which young, middle-aged, and older adults read and recalled ambiguous texts either with or without the topic title that supplied contextual knowledge. Within each of the age groups, the participants were divided into those with high or low working memory (WM) spans, with available WM capacity further manipulated by the presence or absence of an auditory target detection task concurrent with the reading task. Differences in reading efficiency (reading time per proposition recalled) between low WM span and high WM span groups were greater among readers who had access to contextual knowledge relative to those who did not, suggesting that contextual knowledge reduces demands on WM capacity. This position was further supported by the finding that increased age and attentional demands, two factors associated with reduced WM capacity, exaggerated the benefits of contextual knowledge on reading efficiency. The relative strengths of additional potential predictors of reading efficiency (e.g., interest, effort, and memory beliefs), along with knowledge, WM span, and age, are reported. Findings showed that contextual knowledge was the strongest predictor of reading efficiency even after controlling for the effects of all of the other predictors.

A Memory-based Robot Architecture based on Contextual Information

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Pratama, Ferdian; Mastrogiovanni, Fulvio; Chong, Nak Young

2014-01-01

In this paper, we present a preliminary conceptual design for a robot long-term memory architecture based on the notion of context. Contextual information is used to organize the data flow between Working Memory (including Perceptual Memory) and Long-Term Memory components. We discuss the major influence of the notion of context within Episodic Memory on Semantic and Procedural Memory, respectively. We address how the occurrence of specific object-related events in time impacts on the semanti...

Spectral characteristics of the hippocampal LFP during contextual fear conditioning

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Birajara Soares Machado

2012-06-01

Full Text Available Objective: The hippocampus has an important role in the acquisitionand recall of aversive memories. The objective of this study was toinvestigate the relationship among hippocampal rhythms. Methods:Microeletrodes arrays were implanted in the hippocampus of Wistarrats. The animals were trained and tested in a contextual fearconditioning task. The training consisted in applying shocks in thelegs. The memory test was performed 1 day (recent memory or 18days (remote memory after training. We proposed a measure basedon the FFT power spectrum, denominated “delta-theta ratio”, tocharacterize the different behaviors (active exploration and freezingand the memories types. Results: The delta-theta ratio was able todistinguish recent and remote memories. In this study, the ratio forthe 18-day group was smaller than for the 1-day group. Moreover,this measure was useful to distinguish the different behavior states– active exploration and freezing. Conclusions: The results suggestdelta-theta oscillations could reflect the demands on informationprocessing during recent and remote memory recalls.

Running rescues a fear-based contextual discrimination deficit in aged mice

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Melody V. Wu

2015-08-01

Full Text Available Normal aging and exercise exert extensive, often opposing, effects on the dentate gyrus (DG of the hippocampus altering volume, synaptic function, and behaviors. The DG is especially important for behaviors requiring pattern separation—a cognitive process that enables animals to differentiate between highly similar contextual experiences. To determine how age and exercise modulate pattern separation in an aversive setting, young, aged, and aged mice provided with a running wheel were assayed on a fear-based contextual discrimination task. Aged mice showed a profound impairment in contextual discrimination compared to young animals. Voluntary exercise rescued this deficit to such an extent that behavioral pattern separation of aged-run mice was now similar to young animals. Running also resulted in a significant increase in the number of immature neurons with tertiary dendrites in aged mice. Despite this, neurogenesis levels in aged-run mice were still considerably lower than in young animals. Thus, mechanisms other than DG neurogenesis likely play significant roles in improving behavioral pattern separation elicited by exercise in aged animals.

Reconsolidation or extinction: transcription factor switch in the determination of memory course after retrieval.

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de la Fuente, Verónica; Freudenthal, Ramiro; Romano, Arturo

2011-04-13

In fear conditioning, aversive stimuli are readily associated with contextual features. A brief reexposure to the training context causes fear memory reconsolidation, whereas a prolonged reexposure induces memory extinction. The regulation of hippocampal gene expression plays a key role in contextual memory consolidation and reconsolidation. However, the mechanisms that determine whether memory will reconsolidate or extinguish are not known. Here, we demonstrate opposing roles for two evolutionarily related transcription factors in the mouse hippocampus. We found that nuclear factor-κB (NF-κB) is required for fear memory reconsolidation. Conversely, calcineurin phosphatase inhibited NF-κB and induced nuclear factor of activated T-cells (NFAT) nuclear translocation in the transition between reconsolidation and extinction. Accordingly, the hippocampal inhibition of both calcineurin and NFAT independently impaired memory extinction, whereas inhibition of NF-κB enhanced memory extinction. These findings represent the first insight into the molecular mechanisms that determine memory reprocessing after retrieval, supporting a transcriptional switch that directs memory toward reconsolidation or extinction. The precise molecular characterization of postretrieval processes has potential importance to the development of therapeutic strategies for fear memory disorders.

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

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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.

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

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Ana Montero-Pedrazuela

Full Text Available 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.

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

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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

Stress Enables Reinforcement-Elicited Serotonergic Consolidation of Fear Memory.

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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

2016-05-15

Prior exposure to stress is a risk factor for developing posttraumatic 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. Adult mice were exposed to repeated immobilization stress or handling, and the role of serotonin in subsequent fear learning was assessed using pharmacologic manipulation and western blot detection of serotonin receptors, measurements of serotonin, high-speed optogenetic silencing, and behavior. Both dorsal raphe serotonergic activity during aversive reinforcement and amygdala serotonin 2C receptor (5-HT2CR) activity during memory consolidation were necessary for stress enhancement of fear memory, but neither process affected fear memory in unstressed mice. Additionally, prior stress increased amygdala sensitivity to serotonin by promoting surface expression of 5-HT2CR without affecting tissue levels of serotonin in the amygdala. We also showed 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. 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. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Stress, glucocorticoids and memory: implications for treating fear-related disorders.

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de Quervain, Dominique; Schwabe, Lars; Roozendaal, Benno

2017-01-01

Glucocorticoid stress hormones are crucially involved in modulating mnemonic processing of emotionally arousing experiences. They enhance the consolidation of new memories, including those that extinguish older memories, but impair the retrieval of information stored in long-term memory. As strong aversive memories lie at the core of several fear-related disorders, including post-traumatic stress disorder and phobias, the memory-modulating properties of glucocorticoids have recently become of considerable translational interest. Clinical trials have provided the first evidence that glucocorticoid-based pharmacotherapies aimed at attenuating aversive memories might be helpful in the treatment of fear-related disorders. Here, we review important advances in the understanding of how glucocorticoids mediate stress effects on memory processes, and discuss the translational potential of these new conceptual insights.

Role of the orexin (hypocretin) system in contextual fear conditioning in rats.

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Wang, Huiying; Li, Sa; Kirouac, Gilbert J

2017-01-01

Orexin (hypocretin) neurons located in the posterior hypothalamus send projections to multiple areas of the brain involved in arousal and experimental evidence indicates that these neurons play a role in the physiological and behavioral responses to stress. This study was done to determine if the orexin system was involved in mediating the fear associated with shock context (5×2s of 1.5mA). First, real-time RT-PCR was used to examine changes in the mRNA levels for prepro-orexin (ppOX), the orexin-1 receptor (OX1R) and the orexin-2 receptor (OX2R) at two weeks post-shock. We found that the mRNA levels for ppOX and OX1R were increased in the posterior hypothalamus of shocked rats. In contrast, no significant difference was found in the midline thalamus or the locus coeruleus/parabrachial region. Second, the study examined if systemic injections of antagonists for orexin receptors attenuated the freezing related to contextual fear. The OX1R antagonist SB334867 (20 or 30mg/kg; i.p.) decreased freezing while the same doses of the OX2R antagonist TCSOX229 had no effect. The dual orexin antagonist TCS1102 (20mg/kg; i.p.) also decreased the freezing to the shock context. The results of the present study show upregulation of orexin activity and of the OX1R in the hypothalamus following exposure of rats to footshocks and highlight a specific role of OX1R in contextual fear. Copyright © 2016 Elsevier B.V. All rights reserved.

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

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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

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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

Neuropeptide Y2 receptors in anteroventral BNST control remote fear memory depending on extinction training.

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Verma, Dilip; Tasan, Ramon; Sperk, Guenther; Pape, Hans-Christian

2018-03-01

The anterior bed nucleus of stria terminalis (BNST) is involved in reinstatement of extinguished fear, and neuropeptide Y2 receptors influence local synaptic signaling. Therefore, we hypothesized that Y2 receptors in anteroventral BNST (BNSTav) interfere with remote fear memory and that previous fear extinction is an important variable. C57BL/6NCrl mice were fear-conditioned, and a Y2 receptor-specific agonist (NPY 3-36 ) or antagonist (JNJ-5207787) was applied in BNSTav before fear retrieval at the following day. Remote fear memory was tested on day 16 in two groups of mice, which had (experiment 1) or had not (experiment 2) undergone extinction training after conditioning. In the group with extinction training, tests of remote fear memory revealed partial retrieval of extinction, which was prevented after blockade of Y2 receptors in BNSTav. No such effect was observed in the group with no extinction training, but stimulation of Y2 receptors in BNSTav mimicked the influence of extinction during tests of remote fear memory. Pharmacological manipulation of Y2 receptors in BNSTav before fear acquisition (experiment 3) had no effect on fear memory retrieval, extinction or remote fear memory. Furthermore, partial retrieval of extinction during tests of remote fear memory was associated with changes in number of c-Fos expressing neurons in BNSTav, which was prevented or mimicked upon Y2 blockade or stimulation in BNSTav. These results indicate that Y2 receptor manipulation in BNSTav interferes with fear memory and extinction retrieval at remote stages, likely through controlling neuronal activity in BNSTav during extinction training. Copyright © 2018 Elsevier Inc. All rights reserved.

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

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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

Direct dorsal hippocampal-prelimbic cortex connections strengthen fear memories.

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Ye, Xiaojing; Kapeller-Libermann, Dana; Travaglia, Alessio; Inda, M Carmen; Alberini, Cristina M

2017-01-01

The ability to regulate the consolidation and strengthening of memories for threatening experiences is critical for mental health, and its dysregulation may lead to psychopathologies. Re-exposure to the context in which the threat was experienced can either increase or decrease fear response through distinct processes known, respectively, as reconsolidation or extinction. Using a context retrieval-dependent memory-enhancement model in rats, we report that memory strengthens through activation of direct projections from dorsal hippocampus to prelimbic (PL) cortex and activation of critical PL molecular mechanisms that are not required for extinction. Furthermore, while sustained PL brain-derived neurotrophic factor (BDNF) expression is required for memory consolidation, retrieval engages PL BDNF to regulate excitatory and inhibitory synaptic proteins neuroligin 1 and neuroligin 2, which promote memory strengthening while inhibiting extinction. Thus, context retrieval-mediated fear-memory enhancement results from a concerted action of mechanisms that strengthen memory through reconsolidation while suppressing extinction.

Enhanced hippocampal long-term potentiation and fear memory in Btbd9 mutant mice.

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Mark P DeAndrade

Full Text Available Polymorphisms in BTBD9 have recently been associated with higher risk of restless legs syndrome (RLS, a neurological disorder characterized by uncomfortable sensations in the legs at rest that are relieved by movement. The BTBD9 protein contains a BTB/POZ domain and a BACK domain, but its function is unknown. To elucidate its function and potential role in the pathophysiology of RLS, we generated a line of mutant Btbd9 mice derived from a commercial gene-trap embryonic stem cell clone. Btbd9 is the mouse homolog of the human BTBD9. Proteins that contain a BTB/POZ domain have been reported to be associated with synaptic transmission and plasticity. We found that Btbd9 is naturally expressed in the hippocampus of our mutant mice, a region critical for learning and memory. As electrophysiological characteristics of CA3-CA1 synapses of the hippocampus are well characterized, we performed electrophysiological recordings in this region. The mutant mice showed normal input-output relationship, a significant impairment in pre-synaptic activity, and an enhanced long-term potentiation. We further performed an analysis of fear memory and found the mutant mice had an enhanced cued and contextual fear memory. To elucidate a possible molecular basis for these enhancements, we analyzed proteins that have been associated with synaptic plasticity. We found an elevated level of dynamin 1, an enzyme associated with endocytosis, in the mutant mice. These results suggest the first identified function of Btbd9 as being involved in regulating synaptic plasticity and memory. Recent studies have suggested that enhanced synaptic plasticity, analogous to what we have observed, in other regions of the brain could enhance sensory perception similar to what is seen in RLS patients. Further analyses of the mutant mice will help shine light on the function of BTBD9 and its role in RLS.

Enhanced hippocampal long-term potentiation and fear memory in Btbd9 mutant mice.

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DeAndrade, Mark P; Zhang, Li; Doroodchi, Atbin; Yokoi, Fumiaki; Cheetham, Chad C; Chen, Huan-Xin; Roper, Steven N; Sweatt, J David; Li, Yuqing

2012-01-01

Polymorphisms in BTBD9 have recently been associated with higher risk of restless legs syndrome (RLS), a neurological disorder characterized by uncomfortable sensations in the legs at rest that are relieved by movement. The BTBD9 protein contains a BTB/POZ domain and a BACK domain, but its function is unknown. To elucidate its function and potential role in the pathophysiology of RLS, we generated a line of mutant Btbd9 mice derived from a commercial gene-trap embryonic stem cell clone. Btbd9 is the mouse homolog of the human BTBD9. Proteins that contain a BTB/POZ domain have been reported to be associated with synaptic transmission and plasticity. We found that Btbd9 is naturally expressed in the hippocampus of our mutant mice, a region critical for learning and memory. As electrophysiological characteristics of CA3-CA1 synapses of the hippocampus are well characterized, we performed electrophysiological recordings in this region. The mutant mice showed normal input-output relationship, a significant impairment in pre-synaptic activity, and an enhanced long-term potentiation. We further performed an analysis of fear memory and found the mutant mice had an enhanced cued and contextual fear memory. To elucidate a possible molecular basis for these enhancements, we analyzed proteins that have been associated with synaptic plasticity. We found an elevated level of dynamin 1, an enzyme associated with endocytosis, in the mutant mice. These results suggest the first identified function of Btbd9 as being involved in regulating synaptic plasticity and memory. Recent studies have suggested that enhanced synaptic plasticity, analogous to what we have observed, in other regions of the brain could enhance sensory perception similar to what is seen in RLS patients. Further analyses of the mutant mice will help shine light on the function of BTBD9 and its role in RLS.

Reversible Inactivation of the Higher Order Auditory Cortex during Fear Memory Consolidation Prevents Memory-Related Activity in the Basolateral Amygdala during Remote Memory Retrieval.

