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Conditioning, and Fear Reconsolidation Contextual Blockade Fear Extinction,

dartveydr
06.11.2018

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  • Conditioning, and Fear Reconsolidation Contextual Blockade Fear Extinction,
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  • Introduction
  • Keywords: fear memory, reconsolidation blockade, cannabidiol, to the conditioned context favors reconsolidation and preserves the fear response, impair both reconsolidation and extinction of a contextual fear memory in. Keywords: fear conditioning, Arc catFISH, extinction, reconsolidation, retrieval + In reconsolidation blockade, retrieval of a consolidated memory .. Role of conditioned contextual stimuli in reinstatement of extinguished fear. Finally, blocking ERK1/2 activity prior to CFC retrieval prevented the deficit of Contextual fear conditioning (CFC) is a well-established paradigm to .. memory and therefore does not reflect spontaneous extinction of the.

    Conditioning, and Fear Reconsolidation Contextual Blockade Fear Extinction,

    Similarly, decreasing NE transmission with clonidine produced dose-dependent reductions in fear expression whereas elevating NE piperoxane or yohimbine increased fear expression as measured by potentiated startle in the presence of a formerly trained CS Davis et al.

    This finding was replicated with intra-LA infusions of clonidine Schulz et al. Moreover, slice recordings have shown that while NE did not disrupt glutamatergic BLA signaling, inhibitory neurotransmission was decreased in the BLA following recall of a cued fear memory. Interestingly, a handful of reports suggest NE manipulations had no effect on cued fear expression Murchison et al.

    Importantly, the training protocols used in these studies may help explain the observed effects or lack thereof. Weaker conditioning protocols are apparently less likely to recruit LC-NE given that they appear insensitive to NE manipulations. Similar to the effects reported on the acquisition of context fear, NE manipulations impact context fear expression.

    Moreover, pharmacologically driven increases in NE acute treatment with reobxetine, a norepinephrine reuptake inhibitor enhanced context fear expression Inoue et al. It would be interesting to know if DBH KO mice show similar deficits using a multi-trial conditioning protocol which would more likely to result in stress-induced LC-NE signaling. After initial training occurs short-term memory undergoes consolidation processes to form a long-term memory.

    Post-training manipulations have been used to examined the involvement of NE in both cued and context fear memory consolidation.

    An interesting dichotomy emerges here, where it seems that NE is not necessarily needed for the consolidation of cued fear learning, but is for context.

    While NE particularly in the BLA is critical for the formation of cued fear memories it may not be essential for the consolidation of such memories.

    Mice lacking NE showed no deficits in cued fear memory consolidation using single-trial conditioning procedures Murchison et al. Further supporting this idea, post training systemic administration of either epinephrine or amphetamine had no effects on consolidation Lee et al.

    In line with this, intra-BLA atenolol only impaired corticosterone enhanced cued fear memories, but had no effect in rats that just received auditory fear conditioning and post-training BLA infusions of atenolol Roozendaal et al. Interestingly, mice heterozygous for a mutation in the gene encoding tyrosine hydroxylase a precursor enzyme in the biosynthetic pathway for NE show impaired cued fear memory and this could be restored by drug-induced NE stimulation after training Kobayashi et al.

    However, these mutant mice only show a modest reduction in NE accumulation and release; they may also have differences in the distribution and density of AR expression as a compensatory mechanism complicating the interpretation of the results. The existing literature primarily suggests that NE manipulations have minimal consequences for the consolidation of cued fear conditioning memories. As noted above, an intriguing difference emerges when comparing the role of NE in cued vs. This may relate to the extensive and long-lasting effects of NE manipulations on hippocampal LTP, which would favor the strengthening of contextual memories.

    Increasing NE with yohimbine administration has been shown to enhance context fear memory consolidation. In addition, dampening NE-transmission with clonidine reduced contextual fear memory consolidation Gazarini et al. The involvement of NE in the consolidation of contextual, but not cued, fear conditioning suggests that NE is operating on the consolidation of context representations, rather than context-US or CS-US associations.

    Moreover, signaled and unsignaled shocks produced marked differences in neuronal activity in the mPFC Fitzgerald et al. When a memory is reactivated it enters a labile state and undergoes protein synthesis dependent reconsolidation Nader et al. This provides a window of opportunity to disrupt long-term memories. We and others have previously reviewed the effects of NE mainly examining the effects of propranolol on reconsolidation and will therefore only briefly touch on this area in this review Steckler and Risbrough, ; Giustino et al.

    Disrupting the reconsolidation of a fear memory can potentially have far reaching clinical implications for trauma- and stressor-related disorders. Many labs have provided compelling evidence that propranolol delivered after brief memory reactivation disrupts the reconsolidation of both cued and context fear memories in rodents Przybyslawski et al. In addition, systemic clonidine has also mirrored these effects Gamache et al.

    An important consideration regarding these findings is that reconsolidation effects may be subject to certain boundary conditions such as the age and strength of a memory, thus making interference with fear memories more complicated Duvarci et al. Behavioral and pharmacological approaches aimed at improving extinction learning in rodents have received much attention due to the clinical importance of extinction based cognitive behavioral therapies Myers and Davis, ; Quirk and Mueller, ; Holmes and Quirk, ; Mueller and Cahill, ; Vervliet et al.

    It is generally thought that stress impairs extinction learning and this may relate to alterations in NE transmission Mason and Fibiger, ; Mason et al. While NE primarily strengthens the acquisition of fear learning, it has bidirectional effects on extinction learning that may depend on the extant level of noradrenergic arousal. For example, reducing or depleting NE levels impairs delayed extinction occurring at least 24 h following fear conditioning; Mason and Fibiger, ; Tsaltas et al.

    Indeed increasing NE with yohimbine can facilitate delayed extinction learning Cain et al. Our lab and others have demonstrated that the timing of extinction training relative to conditioning is an important factor regulating the long-term success of extinction in rodent models and humans Maren and Chang, ; Chang et al.

    These effects may be due to high levels of stress and NE soon after conditioning that interferes with new learning. In line with this idea, we have shown that systemic or intra-BLA propranolol enables learning where it normally fails Fitzgerald et al.

    In addition, systemic propranolol administered prior to delayed extinction, when stress levels are presumably lower, impaired learning when tested in a drug free state the following day Fitzgerald et al. These data are supported by the idea that stress generally impairs extinction learning which may be due to alterations in NE signaling Lin et al. Importantly, the fact that reducing NE signaling prior to delayed extinction has impairing effects suggests that CS-evoked NE actually facilitates learning under lower levels of arousal.

    In the case of immediate extinction a state of higher arousal at the onset of learning , it is likely that propranolol is reducing NE signaling to more optimal levels, thus facilitating learning. Our data and others suggest that heightened NE in the BLA strengthens fear memories perhaps at the expense of forming a new extinction memory. Overall, NE can bidirectionally modulate extinction learning and this seems to depend on the prevailing level of stress at the onset of learning.

    Low levels of NE can enhance prefrontal function which may act to blunt downstream signaling in the BLA to promote extinction learning Figure 1. These findings have important clinical implications and warrant careful consideration when interpreting effects of NE-altering drugs and their effects on the treatment of trauma- and stressor-related disorders discussed further below. As with context fear, the extinction of contextual fear may rely heavily on hippocampal function.

    It seems that NE is critical to context fear extinction and its consolidation. Methylphenidate a NET and DAT blocker delivered either before or after context extinction enhanced learning in a dose-dependent manner Abraham et al.

    These data support the notion that NE is a critical factor for the extinction of contextual fear. It is likely that these effects are at least in part mediated by HPC plasticity, which can be regulated by NE transmission. Noradrenergic modulating drugs are used to treat an array of neuropsychiatric disorders, though the only two FDA approved drugs for PTSD are selective serotonin reuptake inhibitors Steckler and Risbrough, ; Tawa and Murphy, ; Fitzgerald et al.

    Drugs that either elevate or reduce NE transmission have been studied and used off-label for the treatment of PTSD and its symptoms with varying success Southwick et al. It has recently been shown that threat is associated with increased LC activity in healthy human volunteers and this acts to strengthen prioritized memory representations Clewett et al. This suggests that heightened states of arousal may promote fear memory formation and maintenance. While the LC-NE system plays an important role in learning and memory, including extinction learning Sterpenich et al.

    Indeed, yohimbine has been used in healthy human subjects to enhance fear learning and it also has been shown to hinder extinction learning van Stegeren et al.