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Cambiaghi, Marco; Renna, Annamaria; Milano, Luisella; Sacchetti, Benedetto

2017-01-01

Recent findings have shown that the auditory cortex, and specifically the higher order Te2 area, is necessary for the consolidation of long-term fearful memories and that it interacts with the amygdala during the retrieval of long-term fearful memories. Here, we tested whether the reversible blockade of Te2 during memory consolidation may affect the activity changes occurring in the amygdala during the retrieval of fearful memories. To address this issue, we blocked Te2 in a reversible manner during memory consolidation processes. After 4 weeks, we assessed the activity of Te2 and individual nuclei of the amygdala during the retrieval of long-term memories. Rats in which Te2 was inactivated upon memory encoding showed a decreased freezing and failed to show Te2-to-basolateral amygdala (BLA) synchrony during memory retrieval. In addition, the expression of the immediate early gene zif268 in the lateral, basal and central amygdala nuclei did not show memory-related enhancement. As all sites were intact upon memory retrieval, we propose that the auditory cortex represents a key node in the consolidation of fear memories and it is essential for amygdala nuclei to support memory retrieval process.

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

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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.

Alteration of synaptic transmission in the hippocampal-mPFC pathway during extinction trials of context-dependent fear memory in juvenile rat stress models.

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Koseki, Hiroyo; Matsumoto, Machiko; Togashi, Hiroko; Miura, Yoshihide; Fukushima, Kazuaki; Yoshioka, Mitsuhiro

2009-09-01

The medial prefrontal cortex (mPFC) has been proposed to be essential for extinction of fear memory, but its neural mechanism has been poorly understood. The present study examined whether synaptic transmission in the hippocampal-mPFC pathway is related to extinction of context-dependent fear memory in freely moving rats using electrophysiological approaches combined with behavioral analysis. Population spike amplitude in the mPFC was decreased during the first extinction trial by exposure to contextual fear conditioning. This synaptic inhibition was reversed by repeated extinction trials, accompanied by decreases in fear-related freezing behavior. These results suggest that alteration of synaptic transmission in the hippocampal-mPFC pathway is associated with the extinction processes of context-dependent fear memory. Further experiments were performed to elucidate whether early postnatal stress alters the synaptic response in the mPFC during extinction trials using a juvenile stress model, based on our previous findings that early postnatal stress affects the behavioral response to emotional stress. Adult rats that previously were exposed to five footshocks (FS) (shock intensity, 0.5 mA; intershock interval, 28 seconds; shock duration, 2 seconds) at postnatal day 21 to 25 (week 3; 3W-FS) exhibited impaired reversal of both inhibitory synaptic transmission and freezing behavior induced by repeated extinction trials. The neuronal and behavioral deficits observed in the 3W-FS group were prevented by pretreatment with the serotonin(1A) receptor agonist tandospirone (1 mg/kg, i.p.). These results indicate the possiblity that aversive stress exposure during the third postnatal week impaired extinction processes of context-dependent fear memory. The deficits in extinction observed in the 3W-FS group might be attributable to dysfunction of hippocampal-mPFC neural circuits involving 5-HT(1A) receptor mechanisms. 2009 Wiley-Liss, Inc.

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

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

2013-07-01

It is widely assumed that learning and memory processes play an important role in the pathogenesis, expression, maintenance and therapy of anxiety disorders, such as phobias or post-traumatic stress disorder (PTSD). Memory retrieval is involved in symptom expression and maintenance of these disorders, while memory extinction is believed to be the underlying mechanism of behavioral exposure therapy of anxiety disorders. There is abundant evidence that stress and stress hormones can reduce memory retrieval of emotional information, whereas they enhance memory consolidation of extinction training. In this study we aimed at investigating if stress affects these memory processes in a fear conditioning paradigm in healthy human subjects. On day 1, fear memory was acquired through a standard differential fear conditioning procedure. On day 2 (24h after fear acquisition), participants either underwent a stressful cold pressor test (CPT) or a control condition, 20 min before memory retrieval testing and extinction training. Possible prolonged effects of the stress manipulation were investigated on day 3 (48 h after fear acquisition), when memory retrieval and extinction were tested again. On day 2, men in the stress group showed a robust cortisol response to stress and showed lower unconditioned stimulus (US) expectancy ratings than men in the control group. This reduction in fear memory retrieval was maintained on day 3. In women, who showed a significantly smaller cortisol response to stress than men, no stress effects on fear memory retrieval were observed. No group differences were observed with respect to extinction. In conclusion, the present study provides evidence that stress can reduce memory retrieval of conditioned fear in men. Our findings may contribute to the understanding of the effects of stress and glucocorticoids on fear symptoms in anxiety disorders and suggest that such effects may be sex-specific. Copyright © 2013 Elsevier Ltd. All rights reserved.

PKMzeta maintains spatial, instrumental, and classically conditioned long-term memories.

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Peter Serrano

2008-12-01

Full Text Available How long-term memories are stored is a fundamental question in neuroscience. The first molecular mechanism for long-term memory storage in the brain was recently identified as the persistent action of protein kinase Mzeta (PKMzeta, an autonomously active atypical protein kinase C (PKC isoform critical for the maintenance of long-term potentiation (LTP. PKMzeta maintains aversively conditioned associations, but what general form of information the kinase encodes in the brain is unknown. We first confirmed the specificity of the action of zeta inhibitory peptide (ZIP by disrupting long-term memory for active place avoidance with chelerythrine, a second inhibitor of PKMzeta activity. We then examined, using ZIP, the effect of PKMzeta inhibition in dorsal hippocampus (DH and basolateral amygdala (BLA on retention of 1-d-old information acquired in the radial arm maze, water maze, inhibitory avoidance, and contextual and cued fear conditioning paradigms. In the DH, PKMzeta inhibition selectively disrupted retention of information for spatial reference, but not spatial working memory in the radial arm maze, and precise, but not coarse spatial information in the water maze. Thus retention of accurate spatial, but not procedural and contextual information required PKMzeta activity. Similarly, PKMzeta inhibition in the hippocampus did not affect contextual information after fear conditioning. In contrast, PKMzeta inhibition in the BLA impaired retention of classical conditioned stimulus-unconditioned stimulus (CS-US associations for both contextual and auditory fear, as well as instrumentally conditioned inhibitory avoidance. PKMzeta inhibition had no effect on postshock freezing, indicating fear expression mediated by the BLA remained intact. Thus, persistent PKMzeta activity is a general mechanism for both appetitively and aversively motivated retention of specific, accurate learned information, but is not required for processing contextual, imprecise

PKMzeta maintains spatial, instrumental, and classically conditioned long-term memories.

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Serrano, Peter; Friedman, Eugenia L; Kenney, Jana; Taubenfeld, Stephen M; Zimmerman, Joshua M; Hanna, John; Alberini, Cristina; Kelley, Ann E; Maren, Stephen; Rudy, Jerry W; Yin, Jerry C P; Sacktor, Todd C; Fenton, André A

2008-12-23

How long-term memories are stored is a fundamental question in neuroscience. The first molecular mechanism for long-term memory storage in the brain was recently identified as the persistent action of protein kinase Mzeta (PKMzeta), an autonomously active atypical protein kinase C (PKC) isoform critical for the maintenance of long-term potentiation (LTP). PKMzeta maintains aversively conditioned associations, but what general form of information the kinase encodes in the brain is unknown. We first confirmed the specificity of the action of zeta inhibitory peptide (ZIP) by disrupting long-term memory for active place avoidance with chelerythrine, a second inhibitor of PKMzeta activity. We then examined, using ZIP, the effect of PKMzeta inhibition in dorsal hippocampus (DH) and basolateral amygdala (BLA) on retention of 1-d-old information acquired in the radial arm maze, water maze, inhibitory avoidance, and contextual and cued fear conditioning paradigms. In the DH, PKMzeta inhibition selectively disrupted retention of information for spatial reference, but not spatial working memory in the radial arm maze, and precise, but not coarse spatial information in the water maze. Thus retention of accurate spatial, but not procedural and contextual information required PKMzeta activity. Similarly, PKMzeta inhibition in the hippocampus did not affect contextual information after fear conditioning. In contrast, PKMzeta inhibition in the BLA impaired retention of classical conditioned stimulus-unconditioned stimulus (CS-US) associations for both contextual and auditory fear, as well as instrumentally conditioned inhibitory avoidance. PKMzeta inhibition had no effect on postshock freezing, indicating fear expression mediated by the BLA remained intact. Thus, persistent PKMzeta activity is a general mechanism for both appetitively and aversively motivated retention of specific, accurate learned information, but is not required for processing contextual, imprecise, or

The Regulation of Cytokine Networks in Hippocampal CA1 Differentiates Extinction from Those Required for the Maintenance of Contextual Fear Memory after Recall

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Scholz, Birger; Doidge, Amie N.; Barnes, Philip; Hall, Jeremy; Wilkinson, Lawrence S.; Thomas, Kerrie L.

2016-01-01

We investigated the distinctiveness of gene regulatory networks in CA1 associated with the extinction of contextual fear memory (CFM) after recall using Affymetrix GeneChip Rat Genome 230 2.0 Arrays. These data were compared to previously published retrieval and reconsolidation-attributed, and consolidation datasets. A stringent dual normalization and pareto-scaled orthogonal partial least-square discriminant multivariate analysis together with a jack-knifing-based cross-validation approach was used on all datasets to reduce false positives. Consolidation, retrieval and extinction were correlated with distinct patterns of gene expression 2 hours later. Extinction-related gene expression was most distinct from the profile accompanying consolidation. A highly specific feature was the discrete regulation of neuroimmunological gene expression associated with retrieval and extinction. Immunity–associated genes of the tyrosine kinase receptor TGFβ and PDGF, and TNF families’ characterized extinction. Cytokines and proinflammatory interleukins of the IL-1 and IL-6 families were enriched with the no-extinction retrieval condition. We used comparative genomics to predict transcription factor binding sites in proximal promoter regions of the retrieval-regulated genes. Retrieval that does not lead to extinction was associated with NF-κB-mediated gene expression. We confirmed differential NF-κBp65 expression, and activity in all of a representative sample of our candidate genes in the no-extinction condition. The differential regulation of cytokine networks after the acquisition and retrieval of CFM identifies the important contribution that neuroimmune signalling plays in normal hippocampal function. Further, targeting cytokine signalling upon retrieval offers a therapeutic strategy to promote extinction mechanisms in human disorders characterised by dysregulation of associative memory. PMID:27224427

Immunomodulatory Properties of Carvone Inhalation and Its Effects on Contextual Fear Memory in Mice

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Lasarte-Cia, Aritz; Lozano, Teresa; Pérez-González, Marta; Gorraiz, Marta; Iribarren, Kristina; Hervás-Stubbs, Sandra; Sarobe, Pablo; Rabal, Obdulia; Cuadrado-Tejedor, Mar; García-Osta, Ana; Casares, Noelia; Lasarte, Juan José

2018-01-01

A complex network of interactions exists between the immune, the olfactory, and the central nervous system (CNS). Inhalation of different fragrances can affect immunological reactions in response to an antigen but also may have effects on the CNS and cognitive activity. We performed an exploratory study of the immunomodulatory ability of a series of compounds representing each of the 10 odor categories or clusters described previously. We evaluated the impact of each particular odor on the immune response after immunization with the model antigen ovalbumin in combination with the TLR3 agonist poly I:C. We found that some odors behave as immunostimulatory agents, whereas others might be considered as potential immunosuppressant odors. Interestingly, the immunomodulatory capacity was, in some cases, strain-specific. In particular, one of the fragrances, carvone, was found to be immunostimulatory in BALB/c mice and immunosuppressive in C57BL/6J mice, facilitating or impairing viral clearance, respectively, in a model of a viral infection with a recombinant adenovirus. Importantly, inhalation of the odor improved the memory capacity in BALB/c mice in a fear-conditioning test, while it impaired this same capacity in C57BL/6J mice. The improvement in memory capacity in BALB/c was associated with higher CD3+ T cell infiltration into the hippocampus and increased local expression of mRNA coding for IL-1β, TNF-α, and IL-6 cytokines. In contrast, the memory impairment in C57BL/6 was associated with a reduction in CD3 numbers and an increase in IFN-γ. These data suggest an association between the immunomodulatory capacity of smells and their impact on the cognitive functions of the animals. These results highlight the potential of studying odors as therapeutic agents for CNS-related diseases. PMID:29422905

β-Adrenergic signaling is required for the induction of a labile state during memory reconsolidation.

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Lim, Chae-Seok; Kim, Jae-Ick; Kwak, Chuljung; Lee, Jaehyun; Jang, Eun Hae; Oh, Jihae; Kaang, Bong-Kiun

2018-04-20

Memory reconsolidation is the process by which previously consolidated memories reenter a labile state through reactivation of the memory trace and are actively consolidated through de novo protein synthesis. Although extensive studies have shown that β-adrenergic signaling plays a critical role in the restabilization of reactivated memory, its role in the destabilization of long-term memory is not well-studied. In this study, we found that membrane excitability increased in hippocampal CA1 neurons immediately after the retrieval of contextual fear memory. Interestingly, this increase in membrane excitability diminished after treatment with propranolol (a β-adrenergic receptor antagonist), an NMDA receptor antagonist, and a PKA inhibitor. In addition, we found that administration of propranolol prior to, but not after, the retrieval of fear memory ameliorated the memory impairment caused by anisomycin, indicating that inhibition of β-adrenergic signaling blocks the destabilization of contextual fear memory. Taken together, these results indicate that β-adrenergic signaling via NMDA receptors and PKA signaling pathway induces a labile state of long-term memory through increased neuronal membrane excitability. Copyright © 2018 Elsevier Inc. All rights reserved.

Neural circuits involved in the renewal of extinguished fear.

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Chen, Weihai; Wang, Yan; Wang, Xiaqing; Li, Hong

2017-07-01

The last 10 years have witnessed a substantial progress in understanding the neural mechanisms for the renewal of the extinguished fear memory. Based on the theory of fear extinction, exposure therapy has been developed as a typical cognitive behavioral therapy for posttraumatic stress disorder. Although the fear memory can be extinguished by repeated presentation of conditioned stimulus without unconditioned stimulus, the fear memory is not erased and tends to relapse outside of extinction context, which is referred to as renewal. Therefore, the renewal is regarded as a great obstruction interfering with the effect of exposure therapy. In recent years, there has been a great deal of studies in understanding the neurobiological underpinnings of fear renewal. These offer a foundation upon which novel therapeutic interventions for the renewal may be built. This review focuses on behavioral, anatomical and electrophysiological studies that interpret roles of the hippocampus, prelimbic cortex and amygdala as well as the connections between them for the renewal of the extinguished fear. Additionally, this review suggests the possible pathways for the renewal: (1) the prelimbic cortex may integrate contextual information from hippocampal inputs and project to the basolateral amygdala to mediate the renewal of extinguished fear memory; the ventral hippocampus may innervate the activities of the basolateral amygdala or the central amygdala directly for the renewal. © 2017 IUBMB Life, 69(7):470-478, 2017. © 2017 International Union of Biochemistry and Molecular Biology.

Contextual consistency facilitates long-term memory of perceptual detail in barely seen images.