    Despite this, there has been some interest in yohimbine as a pharmaceutical agent to augment the treatment of PTSD, which has yielded mixed results Powers et al. While the evidence for the efficacy of either drug is somewhat limited, these drugs may have some use in the treatment of PTSD and related disorders Arnsten et al.

    Further research is warranted on the efficacy of these compounds. Results with noradrenergic receptor antagonists, such as propranolol, have yielded mixed results in both healthy human volunteers and individuals with PTSD. Propranolol is already used safely in humans for other conditions and has been shown to reduce long-term memory for an emotionally arousing story Cahill et al.

    However, some have suggested that propranolol treatment soon after trauma has no effects, although this was done in the absence of any extinction based therapy Stein et al. In addition, one report found that propranolol has no effects on the acquisition or retention of extinction learning Orr et al. Others have shown that propranolol impairs extinction learning in healthy subjects Bos et al. At first glance, these conflicting reports would imply that researchers and clinicians alike should look elsewhere for a pharmaceutical adjunct for exposure therapy.

    However, we have argued that the timing of propranolol administration coupled with behavioral therapy is an often overlooked, and highly important, factor regulating the long-term outcome of extinction learning Giustino et al. This may be due to differences in the prevailing level of noradrenergic arousal at the time of administration.

    There is some empirical evidence to support this idea in humans though more research coupling propranolol and extinction soon after trauma is needed Pitman et al. One area that has shown promise centers on blocking the reconsolidation of a fearful memory.

    Several studies in both healthy human volunteers and individuals with PTSD have suggested that propranolol can be used to disrupt reconsolidation Brunet et al. As discussed previously, effects on reconsolidation may be subject to certain boundary conditions and memories do not necessarily even undergo reconsolidation unless new learning occurs Sevenster et al. Moreover, many of these reconsolidation effects have not been replicated which further complicates approaches focusing on reconsolidation blockade as an effective treatment strategy for PTSD Tollenaar et al.

    It seems unlikely that acute administration of propranolol, or any drug, would effectively eradicate a long-standing fear memory, such as those observed in individuals suffering from PTSD. However, this does not preclude the idea that propranolol may reduce fear under some circumstances and thus has utility moving forward Giustino et al. Prazosin has shown promise in ameliorating nightmares and sleep disturbances associated with PTSD Raskind et al.

    However, a recent clinical trial demonstrated that prazosin did not ameliorate sleep-related disturbances in military veterans with PTSD Raskind et al. Less is known about how prazosin affects other aspects of PTSD symptomatology.

    A recent study in healthy human subjects suggests that prazosin delivered prior to fear conditioning enhanced future discrimination between fearful and safe stimuli during extinction Homan et al. Further work is needed to examine the effects of prazosin as well as other NE-altering drugs in both healthy human volunteers and those with PTSD. Overall, the LC-NE system critically regulates most aspects of emotional learning and memory in rodent models, healthy human subjects, and individuals suffering from trauma- and stressor-related disorders.

    Recent advances in technology for basic science research will be crucial to further our understanding of how stress and the LC-NE system regulate these effects in rodent models.

    Target-specific approaches have led to a new appreciation of LC function and while the precise effects of distinct LC subpopulations are not well characterized several recent articles have pinpointed unique contributions to learning and memory as well as anxiety in rodents Schwarz and Luo, ; Schwarz et al. An important area of research moving forward may center around individualized medicine based on differences in the LC-NE system and stress responsivity. Human imaging protocols have improved to better isolate the LC Keren et al.

    An improved appreciation of how the LC-NE system contributes to aversive learning and memory and its subsequent extinction may help improve empirically driven treatment options.

    We propose that the LC-NE system dynamically regulates the acquisition and extinction of both cued and contextual fear and these effects are dependent upon the prevailing level of stress and NE at the onset of learning Figure 1.

    Regarding contextual fear conditioning, we suggest that the LC-NE system acts to regulate hippocampal LTP, which is involved in the acquisition, consolidation, and extinction of contextual representations as opposed to context-US associations.

    In terms of cued fear conditioning, low levels of NE release prior to delayed extinction would enhance extinction learning by promoting mPFC function, which would, in turn, inhibit BLA output to enable extinction learning. In contrast, high levels of NE released under stress such as that accompanying footshock promotes fear expression while inhibiting new learning as is observed with immediate extinction procedures by strengthening BLA function and simultaneously impairing mPFC function via target-specific LC subpopulations.

    The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Characterization of hippocampal norepinephrine release as measured by microdialysis perfusion: Methylphenidate enhances extinction of contextual fear. Administration of corticosterone after memory reactivation disrupts subsequent retrieval of a contextual conditioned fear memory: Evidence for a regional specificity in the density and distribution of noradrenergic varicosities in rat cortex.

    Stress signalling pathways that impair prefrontal cortex structure and function. Stress weakens prefrontal networks: Selective prefrontal cortical projections to the region of the locus coeruleus and raphe nuclei in the rhesus monkey.

    Neurobiology of executive functions: The effects of stress exposure on prefrontal cortex: Activity of norepinephrine-containing locus coeruleus neurons in behaving rats anticipates fluctuations in the sleep-waking cycle. PubMed Abstract Google Scholar. Norepinephrine-containing locus coeruleus neurons in behaving rats exhibit pronounced responses to non-noxious environmental stimuli. An integrative theory of locus coeruleus-norepinephrine function: The brain nucleus locus coeruleus: Role of locus coeruleus in attention and behavioral flexibility.

    Numerous GABAergic afferents to locus ceruleus in the pericerulear dendritic zone: Enhancement of extinction memory consolidation: The locus coeruleus-noradrenergic system: In vivo MRI assessment of the human locus coeruleus along its rostrocaudal extent in young and older adults. Protein kinase C overactivity impairs prefrontal cortical regulation of working memory.

    Fear conditioning in posttraumatic stress disorder: Reduction of long-term potentiation in the dentate gyrus of the rat following selective depletion of monoamines. The effects of noradrenergic blockade on extinction in humans. Noradrenergic blockade of memory reconsolidation: Reward expectation, orientation of attention and locus coeruleus-medial frontal cortex interplay during learning.

    Contextual and temporal modulation of extinction: Noradrenergic mechanisms in stress and anxiety: Resolving the brainstem contributions to attentional analgesia.

    Effect of post-retrieval propranolol on psychophysiologic responding during subsequent script-driven traumatic imagery in post-traumatic stress disorder. Trauma reactivation under the influence of propranolol decreases posttraumatic stress symptoms and disorder: Trauma reactivation plus propranolol is associated with durably low physiological responding during subsequent script-driven traumatic imagery.

    Noradrenergic modulation of basolateral amygdala neuronal activity: Adrenergic transmission facilitates extinction of conditional fear in mice. Afferent projections to the rat locus coeruleus as determined by a retrograde tracing technique. Delayed noradrenergic activation in the dorsal hippocampus promotes the long-term persistence of extinguished fear. Heterogeneous organization of the locus coeruleus projections to prefrontal and motor cortices.

    U S A , — Identification and distribution of projections from monoaminergic and cholinergic nuclei to functionally differentiated subregions of prefrontal cortex. Evidence for broad versus segregated projections from cholinergic and noradrenergic nuclei to functionally and anatomically discrete subregions of prefrontal cortex. Single-unit activity in the medial prefrontal cortex during immediate and delayed extinction of fear in rats. Intracerebroventricular norepinephrine potentiation of the perforant path-evoked potential in dentate gyrus of anesthetized and awake rats: Locus coeruleus activation by foot shock or electrical stimulation inhibits amygdala neurons.

    Neural circuits involved in the renewal of extinguished fear. Encoding of conditioned fear in central amygdala inhibitory circuits. Norepinephrine enhances a discrete form of long-term depression during fear memory storage. Locus coeruleus activity strengthens prioritized memories under arousal. Propranolol antagonizes the enhanced conditioned fear produced by corticotropin releasing factor. Dissociable effects of lesions to the dorsal or ventral noradrenergic bundle on the acquisition, performance, and extinction of aversive conditioning.

    An open-label study of guanfacine extended release for traumatic stress related symptoms in children and adolescents. Norepinephrine induces pathway-specific long-lasting potentiation and depression in the hippocampal dentate gyrus.