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Gronau, Nurit; Shachar, Meytal

2015-08-01

It is long known that contextual information affects memory for an object's identity (e.g., its basic level category), yet it is unclear whether schematic knowledge additionally enhances memory for the precise visual appearance of an item. Here we investigated memory for visual detail of merely glimpsed objects. Participants viewed pairs of contextually related and unrelated stimuli, presented for an extremely brief duration (24 ms, masked). They then performed a forced-choice memory-recognition test for the precise perceptual appearance of 1 of 2 objects within each pair (i.e., the "memory-target" item). In 3 experiments, we show that memory-target stimuli originally appearing within contextually related pairs are remembered better than targets appearing within unrelated pairs. These effects are obtained whether the target is presented at test with its counterpart pair object (i.e., when reiterating the original context at encoding) or whether the target is presented alone, implying that the contextual consistency effects are mediated predominantly by processes occurring during stimulus encoding, rather than during stimulus retrieval. Furthermore, visual detail encoding is improved whether object relations involve implied action or not, suggesting that, contrary to some prior suggestions, action is not a necessary component for object-to-object associative "grouping" processes. Our findings suggest that during a brief glimpse, but not under long viewing conditions, contextual associations may play a critical role in reducing stimulus competition for attention selection and in facilitating rapid encoding of sensory details. Theoretical implications with respect to classic frame theories are discussed. (PsycINFO Database Record (c) 2015 APA, all rights reserved).

Dorsal and ventral working memory-related brain areas support distinct processes in contextual cueing.

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Manginelli, Angela A; Baumgartner, Florian; Pollmann, Stefan

2013-02-15

Behavioral evidence suggests that the use of implicitly learned spatial contexts for improved visual search may depend on visual working memory resources. Working memory may be involved in contextual cueing in different ways: (1) for keeping implicitly learned working memory contents available during search or (2) for the capture of attention by contexts retrieved from memory. We mapped brain areas that were modulated by working memory capacity. Within these areas, activation was modulated by contextual cueing along the descending segment of the intraparietal sulcus, an area that has previously been related to maintenance of explicit memories. Increased activation for learned displays, but not modulated by the size of contextual cueing, was observed in the temporo-parietal junction area, previously associated with the capture of attention by explicitly retrieved memory items, and in the ventral visual cortex. This pattern of activation extends previous research on dorsal versus ventral stream functions in memory guidance of attention to the realm of attentional guidance by implicit memory. Copyright © 2012 Elsevier Inc. All rights reserved.

Modulation of the consolidation and reconsolidation of fear memory by three different serotonin receptors in hippocampus.

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Schmidt, S D; Furini, C R G; Zinn, C G; Cavalcante, L E; Ferreira, F F; Behling, J A K; Myskiw, J C; Izquierdo, I

2017-07-01

The process of memory formation is complex and highly dynamic. During learning, the newly acquired information is found in a fragile and labile state. Through a process known as consolidation, which requires specific mechanisms such as protein synthesis, the memory trace is stored and stabilized. It is known that when a consolidated memory is recalled, it again becomes labile and sensitive to disruption. To be maintained, this memory must undergo an additional process of restabilization called reconsolidation, which requires another phase of protein synthesis. Memory consolidation has been studied for more than a century, while the molecular mechanisms underlying the memory reconsolidation are starting to be elucidated. For this, is essential compare the participation of important neurotransmitters and its receptors in both processes in brain regions that play a central role in the fear response learning. With focus on serotonin (5-HT), a well characterized neurotransmitter that has been strongly implicated in learning and memory, we investigated, in the CA1 region of the dorsal hippocampus, whether the latest discovered serotonergic receptors, 5-HT 5A , 5-HT 6 and 5-HT 7 , are involved in the consolidation and reconsolidation of contextual fear conditioning (CFC) memory. For this, male rats with cannulae implanted in the CA1 region received immediately after the training or reactivation session, or 3h post-reactivation of the CFC, infusions of agonists or antagonists of the 5-HT 5A , 5-HT 6 and 5-HT 7 receptors. After 24h, animals were subjected to a 3-min retention test. The results indicated that in the CA1 region of the hippocampus the 5-HT 5A , 5-HT 6 and 5-HT 7 serotonin receptors participate in the reconsolidation of the CFC memory 3h post-reactivation. Additionally, the results suggest that the 5-HT 6 and 5-HT 7 receptors also participate in the consolidation of the CFC memory. Copyright © 2017 Elsevier Inc. All rights reserved.

Rapid changes in the light/dark cycle disrupt memory of conditioned fear in mice.

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Dawn H Loh

Full Text Available BACKGROUND: Circadian rhythms govern many aspects of physiology and behavior including cognitive processes. Components of neural circuits involved in learning and memory, e.g., the amygdala and the hippocampus, exhibit circadian rhythms in gene expression and signaling pathways. The functional significance of these rhythms is still not understood. In the present study, we sought to determine the impact of transiently disrupting the circadian system by shifting the light/dark (LD cycle. Such "jet lag" treatments alter daily rhythms of gene expression that underlie circadian oscillations as well as disrupt the synchrony between the multiple oscillators found within the body. METHODOLOGY/PRINCIPAL FINDINGS: We subjected adult male C57Bl/6 mice to a contextual fear conditioning protocol either before or after acute phase shifts of the LD cycle. As part of this study, we examined the impact of phase advances and phase delays, and the effects of different magnitudes of phase shifts. Under all conditions tested, we found that recall of fear conditioned behavior was specifically affected by the jet lag. We found that phase shifts potentiated the stress-evoked corticosterone response without altering baseline levels of this hormone. The jet lag treatment did not result in overall sleep deprivation, but altered the temporal distribution of sleep. Finally, we found that prior experience of jet lag helps to compensate for the reduced recall due to acute phase shifts. CONCLUSIONS/SIGNIFICANCE: Acute changes to the LD cycle affect the recall of fear-conditioned behavior. This suggests that a synchronized circadian system may be broadly important for normal cognition and that the consolidation of memories may be particularly sensitive to disruptions of circadian timing.

Deep brain stimulation of the amygdala alleviates fear conditioning-induced alterations in synaptic plasticity in the cortical-amygdala pathway and fear memory.

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Sui, Li; Huang, SiJia; Peng, BinBin; Ren, Jie; Tian, FuYing; Wang, Yan

2014-07-01

Deep brain stimulation (DBS) of the amygdala has been demonstrated to modulate hyperactivity of the amygdala, which is responsible for the symptoms of post-traumatic stress disorder (PTSD), and thus might be used for the treatment of PTSD. However, the underlying mechanism of DBS of the amygdala in the modulation of the amygdala is unclear. The present study investigated the effects of DBS of the amygdala on synaptic transmission and synaptic plasticity at cortical inputs to the amygdala, which is critical for the formation and storage of auditory fear memories, and fear memories. The results demonstrated that auditory fear conditioning increased single-pulse-evoked field excitatory postsynaptic potentials in the cortical-amygdala pathway. Furthermore, auditory fear conditioning decreased the induction of paired-pulse facilitation and long-term potentiation, two neurophysiological models for studying short-term and long-term synaptic plasticity, respectively, in the cortical-amygdala pathway. In addition, all these auditory fear conditioning-induced changes could be reversed by DBS of the amygdala. DBS of the amygdala also rescued auditory fear conditioning-induced enhancement of long-term retention of fear memory. These findings suggested that DBS of the amygdala alleviating fear conditioning-induced alterations in synaptic plasticity in the cortical-amygdala pathway and fear memory may underlie the neuromodulatory role of DBS of the amygdala in activities of the amygdala.

The effects of acute nicotine on contextual safety discrimination.

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Kutlu, Munir G; Oliver, Chicora; Gould, Thomas J

2014-11-01

Anxiety disorders, such as post-traumatic stress disorder (PTSD), may be related to an inability to distinguish safe versus threatening environments and to extinguish fear memories. Given the high rate of cigarette smoking in patients with PTSD, as well as the recent finding that an acute dose of nicotine impairs extinction of contextual fear memory, we conducted a series of experiments to investigate the effect of acute nicotine in an animal model of contextual safety discrimination. Following saline or nicotine (at 0.0275, 0.045, 0.09 and 0.18 mg/kg) administration, C57BL/6J mice were trained in a contextual discrimination paradigm, in which the subjects received presentations of conditioned stimuli (CS) that co-terminated with a foot-shock in one context (context A (CXA)) and only CS presentations without foot-shock in a different context (context B (CXB)). Therefore, CXA was designated as the 'dangerous context', whereas CXB was designated as the 'safe context'. Our results suggested that saline-treated animals showed a strong discrimination between dangerous and safe contexts, while acute nicotine dose-dependently impaired contextual safety discrimination (Experiment 1). Furthermore, our results demonstrate that nicotine-induced impairment of contextual safety discrimination learning was not a result of increased generalized freezing (Experiment 2) or contingent on the common CS presentations in both contexts (Experiment 3). Finally, our results show that increasing the temporal gap between CXA and CXB during training abolished the impairing effects of nicotine (Experiment 4). The findings of this study may help link nicotine exposure to the safety learning deficits seen in anxiety disorder and PTSD patients. © The Author(s) 2014.

Cannabidiol regulation of learned fear: implications for treating anxiety-related disorders

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Regimantas Jurkus

2016-11-01

Full Text Available Anxiety and trauma-related disorders are psychiatric diseases with a lifetime prevalence of up to 25%. Phobias and post-traumatic stress disorder (PTSD are characterized by abnormal and persistent memories of fear-related contexts and cues. The effects of psychological treatments such as exposure therapy are often only temporary and medications can be ineffective and have adverse side effects. Growing evidence from human and animal studies indicates that cannabidiol, the main non-psychotomimetic phytocannabinoid present in Cannabis sativa, alleviates anxiety in paradigms assessing innate fear. More recently, the effects of cannabidiol on learned fear have been investigated in preclinical studies with translational relevance for phobias and PTSD. Here we review the findings from these studies, with an emphasis on cannabidiol regulation of contextual fear. The evidence indicates that cannabidiol reduces learned fear in different ways: (1 cannabidiol decreases fear expression acutely, (2 cannabidiol disrupts memory reconsolidation, leading to sustained fear attenuation upon memory retrieval, and (3 cannabidiol enhances extinction, the psychological process by which exposure therapy inhibits learned fear. We also present novel data on cannabidiol regulation of learned fear related to explicit cues, which indicates that auditory fear expression is also reduced acutely by cannabidiol. We conclude by outlining future directions for research to elucidate the neural circuit, psychological, cellular, and molecular mechanisms underlying the regulation of fear memory processing by cannabidiol. This line of investigation may lead to the development of cannabidiol as a novel therapeutic approach for treating anxiety and trauma-related disorders such as phobias and PTSD in the future.

Acute alcohol effects on narrative recall and contextual memory: an examination of fragmentary blackouts.

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Wetherill, Reagan R; Fromme, Kim

2011-08-01

The present study examined the effects of alcohol consumption on narrative recall and contextual memory among individuals with and without a history of fragmentary blackouts in an attempt to better understand why some individuals experience alcohol-induced memory impairments whereas others do not, even at comparable blood alcohol concentrations (BACs). Standardized beverage (alcohol and no alcohol) administration procedures and neuropsychological assessments measured narrative recall and context memory performance before and after alcohol consumption in individuals with (n=44) and without (n=44) a history of fragmentary blackouts. Findings indicate that acute alcohol intoxication led to impairments in free recall, but not next-day cued recall. Further, participants showed similar memory performance when sober, but individuals who consumed alcohol and had a positive history of fragmentary blackouts showed greater contextual memory impairments than those who had not previously experienced a fragmentary blackout. Thus, it appears that some individuals may have an inherent vulnerability to alcohol-induced memory impairments due to alcohol's effects on contextual memory processes. Copyright © 2011 Elsevier Ltd. All rights reserved.

Neural and Cellular Mechanisms of Fear and Extinction Memory Formation

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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

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

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

2012-01-01

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

Memory Contextualization: The Role of Prefrontal Cortex in Functional Integration across Item and Context Representational Regions.

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Zhang, Wei; van Ast, Vanessa A; Klumpers, Floris; Roelofs, Karin; Hermans, Erno J

2018-04-01

Memory recall is facilitated when retrieval occurs in the original encoding context. This context dependency effect likely results from the automatic binding of central elements of an experience with contextual features (i.e., memory "contextualization") during encoding. However, despite a vast body of research investigating the neural correlates of explicit associative memory, the neural interactions during encoding that predict implicit context-dependent memory remain unknown. Twenty-six participants underwent fMRI during encoding of salient stimuli (faces), which were overlaid onto unique background images (contexts). To index subsequent context-dependent memory, face recognition was tested either in intact or rearranged contexts, after scanning. Enhanced face recognition in intact relative to rearranged contexts evidenced successful memory contextualization. Overall subsequent memory effects (brain activity predicting whether items were later remembered vs. forgotten) were found in the left inferior frontal gyrus (IFG) and right amygdala. Effective connectivity analyses showed that stronger context-dependent memory was associated with stronger coupling of the left IFG with face- and place-responsive areas, both within and between participants. Our findings indicate an important role for the IFG in integrating information across widespread regions involved in the representation of salient items and contextual features.

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

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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.

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

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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.

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

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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.

Selective post-training time window for memory consolidation interference of cannabidiol into the prefrontal cortex: Reduced dopaminergic modulation and immediate gene expression in limbic circuits.

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Rossignoli, Matheus Teixeira; Lopes-Aguiar, Cleiton; Ruggiero, Rafael Naime; Do Val da Silva, Raquel Araujo; Bueno-Junior, Lezio Soares; Kandratavicius, Ludmyla; Peixoto-Santos, José Eduardo; Crippa, José Alexandre; Cecilio Hallak, Jaime Eduardo; Zuardi, Antonio Waldo; Szawka, Raphael Escorsim; Anselmo-Franci, Janete; Leite, João Pereira; Romcy-Pereira, Rodrigo Neves

2017-05-14

The prefrontal cortex (PFC), amygdala and hippocampus display a coordinated activity during acquisition of associative fear memories. Evidence indicates that PFC engagement in aversive memory formation does not progress linearly as previously thought. Instead, it seems to be recruited at specific time windows after memory acquisition, which has implications for the treatment of post-traumatic stress disorders. Cannabidiol (CBD), the major non-psychotomimetic phytocannabinoid of the Cannabis sativa plant, is known to modulate contextual fear memory acquisition in rodents. However, it is still not clear how CBD interferes with PFC-dependent processes during post-training memory consolidation. Here, we tested whether intra-PFC infusions of CBD immediately after or 5h following contextual fear conditioning was able to interfere with memory consolidation. Neurochemical and cellular correlates of the CBD treatment were evaluated by the quantification of extracellular levels of dopamine (DA), serotonin, and their metabolites in the PFC and by measuring the cellular expression of activity-dependent transcription factors in cortical and limbic regions. Our results indicate that bilateral intra-PFC CBD infusion impaired contextual fear memory consolidation when applied 5h after conditioning, but had no effect when applied immediately after it. This effect was associated with a reduction in DA turnover in the PFC following retrieval 5days after training. We also observed that post-conditioning infusion of CBD reduced c-fos and zif-268 protein expression in the hippocampus, PFC, and thalamus. Our findings support that CBD interferes with contextual fear memory consolidation by reducing PFC influence on cortico-limbic circuits. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

Fast neutron irradiation deteriorates hippocampus-related memory ability in adult mice.

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Yang, Miyoung; Kim, Hwanseong; Kim, Juhwan; Kim, Sung-Ho; Kim, Jong-Choon; Bae, Chun-Sik; Kim, Joong-Sun; Shin, Taekyun; Moon, Changjong

2012-03-01

Object recognition memory and contextual fear conditioning task performance in adult C57BL/6 mice exposed to cranial fast neutron irradiation (0.8 Gy) were examined to evaluate hippocampus-related behavioral dysfunction following acute exposure to relatively low doses of fast neutrons. In addition, hippocampal neurogenesis changes in adult murine brain after cranial irradiation were analyzed using the neurogenesis immunohistochemical markers Ki-67 and doublecortin (DCX). In the object recognition memory test and contextual fear conditioning, mice trained 1 and 7 days after irradiation displayed significant memory deficits compared to the sham-irradiated controls. The number of Ki-67- and DCX-positive cells decreased significantly 24 h post-irradiation. These results indicate that acute exposure of the adult mouse brain to a relatively low dose of fast neutrons interrupts hippocampal functions, including learning and memory, possibly by inhibiting neurogenesis.

High trait anxiety: a challenge for disrupting fear memory reconsolidation

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Soeter, M.; Kindt, M.

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

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

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

2018-04-23

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 (PTSD) and opioid addiction. Transmission through PFC DA D4 receptors (D4R) has been shown to potentiate the emotional salience of normally non-salient emotional memories whereas transmission through PFC DA D1 receptors (D1R) 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 sub-threshold 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 (CaMKII-α) or extracellular-signal-related-kinase 1-2 (ERK 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

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

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Field, Zoë C; Field, Andy P

2013-06-01

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

Aversive Memory Reactivation Engages in the Amygdala Only Some Neurotransmitters Involved in Consolidation

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Bucherelli, Corrado; Baldi, Elisabetta; Mariottini, Chiara; Passani, Maria Beatrice; Blandina, Patrizio

2006-01-01

Consolidation refers to item stabilization in long-term memory. Retrieval renders a consolidated memory sensitive, and a "reconsolidation" process has been hypothesized to keep the original memory persistent. Some authors could not detect this phenomenon. Here we show that retrieved contextual fear memory is vulnerable to amnesic treatments and…

The Parahippocampal Cortex Mediates Contextual Associative Memory: Evidence from an fMRI Study

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Li, Mi; Lu, Shengfu; Zhong, Ning

2016-01-01

The parahippocampal cortex (PHC) plays a key role in episodic memory, spatial processing, and the encoding of novel stimuli. Recent studies proposed that the PHC is largely involved in contextual associative processing. Consequently, the function of this region has been a hot debate in cognitive neuroscience. To test this assumption, we used two types of experimental materials to form the contextual associative memory: visual objects in reality and meaningless visual shapes. New associations ...

Epinephrine increases contextual learning through activation of peripheral β2-adrenoceptors.

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Alves, Ester; Lukoyanov, Nikolay; Serrão, Paula; Moura, Daniel; Moreira-Rodrigues, Mónica

2016-06-01

Phenylethanolamine-N-methyltransferase knockout (Pnmt-KO) mice are unable to synthesize epinephrine and display reduced contextual fear. However, the precise mechanism responsible for impaired contextual fear learning in these mice is unknown. Our aim was to study the mechanism of epinephrine-dependent contextual learning. Wild-type (WT) or Pnmt-KO (129x1/SvJ) mice were submitted to a fear conditioning test either in the absence or in the presence of epinephrine, isoprenaline (non-selective β-adrenoceptor agonist), fenoterol (selective β2-adrenoceptor agonist), epinephrine plus sotalol (non-selective β-adrenoceptor antagonist), and dobutamine (selective β1-adrenoceptor agonist). Catecholamines were separated by reverse-phase HPLC and quantified by electrochemical detection. Blood glucose was measured by coulometry. Re-exposure to shock context induced higher freezing in WT and Pnmt-KO mice treated with epinephrine and fenoterol than in mice treated with vehicle. In addition, freezing response in Pnmt-KO mice was much lower than in WT mice. Freezing induced by epinephrine was blocked by sotalol in Pnmt-KO mice. Epinephrine and fenoterol treatment restored glycemic response in Pnmt-KO mice. Re-exposure to shock context did not induce a significant difference in freezing in Pnmt-KO mice treated with dobutamine and vehicle. Aversive memories are best retained if moderately high plasma epinephrine concentrations occur at the same moment as the aversive stimulus. In addition, epinephrine increases context fear learning by acting on peripheral β2-adrenoceptors, which may induce high levels of blood glucose. Since glucose crosses the blood-brain barrier, it may enhance hippocampal-dependent contextual learning.

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

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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.

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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.

Memory contextualization: The role of prefrontal cortex in functional integration across item and context representational regions

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Zhang, W.; Ast, V.A. van; Klumpers, F.; Roelofs, K.; Hermans, E.

2018-01-01

Memory recall is facilitated when retrieval occurs in the original encoding context. This context dependency effect likely results from the automatic binding of central elements of an experience with contextual features (i.e., memory "contextualization") during encoding. However, despite a vast body

The Effects of Spatial Contextual Familiarity on Remembered Scenes, Episodic Memories, and Imagined Future Events

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Robin, Jessica; Moscovitch, Morris

2014-01-01

Several recent studies have explored the effect of contextual familiarity on remembered and imagined events. The aim of this study was to examine the extent of this effect by comparing the effect of cuing spatial memories, episodic memories, and imagined future events with spatial contextual cues of varying levels of familiarity. We used…

Allopregnanolone induces state-dependent fear via the bed nucleus of the stria terminalis.

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Acca, Gillian M; Mathew, Abel S; Jin, Jingji; Maren, Stephen; Nagaya, Naomi

2017-03-01

Gonadal steroids and their metabolites have been shown to be important modulators of emotional behavior. Allopregnanolone (ALLO), for example, is a metabolite of progesterone that has been linked to anxiety-related disorders such as posttraumatic stress disorder. In rodents, it has been shown to reduce anxiety in a number of behavioral paradigms including Pavlovian fear conditioning. We have recently found that expression of conditioned contextual (but not auditory) freezing in rats can be suppressed by infusion of ALLO into the bed nucleus of the stria terminalis (BNST). To further explore the nature of this effect, we infused ALLO into the BNST of male rats prior to both conditioning and testing. We found that suppression of contextual fear occurred when the hormone was present during either conditioning or testing but not during both procedures, suggesting that ALLO acts in a state-dependent manner within the BNST. A shift in interoceptive context during testing for animals conditioned under ALLO provided further support for this mechanism of hormonal action on contextual fear. Interestingly, infusions of ALLO into the basolateral amygdala produced a state-independent suppression of both conditioned contextual and auditory freezing. Altogether, these results suggest that ALLO can influence the acquisition and expression of fear memories by both state-dependent and state-independent mechanisms. Copyright © 2017 Elsevier Inc. All rights reserved.

Corticosterone regulates fear memory via Rac1 activity in the hippocampus.

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Gan, Ping; Ding, Ze-Yang; Gan, Cheng; Mao, Rong-Rong; Zhou, Heng; Xu, Lin; Zhou, Qi-Xin

2016-09-01

Stressful events can generate enduring memories, which may induce certain psychiatric disorders such as post-traumatic stress disorder (PTSD). However, the underlying molecular mechanisms in these processes remain unclear. In this study, we examined whether the active form of the small G protein Rac1, Rac1-GTP, is involved in fear memory. Firstly, we detected the time course changes of Rac1-GTP after foot shocks (a strong stressor) and exogenous corticosterone (CORT) treatment. The data showed that stress and CORT induced the downregulation of Rac1-GTP in the hippocampus. Changes in the serum CORT level were negatively correlated with the level of Rac1-GTP. Additionally, a glucocorticoid receptor antagonist, RU38486, not only recovered the expression of Rac1-GTP but also impaired fear memory. Furthermore, systemic administration of NSC23766, an inhibitor of Rac1-GTP, improved fear memory at 1.5 and 24h. Therefore, Rac1 activity plays a critical role in stress-related cognition and may be a potential target in stress-related disorders. Copyright © 2016 Elsevier Ltd. All rights reserved.

Extinction of fear is facilitated by social presence: Synergism with prefrontal oxytocin.

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Brill-Maoz, Naama; Maroun, Mouna

2016-04-01

This study addressed the question of whether extinction in pairs would have a beneficial effect on extinction of fear conditioning. To that end, we established an experimental setting for extinction in which we trained animals to extinguish contextual fear memory in pairs. Taking advantage of the role of oxytocin (OT) in the medial prefrontal cortex (mPFC) in the mediation of memory extinction and social interaction, we also sought to study its role in social interaction-induced effects on extinction. Our results clearly show that the social presence of another animal in the extinction context facilitates extinction, and that this facilitation is mediated through mPFC-OT. Our results suggest that social interaction may be a positive regulator of fear inhibition, implying that social interaction may be an easy, accessible therapeutic tool for the treatment of fear-associated disorders. Copyright © 2016. Published by Elsevier Ltd.

Grin1 receptor deletion within CRF neurons enhances fear memory.

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Georgette Gafford

Full Text Available Corticotropin releasing factor (CRF dysregulation is implicated in mood and anxiety disorders such as posttraumatic stress disorder (PTSD. CRF is expressed in areas engaged in fear and anxiety processing including the central amygdala (CeA. Complicating our ability to study the contribution of CRF-containing neurons to fear and anxiety behavior is the wide variety of cell types in which CRF is expressed. To manipulate specific subpopulations of CRF containing neurons, our lab has developed a mouse with a Cre recombinase gene driven by a CRF promoter (CRFp3.0Cre (Martin et al., 2010. In these studies, mice that have the gene that encodes NR1 (Grin1 flanked by loxP sites (floxed were crossed with our previously developed CRFp3.0Cre mouse to selectively disrupt Grin1 within CRF containing neurons (Cre+/fGrin1+. We find that disruption of Grin1 in CRF neurons did not affect baseline levels of anxiety, locomotion, pain sensitivity or exploration of a novel object. However, baseline expression of Grin1 was decreased in Cre+/fGrin1+ mice as measured by RTPCR. Cre+/fGrin1+ mice showed enhanced auditory fear acquisition and retention without showing any significant effect on fear extinction. We measured Gria1, the gene that encodes AMPAR1 and the CREB activator Creb1 in the amygdala of Cre+/fGrin1+ mice after fear conditioning. Both Gria1 and Creb1 were enhanced in the amygdala after training. To determine if the Grin1-expressing CRF neurons within the CeA are responsible for the enhancement of fear memory in adults, we infused a lentivirus with Cre driven by a CRF promoter (LV pCRF-Cre/fGrin1+ into the CeA of floxed Grin1 mice. Cre driven deletion of Grin1 specifically within CRF expressing cells in the CeA also resulted in enhanced fear memory acquisition and retention. Altogether, these findings suggest that selective disruption of Grin1 within CeA CRF neurons strongly enhances fear memory.

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

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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.

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

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

2015-01-01

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

Context-Dependent Human Extinction Memory Is Mediated by a Ventromedial Prefrontal and Hippocampal Network

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Kalisch, Raffael; Korenfeld, Elian; Stephan, Klaas E.; Weiskopf, Nikolaus; Seymour, Ben; Dolan, Raymond J.

2006-01-01

In fear extinction, an animal learns that a conditioned stimulus (CS) no longer predicts a noxious stimulus [unconditioned stimulus (UCS)] to which it had previously been associated, leading to inhibition of the conditioned response (CR). Extinction creates a new CS-noUCS memory trace, competing with the initial fear (CS-UCS) memory. Recall of extinction memory and, hence, CR inhibition at later CS encounters is facilitated by contextual stimuli present during extinction training. In line wit...

Fear memory in a neurodevelopmental model of schizophrenia based on the postnatal blockade of NMDA receptors.

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Latusz, Joachim; Radaszkiewicz, Aleksandra; Bator, Ewelina; Wędzony, Krzysztof; Maćkowiak, Marzena

2017-02-01

Epidemiological data have indicated that memory impairment is observed during adolescence in groups at high risk for schizophrenia and might precede the appearance of schizophrenia symptoms in adulthood. In the present study, we used a neurodevelopmental model of schizophrenia based on the postnatal blockade of N-methyl-d-aspartate (NMDA) receptors in rats to investigate fear memory in adolescence and adulthood. The rats were treated with increasing doses of CGP 37849 (CGP), a competitive antagonist of the NMDA receptor (1.25mg/kg on days 1, 3, 6, 9; 2.5mg/kg on days 12, 15, 18 and 5mg/kg on day 21). Fear memory was analysed in delay and trace fear conditioning. Sensorimotor gating deficit, which is another cognitive symptom of schizophrenia, was also determined in adolescent and adult CGP-treated rats. Postnatal CGP administration disrupted cue- and context-dependent fear memory in adolescent rats in both delay and trace conditioning. In contrast, CGP administration evoked impairment only in cue-dependent fear memory in rats exposed to trace but not delay fear conditioning. The postnatal blockade of NMDA receptors induced sensorimotor gating deficits in adult rats but not in adolescent rats. The postnatal blockade of NMDA receptors induced fear memory impairment in adolescent rats before the onset of neurobehavioral deficits associated with schizophrenia. Copyright © 2016. Published by Elsevier Urban & Partner Sp. z o.o.

Differential Recruitment of Auditory Cortices in the Consolidation of Recent Auditory Fearful Memories.

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Cambiaghi, Marco; Grosso, Anna; Renna, Annamaria; Sacchetti, Benedetto

2016-08-17

Memories of frightening events require a protracted consolidation process. Sensory cortex, such as the auditory cortex, is involved in the formation of fearful memories with a more complex sensory stimulus pattern. It remains controversial, however, whether the auditory cortex is also required for fearful memories related to simple sensory stimuli. In the present study, we found that, 1 d after training, the temporary inactivation of either the most anterior region of the auditory cortex, including the primary (Te1) cortex, or the most posterior region, which included the secondary (Te2) component, did not affect the retention of recent memories, which is consistent with the current literature. However, at this time point, the inactivation of the entire auditory cortices completely prevented the formation of new memories. Amnesia was site specific and was not due to auditory stimuli perception or processing and strictly related to the interference with memory consolidation processes. Strikingly, at a late time interval 4 d after training, blocking the posterior part (encompassing the Te2) alone impaired memory retention, whereas the inactivation of the anterior part (encompassing the Te1) left memory unaffected. Together, these data show that the auditory cortex is necessary for the consolidation of auditory fearful memories related to simple tones in rats. Moreover, these results suggest that, at early time intervals, memory information is processed in a distributed network composed of both the anterior and the posterior auditory cortical regions, whereas, at late time intervals, memory processing is concentrated in the most posterior part containing the Te2 region. Memories of threatening experiences undergo a prolonged process of "consolidation" to be maintained for a long time. The dynamic of fearful memory consolidation is poorly understood. Here, we show that 1 d after learning, memory is processed in a distributed network composed of both primary Te1 and

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

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Aditya Mungee

2016-11-01

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

False Context Fear Memory in Rats

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

2015-01-01

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

The neuronal PAS domain protein 4 (Npas4 is required for new and reactivated fear memories.