    U S A 86, — Localization of monoamines in the lower brain stem. Noradrenergic agonists and antagonists: A placebo-controlled trial of guanfacine for the treatment of posttraumatic stress disorder in veterans. Association of posttraumatic nightmares and psychopathology in a military sample.

    Noradrenergic enhancement of reconsolidation in the amygdala impairs extinction of conditioned fear in rats—a possible mechanism for the persistence of traumatic memories in PTSD. Disruption of reconsolidation but not consolidation of auditory fear conditioning by noradrenergic blockade in the amygdala. Neuronal circuits for fear expression and recovery: Noradrenergic axon terminals in the cerebral cortex of rat.

    Radioautographic visualization after topical application of dl-[3H]norepinephrine. Noradrenergic axon terminals in the cerebral cortex of rat: Treatment of post-traumatic stress disorder nightmares at a veterans affairs medical center.

    Characterization of the amplificatory effect of norepinephrine in the acquisition of Pavlovian threat associations.

    Stress promotes generalization of older but not recent threat memories. Extinction is not a sufficient condition to prevent fear memories from undergoing reconsolidation in the basolateral amygdala. De novo mRNA synthesis is required for both consolidation and reconsolidation of fear memories in the amygdala. A competitive inhibitory circuit for selection of active and passive fear responses.

    Catecholamine innervation of the basal forebrain. Amygdala, suprarhinal cortex and entorhinal cortex. Role of norepinephrine in mediating stress hormone regulation of long-term memory storage: Increased dopamine and norepinephrine release in medial prefrontal cortex induced by acute and chronic stress: Noradrenergic blockade stabilizes prefrontal activity and enables fear extinction under stress. U S A , E—E Can fear extinction be enhanced? A review of pharmacological and behavioral findings.

    Behavioral stress impairs long-term potentiation in rodent hippocampus. Consolidation of CS and US representations in associative fear conditioning. Norepinephrine release in the amygdala in response to footshock stimulation. Preclinical evaluation of reconsolidation blockade by clonidine as a potential novel treatment for posttraumatic stress disorder. PTSD-like memory generated through enhanced noradrenergic activity is mitigated by a dual step pharmacological intervention targeting its reconsolidation.

    Altered locus coeruleus-norepinephrine function following single prolonged stress. Thus, MEK inhibition during recall protected the mice against the deleterious effect of Zif gene knockdown on memory reconsolidation. For example, ERK can modulate dopamine synthesis [59] and the Kv4.

    In the past years, a great deal of effort has been placed on determining whether or not reconsolidation is a repetition of consolidation. This considerable effort unveiled unexpected anatomical, cellular and molecular signatures specific to memory reconsolidation.

    Here, we present the view that Zif gene expression dosage can also distinguish both processes. National Center for Biotechnology Information , U. Published online Aug Author information Article notes Copyright and License information Disclaimer. The authors have declared that no competing interests exist. Received Apr 5; Accepted Jul This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.

    This article has been cited by other articles in PMC. Abstract Compelling evidence points to the existence of independent cellular processes involved in the consolidation and reconsolidation of memory.

    Introduction Contextual fear conditioning CFC is a well-established paradigm to study the neural mechanisms of emotional learning and memory. Materials and Methods Mice A total of mice were used in this study. Open in a separate window. Effect of Zif gene dosage on CFC consolidation and reconsolidation. Effect of Zif gene dosage on reactivated and non-reactivated CFC memories.

    Effect of Zif gene dosage on the reconsolidation of 1 and 8 days-old CFC memories. Effect of Zif gene dosage on CFC memory strengthening. Results Effect of Zif Gene Dosage on CFC Consolidation and Reconsolidation Compelling evidence supports the notion that Zif expression is critical for the reconsolidation of CFC [15] as well as for that of auditory cued-fear conditioning [22] , [23]. Effect of Zif Knockdown on Reactivated and Non-reactivated CFC Memories Reactivation of the original memory has previously been reported to constrain memory reconsolidation [28].

    Effect of Zif Knockdown on the Reconsolidation of Recent and 8 Days-old CFC Memory The influence of the age of the memory has previously been defined as a boundary condition for memory reconsolidation [10]. Fanselow MS Contextual fear, gestalt memories, and the hippocampus. Behav Brain Res McGaugh JL Memory—a century of consolidation. Nader K, Hardt O A single standard for memory: Nat Rev Neurosci Lee JL Reconsolidation: Nat Rev Neurosci 8: Neurobiol Learn Mem Hall J, Thomas KL, Everitt BJ Cellular imaging of zif expression in the hippocampus and amygdala during contextual and cued fear memory retrieval: Fanselow MS Conditioned and unconditional components of post-shock freezing.