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Jonathan E Ploski

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

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

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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.…

Exploring epigenetic regulation of fear memory and biomarkers associated with Post-traumatic stress disorder

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Stephanie A. Maddox

2013-07-01

Full Text Available This review examines recent work on epigenetic mechanisms underlying animal models of fear learning as well as its translational implications in disorders of fear regulation, such as Posttraumatic Stress Disorder (PTSD. Specifically, we will examine work outlining roles of differential histone acetylation and DNA methylation associated with consolidation, reconsolidation and extinction in Pavlovian fear paradigms. We then focus on the numerous studies examining the epigenetic modifications of the Brain-derived neurotrophin factor (BDNF pathway and the extension of these findings from animal models to recent work in human clinical populations. We will also review recently published data on FKBP5 regulation of glucocorticoid receptor function, and how this is modulated in animal models of PTSD and in human clinical populations via epigenetic mechanisms. As glucocorticoid regulation of memory consolidation is well established in fear models, we examine how these recent data contribute to our broader understanding of fear memory formation. The combined recent progress in epigenetic modulation of memory with the advances in fear neurobiology suggest that this area may be critical to progress in our understanding of fear-related disorders with implications for new approaches to treatment and prevention.

Learning and memory in conditioned fear extinction: effects of d-cycloserine

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Vervliet, B.

2008-01-01

This review addresses the effects of the cognitive enhancer D-cycloserine (DCS) on the memory processes that occur in conditioned fear extinction, which is the experimental model for exposure techniques to reduce clinical anxiety. All reported rat studies show an enhanced fear extinction effect when

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

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

2018-01-15

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

Context Memory Formation Requires Activity-Dependent Protein Degradation in the Hippocampus

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Cullen, Patrick K.; Ferrara, Nicole C.; Pullins, Shane E.; Helmstetter, Fred J.

2017-01-01

Numerous studies have indicated that the consolidation of contextual fear memories supported by an aversive outcome like footshock requires de novo protein synthesis as well as protein degradation mediated by the ubiquitin-proteasome system (UPS). Context memory formed in the absence of an aversive stimulus by simple exposure to a novel…

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

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Holliday, Erica D; Gould, Thomas J

2017-01-01

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

Forced Migration of Colombians : Fear, Historical Memory and ...

International Development Research Centre (IDRC) Digital Library (Canada)

This project follows two years of successful research under project 102661 on forced migration of Colombians within Colombia and to Ecuador and Canada. Researchers in Colombia and Canada investigated the ways in which fear, historical memory and social representation by and about forced migrants influence their ...

A fear-inducing odor alters PER2 and c-Fos expression in brain regions involved in fear memory.

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Harry Pantazopoulos

Full Text Available Evidence demonstrates that rodents learn to associate a foot shock with time of day, indicating the formation of a fear related time-stamp memory, even in the absence of a functioning SCN. In addition, mice acquire and retain fear memory better during the early day compared to the early night. This type of memory may be regulated by circadian pacemakers outside of the SCN. As a first step in testing the hypothesis that clock genes are involved in the formation of a time-stamp fear memory, we exposed one group of mice to fox feces derived odor (TMT at ZT 0 and one group at ZT 12 for 4 successive days. A separate group with no exposure to TMT was also included as a control. Animals were sacrificed one day after the last exposure to TMT, and PER2 and c-Fos protein were quantified in the SCN, amygdala, hippocampus, and piriform cortex. Exposure to TMT had a strong effect at ZT 0, decreasing PER2 expression at this time point in most regions except the SCN, and reversing the normal rhythm of PER2 expression in the amygdala and piriform cortex. These changes were accompanied by increased c-Fos expression at ZT0. In contrast, exposure to TMT at ZT 12 abolished the rhythm of PER2 expression in the amygdala. In addition, increased c-Fos expression at ZT 12 was only detected in the central nucleus of the amygdala in the TMT12 group. TMT exposure at either time point did not affect PER2 or c-Fos in the SCN, indicating that under a light-dark cycle, the SCN rhythm is stable in the presence of repeated exposure to a fear-inducing stimulus. Taken together, these results indicate that entrainment to a fear-inducing stimulus leads to changes in PER2 and c-Fos expression that are detected 24 hours following the last exposure to TMT, indicating entrainment of endogenous oscillators in these regions. The observed effects on PER2 expression and c-Fos were stronger during the early day than during the early night, possibly to prepare appropriate systems at ZT 0 to

Pharmacological Enhancement of mGluR5 Facilitates Contextual Fear Memory Extinction

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Sethna, Ferzin; Wang, Hongbing

2014-01-01

Behavioral exposure therapy, which involves extinction of the previously acquired fear, has been used to treat anxiety-related symptoms such as post-traumatic stress disorder. It has been hypothesized that proextinction pharmacotherapeutics may enhance the efficacy of exposure therapy. Systemic administration of the metabotropic glutamate receptor…

Growth hormone secretagogue receptor (GHS-R1a) knockout mice exhibit improved spatial memory and deficits in contextual memory.

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Albarran-Zeckler, Rosie G; Brantley, Alicia Faruzzi; Smith, Roy G

2012-06-15

Although the hormone ghrelin is best known for its stimulatory effect on appetite and regulation of growth hormone release, it is also reported to have beneficial effects on learning and memory formation in mice. Nevertheless, controversy exists about whether endogenous ghrelin acts on its receptors in extra-hypothalamic areas of the brain. The ghrelin receptor (GHS-R1a) is co-expressed in neurons that express dopamine receptor type-1 (DRD1a) and type-2 (DRD2), and we have shown that a subset of GHS-R1a, which are not occupied by the agonist (apo-GHSR1a), heterodimerize with these two receptors to regulate dopamine signaling in vitro and in vivo. To determine the consequences of ghsr ablation on brain function, congenic ghsr -/- mice on the C57BL6/J background were subjected to a battery of behavioral tests. We show that the ghsr -/- mice exhibit normal balance, movement, coordination, and pain sensation, outperform ghsr +/+ mice in the Morris water maze, but show deficits in contextual fear conditioning. Copyright © 2012 Elsevier B.V. All rights reserved.

Harnessing reconsolidation to weaken fear and appetitive memories: A meta-analysis of post-retrieval extinction effects.

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

2016-03-01

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. Postretrieval 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 postretrieval extinction effects and potential moderators of these effects. A PubMed and PsycINFO search was conducted through June 2014. Sixty-three comparisons examining postretrieval extinction for preventing the return of fear or appetitive responses in animals or humans met inclusion criteria. Postretrieval 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 nonsignificant, but moderated by the number of animals housed together and the duration of time between postretrieval extinction/extinction and test. Across paradigms, these findings support the efficacy of this preclinical strategy for preventing the return of conditioned fear and appetitive responses. Overall, findings to date support the continued translation of postretrieval extinction research to human and clinical applications, with particular application to the treatment of anxiety, traumatic stress, and substance use disorders. (c) 2016 APA, all rights reserved).

The effect of contextual cues on the encoding of motor memories.

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Howard, Ian S; Wolpert, Daniel M; Franklin, David W

2013-05-01

Several studies have shown that sensory contextual cues can reduce the interference observed during learning of opposing force fields. However, because each study examined a small set of cues, often in a unique paradigm, the relative efficacy of different sensory contextual cues is unclear. In the present study we quantify how seven contextual cues, some investigated previously and some novel, affect the formation and recall of motor memories. Subjects made movements in a velocity-dependent curl field, with direction varying randomly from trial to trial but always associated with a unique contextual cue. Linking field direction to the cursor or background color, or to peripheral visual motion cues, did not reduce interference. In contrast, the orientation of a visual object attached to the hand cursor significantly reduced interference, albeit by a small amount. When the fields were associated with movement in different locations in the workspace, a substantial reduction in interference was observed. We tested whether this reduction in interference was due to the different locations of the visual feedback (targets and cursor) or the movements (proprioceptive). When the fields were associated only with changes in visual display location (movements always made centrally) or only with changes in the movement location (visual feedback always displayed centrally), a substantial reduction in interference was observed. These results show that although some visual cues can lead to the formation and recall of distinct representations in motor memory, changes in spatial visual and proprioceptive states of the movement are far more effective than changes in simple visual contextual cues.

People, clothing, music, and arousal as contextual retrieval cues in verbal memory.

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Standing, Lionel G; Bobbitt, Kristin E; Boisvert, Kathryn L; Dayholos, Kathy N; Gagnon, Anne M

2008-10-01

Four experiments (N = 164) on context-dependent memory were performed to explore the effects on verbal memory of incidental cues during the test session which replicated specific features of the learning session. These features involved (1) bystanders, (2) the clothing of the experimenter, (3) background music, and (4) the arousal level of the subject. Social contextual cues (bystanders or experimenter clothing) improved verbal recall or recognition. However, recall decreased when the contextual cue was a different stimulus taken from the same conceptual category (piano music by Chopin) that was heard during learning. Memory was unaffected by congruent internal cues, produced by the same physiological arousal level (low, moderate, or high heart rate) during the learning and test sessions. However, recall increased with the level of arousal across the three congruent conditions. The results emphasize the effectiveness as retrieval cues of stimuli which are socially salient, concrete, and external.

Is attention based on spatial contextual memory preferentially guided by low spatial frequency signals?

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Patai, Eva Zita; Buckley, Alice; Nobre, Anna Christina

2013-01-01

A popular model of visual perception states that coarse information (carried by low spatial frequencies) along the dorsal stream is rapidly transmitted to prefrontal and medial temporal areas, activating contextual information from memory, which can in turn constrain detailed input carried by high spatial frequencies arriving at a slower rate along the ventral visual stream, thus facilitating the processing of ambiguous visual stimuli. We were interested in testing whether this model contributes to memory-guided orienting of attention. In particular, we asked whether global, low-spatial frequency (LSF) inputs play a dominant role in triggering contextual memories in order to facilitate the processing of the upcoming target stimulus. We explored this question over four experiments. The first experiment replicated the LSF advantage reported in perceptual discrimination tasks by showing that participants were faster and more accurate at matching a low spatial frequency version of a scene, compared to a high spatial frequency version, to its original counterpart in a forced-choice task. The subsequent three experiments tested the relative contributions of low versus high spatial frequencies during memory-guided covert spatial attention orienting tasks. Replicating the effects of memory-guided attention, pre-exposure to scenes associated with specific spatial memories for target locations (memory cues) led to higher perceptual discrimination and faster response times to identify targets embedded in the scenes. However, either high or low spatial frequency cues were equally effective; LSF signals did not selectively or preferentially contribute to the memory-driven attention benefits to performance. Our results challenge a generalized model that LSFs activate contextual memories, which in turn bias attention and facilitate perception.

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

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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.

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

Directory of Open Access Journals (Sweden)

Marieke eSoeter

2015-05-01

Full Text Available 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. 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.

Fearful, but not angry, expressions diffuse attention to peripheral targets in an attentional blink paradigm.

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Taylor, James M; Whalen, Paul J

2014-06-01

We previously demonstrated that fearful facial expressions implicitly facilitate memory for contextual events whereas angry facial expressions do not. The current study sought to more directly address the implicit effect of fearful expressions on attention for contextual events within a classic attentional paradigm (i.e., the attentional blink) in which memory is tested on a trial-by-trial basis, thereby providing subjects with a clear, explicit attentional strategy. Neutral faces of a single gender were presented via rapid serial visual presentation (RSVP) while bordered by four gray pound signs. Participants were told to watch for a gender change within the sequence (T1). It is critical to note that the T1 face displayed a neutral, fearful, or angry expression. Subjects were then told to detect a color change (i.e., gray to green; T2) at one of the four peripheral pound sign locations appearing after T1. This T2 color change could appear at one of six temporal positions. Complementing previous attentional blink paradigms, participants were told to respond via button press immediately when a T2 target was detected. We found that, compared with the neutral T1 faces, fearful faces significantly increased target detection ability at four of the six temporal locations (all ps enhance environmental monitoring above and beyond explicit attentional effects related to task instructions.

Memory under pressure: secondary-task effects on contextual cueing of visual search.

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Annac, Efsun; Manginelli, Angela A; Pollmann, Stefan; Shi, Zhuanghua; Müller, Hermann J; Geyer, Thomas

2013-11-04

Repeated display configurations improve visual search. Recently, the question has arisen whether this contextual cueing effect (Chun & Jiang, 1998) is itself mediated by attention, both in terms of selectivity and processing resources deployed. While it is accepted that selective attention modulates contextual cueing (Jiang & Leung, 2005), there is an ongoing debate whether the cueing effect is affected by a secondary working memory (WM) task, specifically at which stage WM influences the cueing effect: the acquisition of configural associations (e.g., Travis, Mattingley, & Dux, 2013) versus the expression of learned associations (e.g., Manginelli, Langer, Klose, & Pollmann, 2013). The present study re-investigated this issue. Observers performed a visual search in combination with a spatial WM task. The latter was applied on either early or late search trials--so as to examine whether WM load hampers the acquisition of or retrieval from contextual memory. Additionally, the WM and search tasks were performed either temporally in parallel or in succession--so as to permit the effects of spatial WM load to be dissociated from those of executive load. The secondary WM task was found to affect cueing in late, but not early, experimental trials--though only when the search and WM tasks were performed in parallel. This pattern suggests that contextual cueing involves a spatial WM resource, with spatial WM providing a workspace linking the current search array with configural long-term memory; as a result, occupying this workspace by a secondary WM task hampers the expression of learned configural associations.

Npas4 Is a Critical Regulator of Learning-Induced Plasticity at Mossy Fiber-CA3 Synapses during Contextual Memory Formation

DEFF Research Database (Denmark)

Weng, Feng-Ju; Garcia, Rodrigo I; Lutzu, Stefano

2018-01-01

Synaptic connections between hippocampal mossy fibers (MFs) and CA3 pyramidal neurons are essential for contextual memory encoding, but the molecular mechanisms regulating MF-CA3 synapses during memory formation and the exact nature of this regulation are poorly understood. Here we report...... pyramidal cells that were activated by contextual learning and found that MF inputs on these cells were selectively strengthened. Deletion of Npas4 prevented both contextual memory formation and this learning-induced synaptic modification. We further show that Npas4 regulates MF-CA3 synapses by controlling...... the expression of the polo-like kinase Plk2. Thus, Npas4 is a critical regulator of experience-dependent, structural, and functional plasticity at MF-CA3 synapses during contextual memory formation....

A role for nitric oxide-driven retrograde signaling in the consolidation of a fear memory

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Kathie A Overeem

2010-02-01

Full Text Available In both invertebrate and vertebrate models of synaptic plasticity, signaling via the putative “retrograde messenger” nitric oxide (NO has been hypothesized to serve as a critical link between functional and structural alterations at pre- and postsynaptic sites. However, while in vitro models of synaptic plasticity have consistently implicated NO signaling in linking postsynaptic induction mechanisms with accompanying presynaptic changes, a convincing role of such “retrograde signaling” in mammalian memory formation has remained elusive. Using auditory Pavlovian fear conditioning, we show that synaptic plasticity and NO signaling in the lateral nucleus of the amygdala (LA regulate the expression of the ERK-driven immediate early gene early growth response gene I (EGR-1 in regions of the auditory thalamus that are presynaptic to the LA. Further, antisense knockdown of EGR-1 in the auditory thalamus impairs both fear memory consolidation and the training-induced elevation of two presynaptically localized proteins in the LA. These findings indicate that synaptic plasticity and NO signaling in the LA during auditory fear conditioning promote alterations in ERK-driven gene expression in auditory thalamic neurons that are required for both fear memory consolidation as well as presynaptic correlates of fear memory formation in the LA, and provide general support for a role of NO as a “retrograde signal” in mammalian memory formation.