    Pavlov J Biol Sci Lee JL Memory reconsolidation mediates the strengthening of memories by additional learning. Duvarci S, Nader K, LeDoux JE Activation of extracellular signal-regulated kinase- mitogen-activated protein kinase cascade in the amygdala is required for memory reconsolidation of auditory fear conditioning.

    Eur J Neurosci Malkani S, Rosen JB Specific induction of early growth response gene 1 in the lateral nucleus of the amygdala following contextual fear conditioning in rats. Guzowski JF Insights into immediate-early gene function in hippocampal memory consolidation using antisense oligonucleotide and fluorescent imaging approaches.

    Davis S, Bozon B, Laroche S How necessary is the activation of the immediate early gene zif in synaptic plasticity and learning? Knapska E, Kaczmarek L A gene for neuronal plasticity in the mammalian brain: Thomas KL, Hall J, Everitt BJ Cellular imaging with zif expression in the rat nucleus accumbens and frontal cortex further dissociates the neural pathways activated following the retrieval of contextual and cued fear memory.

    Bozon B, Davis S, Laroche S A requirement for the immediate early gene zif in reconsolidation of recognition memory after retrieval. Front Behav Neurosci 4: Pharmacological dissection with protein synthesis inhibitors following reminder for a passive-avoidance task in young chicks. First, contextual fear conditioning has been used extensively to study behavioral and molecular determinants of reconsolidation in mice Kida et al.

    Second, imaging and lesion experiments indicate that the circuits supporting contextual fear undergo significant reorganization in the month following learning Anagnostaras et al. The current experiments indicate that blocking protein synthesis in the dHPC disrupts recent, but not remote contextual fear memories. The effects of intra-dHPC infusions of ANI on the stability of recent and remote contextual fear memory parallels the time-dependent role the hippocampus plays in the storage of these types of memories.

    Using identical apparatus, behavioral procedures, and retention delays, we previously showed that the hippocampus was activated following recall of recent, but not remote contextual fear memory Frankland et al. Here we found that blocking protein synthesis in the dHPC-disrupted reconsolidation of recent contextual fear memories, regardless of whether mice had been trained using a weak one-shock or strong three-shock protocol.

    However, we found that similar infusions had no effect on remote contextual fear memories, consistent with the lack of involvement of the dHPC in processing contextual fear memories at later time points Hall et al.

    This was still the case even when a longer re-exposure min was used data not shown. This lack of effect on remote contextual fear memory contrasts with a previous study in rats Debiec et al. In this study, intrahippocampal infusions of ANI blocked reconsolidation of both recent 1-d-old and remote i. This discrepancy may reflect species differences between rats and mice. Alternatively, it is possible that infusion of a larger volume or dose would be more effective in destabilizing remote memory in our study.

    However, our data clearly demonstrate a time-dependent stability gradient, with recent memories more sensitive to intra-dHPC infusions of ANI compared with remote memories. We previously found that the ACC was activated following recall of remote but not recent contextual fear memories, and that inactivation of the ACC specifically disrupts recall of these memories Frankland et al. Here we found that post-retrieval blockade of protein synthesis in the ACC does not destabilize remote contextual fear memories.

    This lack of effect on remote memories suggests two possibilities. First, the ACC may only be necessary for retrieval and not storage of remote contextual fear memories.

    Such a situation would suggest a division of labor in the cortex with the ACC coordinating retrieval of memories that are stored in more posterior cortical regions Frankland and Bontempi If this were the case, then post-reactivation disruption of protein synthesis in more posterior cortical regions might disrupt the reconsolidation of remote contextual fear memories.

    A second possibility is that the distributed nature of remote memory protects against the destabilizing effects of locally applied protein synthesis inhibitors. Using cellular imaging approaches, we have previously shown that recall of remote contextual fear memory is associated with activation of multiple cortical regions Frankland et al.

    In the present series of experiments, we found that only systemically applied ANI disrupted subsequent expression of remote contextual fear memory, albeit only when a longer duration context re-exposure was used.

    Therefore, whereas local blockade of protein synthesis in the dHPC was sufficient to destabilize a recent contextual fear memory, a more global disruption of protein synthesis appears to be necessary to destabilize remote contextual fear memory.

    Together, these experiments have started to explore the relationship between memory age and memory stability. Consistent with previous reports Milekic and Alberini ; Pedreira and Maldonado ; Suzuki et al. Gradual reorganization of contextual fear memories in distributed cortical or cortico-hippocampal networks McClelland et al. For the local infusion experiments, these mice were purchased from Taconic Farms. For the systemic injection experiments, they were purchased from Charles River.

    Mice were at least 8 wk of age at the start of experiments, and all behavioral procedures were conducted during the light phase of the cycle. Experiments were conducted blind to the treatment condition of the mouse. Mice were allowed to recover for at least 1 wk following surgery. Following this, they were handled for three consecutive days prior to the commencement of contextual fear conditioning. ANI was infused immediately following the re-exposure phase of the experiment.

    Mice were briefly anesthetized with halothane to facilitate insertion of the injection cannula. Infusions into the dHPC 0. The injection cannula gauge was left in place for 2 min following the infusion. Brains were subsequently prepared for immunocytochemistry using anti-Fos primary rabbit polyclonal antibody 1: Staining was revealed using the avidin-biotin peroxidase method ABC kit.

    Quantitative analysis was performed using a NIH image-processing system and brain regions were anatomically defined according to the Paxinos and Franklin atlas Paxinos and Franklin Immunoreactive neurons were counted by an experimenter unaware of the treatment condition. Brains were subsequently prepared for Fos immunocytochemistry as above. The advantage of using PTZ in these experiments is that it induces high levels of Fos expression. This makes it easier to detect any reductions in Fos expression produced by pretreatment with ANI.

    The apparatus and general procedures for contextual fear conditioning have previously been described Anagnostaras et al. For the systemic injection experiments, a similar, but smaller Each experiment consisted of three phases: Training, re-exposure, and testing. During each of these phases, freezing behavior defined as a complete absence of movement, except for respiration Fanselow was measured using automated procedures Anagnostaras et al.

    In the first series of experiments, during training, mice were placed in the conditioning chamber for 5 min. After 2 min they were presented with three unsignaled footshocks 2-sec duration, 0. During the re-exposure phase, mice were placed back into the conditioning context for 2. One day later, contextual fear memory was assessed in a 2-min test. Mouse numbers were as follows: In the second series of experiments, we first examined the effects of omitting the re-exposure.

    Accordingly, mice were trained as above with three footshocks.

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    of NE in both cued and context fear memory consolidation. in cued fear memory consolidation using single-trial conditioning ; LaLumiere et al., ) and blockade of β-ARs in CA1. Similarly, the reconsolidation of contextual fear, and spatial and blockade can both impair extinction to maintain conditioned fear and disrupt. In contrast, recall of remote contextual fear memories engages a number of different . Intra-ACC blockade of protein synthesis fails to disrupt reconsolidation of remote . We used a contextual fear-conditioning paradigm in mice to examine how .. () Amygdalar circuits required for either consolidation or extinction of.

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    nino2010

    of NE in both cued and context fear memory consolidation. in cued fear memory consolidation using single-trial conditioning ; LaLumiere et al., ) and blockade of β-ARs in CA1.

    tikkurilla

    Similarly, the reconsolidation of contextual fear, and spatial and blockade can both impair extinction to maintain conditioned fear and disrupt.

    Nagel

    In contrast, recall of remote contextual fear memories engages a number of different . Intra-ACC blockade of protein synthesis fails to disrupt reconsolidation of remote . We used a contextual fear-conditioning paradigm in mice to examine how .. () Amygdalar circuits required for either consolidation or extinction of.

    nakos1991

    Adult rats were subjected to a contextual fear conditioning paradigm, reexposed to . In this case, extinction blockade would likely lead to high test freezing in.

    HunterDragon

    Indeed, the likelihood of reconsolidation for fear extinction memory has never . to a more or less protracted blockade of the retrieval process (29–31), conditioned stimulus is presented outside of the extinction context (36).

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