Memory reconsolidation and psychotherapeutic process.

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Liberzon, Israel; Javanbakht, Arash

2015-01-01

Lane et al. propose a heuristic model in which distinct, and seemingly irreconcilable, therapies can coexist. Authors postulate that memory reconsolidation is a key common neurobiological process mediating the therapeutic effects. This conceptualization raises a set of important questions regarding neuroscience and translational aspects of fear memory reconsolidation. We discuss the implications of the target article's memory reconsolidation model in the development of more effective interventions, and in the identification of less effective, or potentially harmful approaches, as well as concepts of contextualization, optimal arousal, and combined therapy.

Neural correlates of fear: insights from neuroimaging

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Garfinkel SN

2014-12-01

Full Text Available Sarah N Garfinkel,1,2 Hugo D Critchley1,2 1Sackler Centre for Consciousness Science, 2Department of Psychiatry, Brighton and Sussex Medical School, University of Sussex, Brighton, UK Abstract: Fear anticipates a challenge to one's well-being and is a reaction to the risk of harm. The expression of fear in the individual is a constellation of physiological, behavioral, cognitive, and experiential responses. Fear indicates risk and will guide adaptive behavior, yet fear is also fundamental to the symptomatology of most psychiatric disorders. Neuroimaging studies of normal and abnormal fear in humans extend knowledge gained from animal experiments. Neuroimaging permits the empirical evaluation of theory (emotions as response tendencies, mental states, and valence and arousal dimensions, and improves our understanding of the mechanisms of how fear is controlled by both cognitive processes and bodily states. Within the human brain, fear engages a set of regions that include insula and anterior cingulate cortices, the amygdala, and dorsal brain-stem centers, such as periaqueductal gray matter. This same fear matrix is also implicated in attentional orienting, mental planning, interoceptive mapping, bodily feelings, novelty and motivational learning, behavioral prioritization, and the control of autonomic arousal. The stereotyped expression of fear can thus be viewed as a special construction from combinations of these processes. An important motivator for understanding neural fear mechanisms is the debilitating clinical expression of anxiety. Neuroimaging studies of anxiety patients highlight the role of learning and memory in pathological fear. Posttraumatic stress disorder is further distinguished by impairment in cognitive control and contextual memory. These processes ultimately need to be targeted for symptomatic recovery. Neuroscientific knowledge of fear has broader relevance to understanding human and societal behavior. As yet, only some of

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

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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.

Facilitation of memory by contextual cues in patients with diencephalic or medial temporal lobe dysfunction.

NARCIS (Netherlands)

Tielemans, N.S.; Hendriks, M.P.; Talamini, L.; Wester, A.J.; Meeter, M.; Kessels, R.P.C.

2012-01-01

Item-context binding is crucial for successful episodic memory formation, and binding deficits have been suggested to underlie episodic-memory deficits. Here, our research investigated the facilitation of cued recall and recognition memory by contextual cues in 20 patients with Korsakoff's amnesia,

Facilitation of memory by contextual cues in patients with diencephalic or medial temporal lobe dysfunction

NARCIS (Netherlands)

Tielemans, N.S.; Hendriks, M.P.H.; Talamini, L.; Wester, A.J.; Meeter, M.; Kessels, R.P.C.

2012-01-01

Item-context binding is crucial for successful episodic memory formation, and binding deficits have been suggested to underlie episodic-memory deficits. Here, our research investigated the facilitation of cued recall and recognition memory by contextual cues in 20 patients with Korsakoff's amnesia,

Memory for fearful faces across development: specialization of amygdala nuclei and medial temporal lobe structures.

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Pinabiaux, Charlotte; Hertz-Pannier, Lucie; Chiron, Catherine; Rodrigo, Sébastian; Jambaqué, Isabelle; Noulhiane, Marion

2013-01-01

Enhanced memory for emotional faces is a significant component of adaptive social interactions, but little is known on its neural developmental correlates. We explored the role of amygdaloid complex (AC) and medial temporal lobe (MTL) in emotional memory recognition across development, by comparing fMRI activations of successful memory encoding of fearful and neutral faces in children (n = 12; 8-12 years) and adolescents (n = 12; 13-17 years). Memory for fearful faces was enhanced compared with neutral ones in adolescents, as opposed to children. In adolescents, activations associated with successful encoding of fearful faces were centered on baso-lateral AC nuclei, hippocampus, enthorhinal and parahippocampal cortices. In children, successful encoding of fearful faces relied on activations of centro-mesial AC nuclei, which was not accompanied by functional activation of MTL memory structures. Successful encoding of neutral faces depended on activations in anterior MTL region (hippocampal head and body) in adolescents, but more posterior ones (hippocampal tail and parahippocampal cortex) in children. In conclusion, two distinct functional specializations emerge from childhood to adolescence and result in the enhancement of memory for these particular stimuli: the specialization of baso-lateral AC nuclei, which is associated with the expertise in processing emotional facial expression, and which is intimately related to the specialization of MTL memory network. How the interplay between specialization of AC nuclei and of MTL memory structures is fundamental for the edification of social interactions remains to be elucidated.

Memory for fearful faces across development: specialization of amygdala nuclei and medial temporal lobe structures

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Charlotte ePinabiaux

2013-12-01

Full Text Available Enhanced memory for emotional faces is a significant component of adaptive social interactions, but little is known on its neural developmental correlates. We explored the role of amygdaloid complex (AC and medial temporal lobe (MTL in emotional memory recognition across development, by comparing fMRI activations of successful memory encoding of fearful and neutral faces in children (n=12; 8-12 years and adolescents (n=12; 13-17 years. Memory for fearful faces was enhanced compared with neutral ones in adolescents, as opposed to children. In adolescents, activations associated with successful encoding of fearful faces were centered on baso-lateral AC nuclei, hippocampus, enthorhinal and parahippocampal cortices. In children, successful encoding of fearful faces relied on activations of centro-mesial AC nuclei, which was not accompanied by functional activation of MTL memory structures. Successful encoding of neutral faces depended on activations in anterior MTL region (hippocampal head and body in adolescents, but more posterior ones (hippocampal tail and parahippocampal cortex in children. In conclusion, two distinct functional specializations emerge from childhood to adolescence and result in the enhancement of memory for these particular stimuli: the specialization of baso-lateral AC nuclei, which is associated with the expertise in processing emotional facial expression, and which is intimately related to the specialization of MTL memory network. How the interplay between specialization of AC nuclei and of MTL memory structures is fundamental for the edification of social interactions remains to be elucidated.

Contribution of Hippocampal 5-HT3 Receptors in Hippocampal Autophagy and Extinction of Conditioned Fear Responses after a Single Prolonged Stress Exposure in Rats.

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Wu, Zhong-Min; Yang, Li-Hua; Cui, Rong; Ni, Gui-Lian; Wu, Feng-Tian; Liang, Yong

2017-05-01

One of the hypotheses about the pathogenesis of posttraumatic stress disorder (PTSD) is the dysfunction of serotonin (5-HT) neurotransmission. While certain 5-HT receptor subtypes are likely critical for the symptoms of PTSD, few studies have examined the role of 5-HT 3 receptor in the development of PTSD, even though 5-HT 3 receptor is critical for contextual fear extinction and anxiety-like behavior. Therefore, we hypothesized that stimulation of 5-HT 3 receptor in the dorsal hippocampus (DH) could prevent hippocampal autophagy and the development of PTSD-like behavior in animals. To this end, we infused SR57227, selective 5-HT 3 agonist, into the DH after a single prolonged stress (SPS) treatment in rats. Three weeks later, we evaluated the effects of this pharmacological treatment on anxiety-related behaviors and extinction of contextual fear memory. We also accessed hippocampal autophagy and the expression of 5-HT 3A subunit, Beclin-1, LC3-I, and LC3-II in the DH. We found that SPS treatment did not alter anxiety-related behaviors but prolonged the extinction of contextual fear memory, and such a behavioral phenomenon was correlated with increased hippocampal autophagy, decreased 5-HT 3A expression, and increased expression of Beclin-1 and LC3-II/LC3-I ratio in the DH. Furthermore, intraDH infusions of SR57227 dose-dependently promoted the extinction of contextual fear memory, prevented hippocampal autophagy, and decreased expression of Beclin-1 and LC3-II/LC3-I ratio in the DH. These results indicated that 5-HT 3 receptor in the hippocampus may play a critical role in the pathogenesis of hippocampal autophagy, and is likely involved in the pathophysiology of PTSD.

Posttraining handling facilitates memory for auditory-cue fear conditioning in rats.

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Hui, Isabel R; Hui, Gabriel K; Roozendaal, Benno; McGaugh, James L; Weinberger, Norman M

2006-09-01

A large number of studies have indicated that stress exposure or the administration of stress hormones and other neuroactive drugs immediately after a learning experience modulates the consolidation of long-term memory. However, there has been little investigation into how arousal induced by handling of the animals in order to administer these drugs affects memory. Therefore, the present study examined whether the posttraining injection or handling procedure per se affects memory of auditory-cue classical fear conditioning. Male Sprague-Dawley rats, which had been pre-handled on three days for 1 min each prior to conditioning, received three pairings of a single-frequency auditory stimulus and footshock, followed immediately by either a subcutaneous injection of a vehicle solution or brief handling without injection. A control group was placed back into their home cages without receiving any posttraining treatment. Retention was tested 24 h later in a novel chamber and suppression of ongoing motor behavior during a 10-s presentation of the auditory-cue served as the measure of conditioned fear. Animals that received posttraining injection or handling did not differ from each other but showed significantly less stimulus-induced movement compared to the non-handled control group. These findings thus indicate that the posttraining injection or handling procedure is sufficiently arousing or stressful to facilitate memory consolidation of auditory-cue classical fear conditioning.

Extinction partially reverts structural changes associated with remote fear memory

DEFF Research Database (Denmark)

Vetere, Gisella; Restivo, Leonardo; Novembre, Giovanni

2011-01-01

Structural synaptic changes occur in medial prefrontal cortex circuits during remote memory formation. Whether extinction reverts or further reshapes these circuits is, however, unknown. Here we show that the number and the size of spines were enhanced in anterior cingulate (aCC) and infralimbic...... the remote memory network, suggesting that the preserved network properties might sustain reactivation of extinguished conditioned fear....

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

Science.gov (United States)

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

Infralimbic dopamine D2 receptors mediate glucocorticoid-induced facilitation of auditory fear memory extinction in rats.

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Dadkhah, Masoumeh; Abdullahi, Payman Raise; Rashidy-Pour, Ali; Sameni, Hamid Reza; Vafaei, Abbas Ali

2018-03-01

The infralimbic (IL) cortex of the medial prefrontal cortex plays an important role in the extinction of fear memory. Also, it has been showed that both brain glucocorticoid and dopamine receptors are involved in many processes such as fear extinction that drive learning and memory; however, the interaction of these receptors in the IL cortex remains unclear. We examined a putative interaction between the effects of glucocorticoid and dopamine receptors stimulation in the IL cortex on fear memory extinction in an auditory fear conditioning paradigm in male rats. Corticosterone (the endogenous glucocorticoid receptor ligand), or RU38486 (the synthetic glucocorticoid receptor antagonist) microinfusion into the IL cortex 10 min before test 1 attenuated auditory fear expression at tests 1-3, suggesting as an enhancement of fear extinction. The effect of corticosterone, but not RU38486 was counteracted by the dopamine D2 receptor antagonist sulpiride pre-treatment administered into the IL (at a dose that failed to alter freezing behavior on its own). In contrast, intra-IL infusion of the dopamine D1 receptor antagonist SCH23390 pre-treatment failed to alter freezing behavior. These findings provide evidence for the involvement of the IL cortex D2 receptors in CORT-induced facilitation of fear memory extinction. Copyright © 2018 Elsevier B.V. All rights reserved.

The Hypocretin/Orexin System Mediates the Extinction of Fear Memories

OpenAIRE

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 condi...

Ensemble coding of context-dependent fear memory in the amygdala

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

2013-01-01

After fear conditioning, presenting the conditioned stimulus (CS) alone yields a context-specific extinction memory; fear is suppressed in the extinction context, but renews in any other context. The context-dependence of extinction is mediated by a brain circuit consisting of the hippocampus, prefrontal cortex and amygdala. In the present work, we sought to determine at what level of this circuit context-dependent representations of the CS emerge. To explore this question, we used cellula...

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

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

2015-04-01

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., 40mg/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. Copyright © 2015 Elsevier Inc. All rights reserved.

Cortisol response mediates the effect of post-reactivation stress exposure on contextualization of emotional memories.

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Bos, Marieke G N; Jacobs van Goethem, Tessa H; Beckers, Tom; Kindt, Merel

2014-12-01

Retrieval of traumatic experiences is often accompanied by strong feelings of distress. Here, we examined in healthy participants whether post-reactivation stress experience affects the context-dependency of emotional memory. First, participants studied words from two distinctive emotional categories (i.e., war and disease) presented against a category-related background picture. One day later, participants returned to the lab and received a reminder of the words of one emotional category followed by exposure to a stress task (Stress group, n=22) or a control task (Control group, n=24). Six days later, memory contextualization was tested using a word stem completion task. Half of the word stems were presented against the encoding context (i.e., congruent context) and the other half of the word stems were presented against the other context (i.e., incongruent context). The results showed that participants recalled more words in the congruent context than in the incongruent context. Interestingly, cortisol mediated the effect of stress exposure on memory contextualization. The stronger the post-reactivation cortisol response, the more memory performance relied on the contextual embedding of the words. Taken together, the current findings suggest that a moderate cortisol response after memory reactivation might serve an adaptive function in preventing generalization of emotional memories over contexts. Copyright © 2014 Elsevier Ltd. All rights reserved.

Sex- and dose-dependent effects of calcium ion irradiation on behavioral performance of B6D2F1 mice during contextual fear conditioning training

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Raber, Jacob; Weber, Sydney J.; Kronenberg, Amy; Turker, Mitchell S.

2016-06-01

The space radiation environment includes energetic charged particles that may impact behavioral and cognitive performance. The relationship between the dose and the ionization density of the various types of charged particles (expressed as linear energy transfer or LET), and cognitive performance is complex. In our earlier work, whole body exposure to 28Si ions (263 MeV/n, LET = 78keV / μ m ; 1.6 Gy) affected contextual fear memory in C57BL/6J × DBA2/J F1 (B6D2F1) mice three months following irradiation but this was not the case following exposure to 48Ti ions (1 GeV/n, LET = 107keV / μ m ; 0.2 or 0.4 Gy). As an increased understanding of the impact of charged particle exposures is critical for assessment of risk to the CNS of astronauts during and following missions, in this study we used 40Ca ion beams (942 MeV/n, LET = 90keV / μm) to determine the behavioral and cognitive effects for the LET region between that of Si ions and Ti ions. 40Ca ion exposure reduced baseline activity in a novel environment in a dose-dependent manner, which suggests reduced motivation to explore and/or a diminished level of curiosity in a novel environment. In addition, exposure to 40Ca ions had sex-dependent effects on response to shock. 40Ca ion irradiation reduced the response to shock in female, but not male, mice. In contrast, 40Ca ion irradiation did not affect fear learning, memory, or extinction of fear memory for either gender at the doses employed in this study. Thus 40Ca ion irradiation affected behavioral, but not cognitive, performance. The effects of 40Ca ion irradiation on behavioral performance are relevant, as a combination of novelty and aversive environmental stimuli is pertinent to conditions experienced by astronauts during and following space missions.

Chronic corticosterone exposure persistently elevates the expression of memory-related genes in the lateral amygdala and enhances the consolidation of a Pavlovian fear memory.

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Melissa S Monsey

Full Text Available Chronic exposure to stress has been widely implicated in the development of anxiety disorders, yet relatively little is known about the long-term effects of chronic stress on amygdala-dependent memory formation. Here, we examined the effects of a history of chronic exposure to the stress-associated adrenal steroid corticosterone (CORT on the consolidation of a fear memory and the expression of memory-related immediate early genes (IEGs in the lateral nucleus of the amygdala (LA. Rats received chronic exposure to CORT (50 μg/ml in their drinking water for 2 weeks and were then titrated off the CORT for an additional 6 days followed by a 2 week 'wash-out' period consisting of access to plain water. Rats were then either sacrificed to examine the expression of memory-related IEG expression in the LA or given auditory Pavlovian fear conditioning. We show that chronic exposure to CORT leads to a persistent elevation in the expression of the IEGs Arc/Arg3.1 and Egr-1 in the LA. Further, we show that rats with a history of chronic CORT exposure exhibit enhanced consolidation of a fear memory; short-term memory (STM is not affected, while long-term memory (LTM is significantly enhanced. Treatment with the selective serotonin reuptake inhibitor (SSRI fluoxetine following the chronic CORT exposure period was observed to effectively reverse both the persistent CORT-related increases in memory-related IEG expression in the LA and the CORT-related enhancement in fear memory consolidation. Our findings suggest that chronic exposure to CORT can regulate memory-related IEG expression and fear memory consolidation processes in the LA in a long-lasting manner and that treatment with fluoxetine can reverse these effects.

Chronic corticosterone exposure persistently elevates the expression of memory-related genes in the lateral amygdala and enhances the consolidation of a Pavlovian fear memory.

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Monsey, Melissa S; Boyle, Lara M; Zhang, Melinda L; Nguyen, Caroline P; Kronman, Hope G; Ota, Kristie T; Duman, Ronald S; Taylor, Jane R; Schafe, Glenn E

2014-01-01

Chronic exposure to stress has been widely implicated in the development of anxiety disorders, yet relatively little is known about the long-term effects of chronic stress on amygdala-dependent memory formation. Here, we examined the effects of a history of chronic exposure to the stress-associated adrenal steroid corticosterone (CORT) on the consolidation of a fear memory and the expression of memory-related immediate early genes (IEGs) in the lateral nucleus of the amygdala (LA). Rats received chronic exposure to CORT (50 μg/ml) in their drinking water for 2 weeks and were then titrated off the CORT for an additional 6 days followed by a 2 week 'wash-out' period consisting of access to plain water. Rats were then either sacrificed to examine the expression of memory-related IEG expression in the LA or given auditory Pavlovian fear conditioning. We show that chronic exposure to CORT leads to a persistent elevation in the expression of the IEGs Arc/Arg3.1 and Egr-1 in the LA. Further, we show that rats with a history of chronic CORT exposure exhibit enhanced consolidation of a fear memory; short-term memory (STM) is not affected, while long-term memory (LTM) is significantly enhanced. Treatment with the selective serotonin reuptake inhibitor (SSRI) fluoxetine following the chronic CORT exposure period was observed to effectively reverse both the persistent CORT-related increases in memory-related IEG expression in the LA and the CORT-related enhancement in fear memory consolidation. Our findings suggest that chronic exposure to CORT can regulate memory-related IEG expression and fear memory consolidation processes in the LA in a long-lasting manner and that treatment with fluoxetine can reverse these effects.

Not all stressors are equal: behavioral and endocrine evidence for development of contextual fear conditioning after a single session of footshocks but not of immobilization.

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Daviu, Núria; Delgado-Morales, Raúl; Nadal, Roser; Armario, Antonio

2012-01-01

Exposure of animals to footshocks (FS) in absence of any specific cue results in the development of fear to the compartment where shocks were given (contextual fear conditioning), and this is usually evaluated by time spent freezing. However, the extent to which contextual fear conditioning always develops when animals are exposed to other stressors is not known. In the present work we firstly demonstrated, using freezing, that exposure of adult rats to a single session of FS resulted in short-term and long-term contextual fear conditioning (freezing) that was paralleled by increased hypothalamic-pituitary-adrenal (HPA) activation. In contrast, using a similar design, no HPA or behavioral evidence for such conditioning was found after exposure to immobilization on boards (IMO), despite this stressor being of similar severity as FS on the basis of standard physiological measures of stress, including HPA activation. In a final experiment we directly compared the exposure to the two stressors in the same type of context and tested for the development of conditioning to the context and to a specific cue for IMO (the board). We observed the expected high levels of freezing and the conditioned HPA activation after FS, but not after IMO, regardless of the presence of the board during testing. Therefore, it can be concluded that development of fear conditioning to context or particular cues, as evaluated by either behavioral or endocrine measures, appears to be dependent on the nature of the aversive stimuli, likely to be related to biologically preparedness to establish specific associations.

Molecular Mechanisms of Stress-Induced Increases in Fear Memory Consolidation within the Amygdala.

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Aubry, Antonio V; Serrano, Peter A; Burghardt, Nesha S

2016-01-01

Stress can significantly impact brain function and increase the risk for developing various psychiatric disorders. Many of the brain regions that are implicated in psychiatric disorders and are vulnerable to the effects of stress are also involved in mediating emotional learning. Emotional learning has been a subject of intense investigation for the past 30 years, with the vast majority of studies focusing on the amygdala and its role in associative fear learning. However, the mechanisms by which stress affects the amygdala and amygdala-dependent fear memories remain unclear. Here we review the literature on the enhancing effects of acute and chronic stress on the acquisition and/or consolidation of a fear memory, as measured by auditory Pavlovian fear conditioning, and discuss potential mechanisms by which these changes occur in the amygdala. We hypothesize that stress-mediated activation of glucocorticoid receptors (GR) and norepinephrine release within the amygdala leads to the mobilization of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors to the synapse, which underlies stress-induced increases in fear memory. We discuss the implications of this hypothesis for evaluating the effects of stress on extinction and for developing treatments for anxiety disorders. Understanding how stress-induced changes in glucocorticoid and norepinephrine signaling might converge to affect emotional learning by increasing the trafficking of AMPA receptors and enhancing amygdala excitability is a promising area for future research.

Molecular Mechanisms of Stress-Induced Increases in Fear Memory Consolidation Within the Amygdala

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Antonio Aubry

2016-10-01

Full Text Available Stress can significantly impact brain function and increase the risk for developing various psychiatric disorders. Many of the brain regions that are implicated in psychiatric disorders and are vulnerable to the effects of stress are also involved in mediating emotional learning. Emotional learning has been a subject of intense investigation for the past 30 years, with the vast majority of studies focusing on the amygdala and its role in associative fear learning. However, the mechanisms by which stress affects the amygdala and amygdala-dependent fear memories remain unclear. Here we review the literature on the enhancing effects of acute and chronic stress on the acquisition and/or consolidation of a fear memory, as measured by auditory Pavlovian fear conditioning, and discuss potential mechanisms by which these changes occur in the amygdala. We hypothesize that stress-mediated activation of glucocorticoid receptors (GR and norepinephrine release within the amygdala leads to the mobilization of AMPA receptors to the synapse, which underlies stress-induced increases in fear memory. We discuss the implications of this hypothesis for evaluating the effects of stress on extinction and for developing treatments for anxiety disorders. Understanding how stress-induced changes in glucocorticoid and norepinephrine signaling might converge to affect emotional learning by increasing the trafficking of AMPA receptors and enhancing amygdala excitability is a promising area for future research.

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

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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…

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

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

2012-01-01

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

Long-term potentiation in the amygdala: a cellular mechanism of fear learning and memory.

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Sigurdsson, Torfi; Doyère, Valérie; Cain, Christopher K; LeDoux, Joseph E

2007-01-01

Much of the research on long-term potentiation (LTP) is motivated by the question of whether changes in synaptic strength similar to LTP underlie learning and memory. Here we discuss findings from studies on fear conditioning, a form of associative learning whose neural circuitry is relatively well understood, that may be particularly suited for addressing this question. We first review the evidence suggesting that fear conditioning is mediated by changes in synaptic strength at sensory inputs to the lateral nucleus of the amygdala. We then discuss several outstanding questions that will be important for future research on the role of synaptic plasticity in fear learning. The results gained from these studies may shed light not only on fear conditioning, but may also help unravel more general cellular mechanisms of learning and memory.

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

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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.

Intrusive images and voluntary memory for affective pictures: contextualization and dual-task interference.

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Krans, Julie; Langner, Oliver; Reinecke, Andrea; Pearson, David G

2013-12-01

The present study addressed the role of context information and dual-task interference during the encoding of negative pictures on intrusion development and voluntary recall. Healthy participants were shown negative pictures with or without context information. Pictures were either viewed alone or concurrently with a visuospatial or verbal task. Participants reported their intrusive images of the pictures in a diary. At follow-up, perceptual and contextual memory was tested. Participants in the context group reported more intrusive images and perceptual voluntary memory than participants in the no context group. No effects of the concurrent tasks were found on intrusive image frequency, but perceptual and contextual memory was affected according to the cognitive load of the task. The analogue method cannot be generalized to real-life trauma and the secondary tasks may differ in cognitive load. The findings challenge a dual memory model of PTSD but support an account in which retrieval strategy, rather than encoding processes, accounts for the experience of involuntary versus voluntary recall. Copyright © 2013 Elsevier Ltd. All rights reserved.

Memory formation for trace fear conditioning requires ubiquitin-proteasome mediated protein degradation in the prefrontal cortex.

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David S Reis

2013-10-01

Full Text Available The cellular mechanisms supporting plasticity during memory consolidation have been a subject of considerable interest. De novo protein and mRNA synthesis in several brain areas are critical, and more recently protein degradation, mediated by the ubiquitin-proteasome system (UPS, has been shown to be important. Previous work clearly establishes a relationship between protein synthesis and protein degradation in the amygdala, but it is unclear whether cortical mechanisms of memory consolidation are similar to those in the amygdala. Recent work demonstrating a critical role for prefrontal cortex (PFC in the acquisition and consolidation of fear memory allows us to address this question. Here we use a PFC-dependent fear conditioning protocol to determine whether UPS mediated protein degradation is necessary for memory consolidation in PFC. Groups of rats were trained with auditory delay or trace fear conditioning and sacrificed 60 min after training. PFC tissue was then analyzed to quantify the amount of polyubiquinated protein. Other animals were trained with similar procedures but were infused with either a proteasome inhibitor (clasto-lactacystin β-lactone or a translation inhibitor (anisomycin in the PFC immediately after training. Our results show increased UPS-mediated protein degradation in the PFC following trace but not delay fear conditioning. Additionally, post-training proteasome or translation inhibition significantly impaired trace but not delay fear memory when tested the next day. Our results further support the idea that the PFC is critical for trace but not delay fear conditioning highlight the role of UPS-mediated degradation as critical for synaptic plasticity.

Methylphenidate Enhances Extinction of Contextual Fear

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Abraham, Antony D.; Cunningham, Christopher L.; Lattal, K. Matthew

2012-01-01

Methylphenidate (MPH, Ritalin) is a norepinephrine and dopamine transporter blocker that is widely used in humans for treatment of attention deficit disorder and narcolepsy. Although there is some evidence that targeted microinjections of MPH may enhance fear acquisition, little is known about the effect of MPH on fear extinction. Here, we show…

Activity dependent protein degradation is critical for the formation and stability of fear memory in the amygdala.

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Timothy J Jarome

Full Text Available Protein degradation through the ubiquitin-proteasome system [UPS] plays a critical role in some forms of synaptic plasticity. However, its role in memory formation in the amygdala, a site critical for the formation of fear memories, currently remains unknown. Here we provide the first evidence that protein degradation through the UPS is critically engaged at amygdala synapses during memory formation and retrieval. Fear conditioning results in NMDA-dependent increases in degradation-specific polyubiquitination in the amygdala, targeting proteins involved in translational control and synaptic structure and blocking the degradation of these proteins significantly impairs long-term memory. Furthermore, retrieval of fear memory results in a second wave of NMDA-dependent polyubiquitination that targets proteins involved in translational silencing and synaptic structure and is critical for memory updating following recall. These results indicate that UPS-mediated protein degradation is a major regulator of synaptic plasticity necessary for the formation and stability of long-term memories at amygdala synapses.

The role of β-arrestin-2 on Fear/anxious-related memory in a rat model of Post-traumatic stress disorder.

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Ding, Jinlan; Han, Fang; Wen, Lili; Xiao, Bing; Shi, Yuxiu

2017-04-15

Post-traumatic stress disorder (PTSD) can be categorised as a disorder of dysregulated fear processing. In the formation and development of PTSD, whether fear/anxious-related memory is regulated by β-arrestin-2, and happened along the signal transduction pathways remains unknown. We used single prolonged stress (SPS) as the animal model of PTSD. Next, elevated plus maze tests (EPM) was performed to examine fear/anxious memory- related behaviors. Then, we detected β-arrestin-2, PDE-4, and signal transduction pathways with immunofluorescence, co-immunoprecipitation, immunohistochemistry, Elisa, western blot, RT-PCR, and real-time PCR. Our data indicated that SPS caused fear/anxious memory-related behaviors enhancement. The low expression of β-arrestin-2, PDE-4 and their complex on SPS 7d, and high expression of signal transduction pathways on SPS7d in basolateral amygdala (BLA). That indicating that β-arrestin-2 is critical for the formation of abnormal fear/anxious memory in PTSD; and fear/anxious memory occured through signal transduction pathways. Finally, these results suggest that β-arrestin-2, PDE-4 and signal transduction pathways may be by influencing the fear/anxious memory thereby involved in the formation and development of PTSD. Copyright © 2017. Published by Elsevier B.V.

Evidence for a developmental role for TLR4 in learning and memory.

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Eitan Okun

Full Text Available Toll-like receptors (TLRs play essential roles in innate immunity and increasing evidence indicates that these receptors are expressed in neurons, astrocytes and microglia in the brain where they mediate responses to infection, stress and injury. Very little is known about the roles of TLRs in cognition. To test the hypothesis that TLR4 has a role in hippocampus-dependent spatial learning and memory, we used mice deficient for TLR4 and mice receiving chronic TLR4 antagonist infusion to the lateral ventricles in the brain. We found that developmental TLR4 deficiency enhances spatial reference memory acquisition and memory retention, impairs contextual fear-learning and enhances motor functions, traits that were correlated with CREB up-regulation in the hippocampus. TLR4 antagonist infusion into the cerebral ventricles of adult mice did not affect cognitive behavior, but instead affected anxiety responses. Our findings indicate a developmental role for TLR4 in shaping spatial reference memory, and fear learning and memory. Moreover, we show that central TLR4 inhibition using a TLR4 antagonist has no discernible physiological role in regulating spatial and contextual hippocampus-dependent cognitive behavior.

Systemic inhibition of mTOR kinase via rapamycin disrupts consolidation and reconsolidation of auditory fear memory.

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Mac Callum, Phillip E; Hebert, Mark; Adamec, Robert E; Blundell, Jacqueline

2014-07-01

The mammalian target of rapamycin (mTOR) kinase is a critical regulator of mRNA translation and is known to be involved in various long lasting forms of synaptic and behavioural plasticity. However, information concerning the temporal pattern of mTOR activation and susceptibility to pharmacological intervention during both consolidation and reconsolidation of long-term memory (LTM) remains scant. Male C57BL/6 mice were injected systemically with rapamycin at various time points following conditioning or retrieval in an auditory fear conditioning paradigm, and compared to vehicle (and/or anisomycin) controls for subsequent memory recall. Systemic blockade of mTOR with rapamycin immediately or 12h after training or reactivation impairs both consolidation and reconsolidation of an auditory fear memory. Further behavioural analysis revealed that the enduring effects of rapamycin on reconsolidation are dependent upon reactivation of the memory trace. Rapamycin, however, has no effect on short-term memory or the ability to retrieve an established fear memory. Collectively, our data suggest that biphasic mTOR signalling is essential for both consolidation and reconsolidation-like activities that contribute to the formation, re-stabilization, and persistence of long term auditory-fear memories, while not influencing other aspects of the memory trace. These findings also provide evidence for a cogent treatment model for reducing the emotional strength of established, traumatic memories analogous to those observed in acquired anxiety disorders such as posttraumatic stress disorder (PTSD) and specific phobias, through pharmacologic blockade of mTOR using systemic rapamycin following reactivation. Copyright © 2013 Elsevier Inc. All rights reserved.

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

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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

EphrinA4 mimetic peptide targeted to EphA binding site impairs the formation of long-term fear memory in lateral amygdala.

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Dines, M; Lamprecht, R

2014-09-30

Fear conditioning leads to long-term fear memory formation and is a model for studying fear-related psychopathologies conditions such as phobias and posttraumatic stress disorder. Long-term fear memory formation is believed to involve alterations of synaptic efficacy mediated by changes in synaptic transmission and morphology in lateral amygdala (LA). EphrinA4 and its cognate Eph receptors are intimately involved in regulating neuronal morphogenesis, synaptic transmission and plasticity. To assess possible roles of ephrinA4 in fear memory formation we designed and used a specific inhibitory ephrinA4 mimetic peptide (pep-ephrinA4) targeted to EphA binding site. We show that this peptide, composed of the ephrinA4 binding domain, interacts with EphA4 and inhibits ephrinA4-induced phosphorylation of EphA4. Microinjection of the pep-ephrinA4 into rat LA 30 min before training impaired long- but not short-term fear conditioning memory. Microinjection of a control peptide derived from a nonbinding E helix site of ephrinA4, that does not interact with EphA, had no effect on fear memory formation. Microinjection of pep-ephrinA4 into areas adjacent to the amygdala had no effect on fear memory. Acute systemic administration of pep-ephrinA4 1 h after training also impaired long-term fear conditioning memory formation. These results demonstrate that ephrinA4 binding sites in LA are essential for long-term fear memory formation. Moreover, our research shows that ephrinA4 binding sites may serve as a target for pharmacological treatment of fear and anxiety disorders.

Sensory-specific associations stored in the lateral amygdala allow for selective alteration of fear memories.

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Díaz-Mataix, Lorenzo; Debiec, Jacek; LeDoux, Joseph E; Doyère, Valérie

2011-06-29

Consolidated long-term fear memories become labile and can be disrupted after being reactivated by the presentation of the unconditioned stimulus (US). Whether this is due to an alteration of the conditioned stimulus (CS) representation in the lateral amygdala (LA) is not known. Here, we show in rats that fear memory reactivation through presentation of the aversive US, like CS presentation, triggers a process which, when disrupted, results in a selective depotentiation of CS-evoked neural responses in the LA in correlation with a selective suppression of CS-elicited fear memory. Thus, an aversive US triggers the reconsolidation of its associated predictor representation in LA. This new finding suggests that sensory-specific associations are stored in the lateral amygdala, allowing for their selective alteration by either element of the association.

Cronobacter sakazakii infection alters serotonin transporter and improved fear memory retention in the rats

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Bhagavathi Sundaram eSivamaruthi

2015-09-01

Full Text Available It is well established that Cronobacter sakazakii infection cause septicemia, necrotizingenterocolitis (NEC and meningitis. In the present study, we tested whether the C. sakazakii infection alter the learning and memory through serotonin transporter (SERT. To investigate the possible effect on SERT, on postnatal day (PND-15, wistar rat pups were administered with single dose of C. sakazakii culture (Infected group: IF; 107 CFU or 100μL of Luria-Bertani broth (LB; Medium Control: MC or without any treatment (Naïve control: NC. All the individuals were subjected to passive avoidance test on PND-30 to test their fear memory. We show that single dose of C. sakazakii infection improved fear memory retention. Subsequently, we show that C. sakazakii infection induced the activation of Toll-like receptor-3 (TLR-3 and heat-shock proteins-90 (Hsp-90. On the other hand, level of serotonin (5-HT and SERT protein was down-regulated. Furthermore, we show that C. sakazakii infection up-regulate microRNA (miR-16 expression. The observed results highlight that C. sakazakii infections was responsible for improved fear memory retention and may have reduced the level of SERT protein, which is possibly associated with the interaction of up-regulated Hsp-90 with SERT protein or miR-16 with SERT mRNA. Taken together, observed results suggest that C. sakazakkii infection alter the fear memory possibly through SERT. Hence, this model may be effective to test the C. sakazakii infection induced changes in synaptic plasticity through SERT and effect of other pharmacological agents against pathogen induced memory disorder.

Epigenetic alterations are critical for fear memory consolidation and synaptic plasticity in the lateral amygdala.

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Melissa S Monsey

Full Text Available Epigenetic mechanisms, including histone acetylation and DNA methylation, have been widely implicated in hippocampal-dependent learning paradigms. Here, we have examined the role of epigenetic alterations in amygdala-dependent auditory Pavlovian fear conditioning and associated synaptic plasticity in the lateral nucleus of the amygdala (LA in the rat. Using Western blotting, we first show that auditory fear conditioning is associated with an increase in histone H3 acetylation and DNMT3A expression in the LA, and that training-related alterations in histone acetylation and DNMT3A expression in the LA are downstream of ERK/MAPK signaling. Next, we show that intra-LA infusion of the histone deacetylase (HDAC inhibitor TSA increases H3 acetylation and enhances fear memory consolidation; that is, long-term memory (LTM is enhanced, while short-term memory (STM is unaffected. Conversely, intra-LA infusion of the DNA methyltransferase (DNMT inhibitor 5-AZA impairs fear memory consolidation. Further, intra-LA infusion of 5-AZA was observed to impair training-related increases in H3 acetylation, and pre-treatment with TSA was observed to rescue the memory consolidation deficit induced by 5-AZA. In our final series of experiments, we show that bath application of either 5-AZA or TSA to amygdala slices results in significant impairment or enhancement, respectively, of long-term potentiation (LTP at both thalamic and cortical inputs to the LA. Further, the deficit in LTP following treatment with 5-AZA was observed to be rescued at both inputs by co-application of TSA. Collectively, these findings provide strong support that histone acetylation and DNA methylation work in concert to regulate memory consolidation of auditory fear conditioning and associated synaptic plasticity in the LA.

Pre-adolescent and adolescent mice are less sensitive to the effects of acute nicotine on extinction and spontaneous recovery.

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Kutlu, Munir Gunes; Zeid, Dana; Tumolo, Jessica M; Gould, Thomas J

2018-04-01

Adolescence is a period of high risk for the initiation of nicotine product usage and exposure to traumatic events. In parallel, nicotine exposure has been found to age-dependently modulate acquisition of contextual fear memories; however, it is unknown if adolescent nicotine exposure alters extinction of fear related memories. Age-related differences in sensitivity to the effects of nicotine on fear extinction could increase or decrease susceptibility to anxiety disorders. In this study, we examined the effects of acute nicotine administration on extinction and spontaneous recovery of contextual fear memories in pre-adolescent (PND 23), late adolescent (PND 38), and adult (PND 53) C57B6/J mice. Mice were first trained in a background contextual fear conditioning paradigm and given an intraperitoneal injection of one of four doses of nicotine (0.045, 0.09, 0.18, or 0.36mg/kg, freebase) prior to subsequent extinction or spontaneous recovery sessions. Results indicated that all acute nicotine doses impaired extinction of contextual fear in adult mice. Late adolescent mice exhibited impaired extinction of contextual fear only following higher doses of acute nicotine, and extinction of contextual fear was unaffected by acute nicotine exposure in pre-adolescent mice. Finally, acute nicotine exposure enhanced spontaneous recovery of fear memory, but only in adult mice. Overall, our results suggest that younger mice were less sensitive to nicotine's impairing effects on extinction of contextual fear and to nicotine's enhancing effects on spontaneous recovery of contextual fear memory. Copyright © 2017 Elsevier Inc. All rights reserved.

Modulation of Long-term Potentiation of Cortico-amygdala Synaptic Responses and Auditory Fear Memory by Dietary Polyunsaturated Fatty Acid

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Daisuke Yamada

2016-08-01

Full Text Available Converging evidence suggests that an imbalance of ω3 to ω6 polyunsaturated fatty acid (PUFA in the brain is involved in mental illnesses such as anxiety disorders. However, the underlying mechanism is unknown. We previously reported that the dietary ratio of ω3 to ω6 PUFA alters this ratio in the brain, and influences contextual fear memory. In addition to behavioral change, enhancement of cannabinoid CB1 receptor-mediated short-term synaptic plasticity and facilitation of the agonist sensitivity of CB1 receptors have been observed in excitatory synaptic responses in the basolateral nucleus of the amygdala. However, it is not known whether long-term synaptic plasticity in the amygdala is influenced by the dietary ratio of ω3 to ω6 PUFA. In the present study, we examined long-term potentiation (LTP of optogenetically–evoked excitatory synaptic responses in synapses between the terminal of the projection from the auditory cortex and the pyramidal cells in the lateral nucleus of the amygdala. We found that LTP in this pathway was attenuated in mice fed a diet with a high ω3 to ω6 PUFA ratio (0.97, compared with mice fed a diet with a low ω3 to ω6 PUFA ratio (0.14. Furthermore, mice in the former condition showed reduced fear responses in an auditory fear conditioning test, compared with mice in the latter condition. In both electrophysiological and behavioral experiments, the effect of a diet with a high ω3 to ω6 PUFA ratio was completely blocked by treatment with a CB1 receptor antagonist. Furthermore, a significant reduction was observed in cholesterol content, but not in the level of an endogenous CB1 receptor agonist, 2-arachidonoylglycerol, in brain samples containing the amygdala. These results suggest that the balance of ω3 to ω6 PUFA has an impact on fear memory and cortico-amygdala synaptic plasticity, both in a CB1 receptor–dependent manner.

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

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

2016-07-01

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

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

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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.

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

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Jung-Won Shin

2017-05-01

Full Text Available 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.

MDMA-assisted psychotherapy for PTSD: Are memory reconsolidation and fear extinction underlying mechanisms?

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Feduccia, Allison A; Mithoefer, Michael C

2018-06-08

MDMA-assisted psychotherapy for treatment of PTSD has recently progressed to Phase 3 clinical trials and received Breakthrough Therapy designation by the FDA. MDMA used as an adjunct during psychotherapy sessions has demonstrated effectiveness and acceptable safety in reducing PTSD symptoms in Phase 2 trials, with durable remission of PTSD diagnosis in 68% of participants. The underlying psychological and neurological mechanisms for the robust effects in mitigating PTSD are being investigated in animal models and in studies of healthy volunteers. This review explores the potential role of memory reconsolidation and fear extinction during MDMA-assisted psychotherapy. MDMA enhances release of monoamines (serotonin, norepinephrine, dopamine), hormones (oxytocin, cortisol), and other downstream signaling molecules (BDNF) to dynamically modulate emotional memory circuits. By reducing activation in brain regions implicated in the expression of fear- and anxiety-related behaviors, namely the amygdala and insula, and increasing connectivity between the amygdala and hippocampus, MDMA may allow for reprocessing of traumatic memories and emotional engagement with therapeutic processes. Based on the pharmacology of MDMA and the available translational literature of memory reconsolidation, fear learning, and PTSD, this review suggests a neurobiological rationale to explain, at least in part, the large effect sizes demonstrated for MDMA in treating PTSD. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Extinction Partially Reverts Structural Changes Associated with Remote Fear Memory

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Vetere, Gisella; Restivo, Leonardo; Novembre, Giovanni; Aceti, Massimiliano; Lumaca, Massimo; Ammassari-Teule, Martine

2011-01-01

Structural synaptic changes occur in medial prefrontal cortex circuits during remote memory formation. Whether extinction reverts or further reshapes these circuits is, however, unknown. Here we show that the number and the size of spines were enhanced in anterior cingulate (aCC) and infralimbic (ILC) cortices 36 d following contextual fear…

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

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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.

Proteolysis of proBDNF is a key regulator in the formation of memory.

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Philip Barnes

2008-09-01

Full Text Available It is essential to understand the molecular processes underlying long-term memory to provide therapeutic targets of aberrant memory that produce pathological behaviour in humans. Under conditions of recall, fully-consolidated memories can undergo reconsolidation or extinction. These retrieval-mediated memory processes may rely on distinct molecular processes. The cellular mechanisms initiating the signature molecular events are not known. Using infusions of protein synthesis inhibitors, antisense oligonucleotide targeting brain-derived neurotrophic factor (BDNF mRNA or tPA-STOP (an inhibitor of the proteolysis of BDNF protein into the hippocampus of the awake rat, we show that acquisition and extinction of contextual fear memory depended on the increased and decreased proteolysis of proBDNF (precursor BDNF in the hippocampus, respectively. Conditions of retrieval that are known to initiate the reconsolidation of contextual fear memory, a BDNF-independent memory process, were not correlated with altered proBDNF cleavage. Thus, the processing of BDNF was associated with the acquisition of new information and the updating of information about a salient stimulus. Furthermore, the differential requirement for the processing of proBDNF by tPA in distinct memory processes suggest that the molecular events actively engaged to support the storage and/or the successful retrieval of memory depends on the integration of ongoing experience with past learning.

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

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

2014-01-01

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