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Michael S Fanselow - One of the best experts on this subject based on the ideXlab platform.
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Chapter 2.2 The use of Conditioning tasks to model Fear and anxiety
Handbook of Behavioral Neuroscience, 2020Co-Authors: Michael S Fanselow, Ravikumar PonnusamyAbstract:Abstract Pavlovian Fear Conditioning is a process that normally plays an adaptive role in generating defensive behaviors in threatening situations. Since this learning process is powerful, rapid and lasts indefinitely, it renders neutral stimuli reminiscent of a threatening situation capable of generating inappropriate Fear reactions in non-threatening situations. Here we describe some of the normal functions of Pavlovian Fear Conditioning and then review how it was used as a model to generate several breakthroughs in our understanding of learning processes and mechanisms. Pavlovian Conditioning is not only a model of Fear acquisition but also a model of the loss of Fear called extinction. We review the processes responsible for extinction, emphasizing recovery of Fear following extinction. We describe the long history of translating Fear acquisition and extinction to humans and the clinic. We end with a discussion of the use of Fear Conditioning to understand individual differences in anxiety disorders and post-traumatic stress disorder (PTSD).
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the role of muscarinic and nicotinic cholinergic neurotransmission in aversive Conditioning comparing Pavlovian Fear Conditioning and inhibitory avoidance
Learning & Memory, 2004Co-Authors: Matthew R Tinsley, Jennifer J Quinn, Michael S FanselowAbstract:Aversive Conditioning is an ideal model for studying cholinergic effects on the processes of learning and memory for several reasons. First, deficits produced by selective lesions of the anatomical structures shown to be critical for Pavlovian Fear Conditioning and inhibitory avoidance (such as the amygdala and hippocampus) resemble those deficits seen in human pathological conditions resulting in damage to these same structures. This supports the suggestion that experimental findings on learning and memory in animal models are informative about similar processes in humans. Second, because aversive Conditioning is learned rapidly, even with a single Conditioning trial, the temporal dynamics of the underlying processes can be examined with a very fine degree of resolution. Third, the Fear memories generated by aversive Conditioning procedures tend to be very stable over long time periods. For example, we have observed robust freezing to both tone and context up to 16 mo following Fear Conditioning (Gale et al. 2003). Finally, Fear is a motivational system that has evolved to protect an animal from danger. Fear responses observed under laboratory conditions are similar to those observed in the animal’s natural habitat, meaning that the results of aversive Conditioning procedures typically have external validity.
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isoflurane causes anterograde but not retrograde amnesia for Pavlovian Fear Conditioning
Anesthesiology, 2002Co-Authors: Robert C Dutton, Michael S Fanselow, Anya J Maurer, James M Sonner, Michael J Laster, Edmond I EgerAbstract:Background: Production of retrograde amnesia by anesthetics would indicate that these drugs can disrupt mechanisms that stabilize memory. Such disruption would allow suppression of memory of previous untoward events. The authors examined whether isoflurane provides retrograde amnesia for classic (Pavlovian) Fear Conditioning. Methods: Rats were trained to Fear tone by applying three (three-trial) or one (one-trial) tone-shock pairs while breathing various constant concentrations of isoflurane. Immediately after training, isoflurane administration was either discontinued, maintained unchanged, or rapidly increased to 1.0 minimum alveolar concentration for 1 h longer. Groups of rats were similarly trained to Fear context while breathing isoflurane by applying shocks (without tones) in a distinctive environment. The next day, memory for the conditioned stimuli was determined by presenting the tone or context (without shock) and measuring the proportion of time each rat froze (appeared immobile). For each Conditioning procedure, the effects of the three posttraining isoflurane treatments were compared. Results: Rapid increases in posttraining isoflurane administration did not suppress conditioned Fear for any of the training procedures. In contrast, isoflurane administration during Conditioning dose-dependently suppressed Conditioning (P < 0.05). Training to tone was more resistant to the effects of isoflurane than training to context (P < 0.05), and the three-trial learning procedure was more was more resistant than the one-trial procedure (P < 0.05). Conclusions: Isoflurane provided intense dose-dependant anterograde but not retrograde amnesia for classic Fear Conditioning. Isoflurane appears to disrupt memory processes that occur at or within a few minutes of the Conditioning procedure.
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the hippocampus and Pavlovian Fear Conditioning reply to bast et al
Hippocampus, 2002Co-Authors: Stephan G Anagnostaras, Greg D Gale, Michael S FanselowAbstract:In a recent article that appeared in Hippocampus, we reviewed findings supporting a mnemonic role for the dorsal hippocampus (DH) in Pavlovian (contextual and tone) Fear Conditioning (Anagnostaras et al., 2001). We also detailed a view that has emerged over the years from this work that suggests that the hippocampus plays a highly selective role in the acquisition and temporary storage of contextual representations, as opposed to a role in conditional stimulus–unconditional stimulus (CS–US) associations or in permanent storage for which the amygdala has been heavily implicated (Kim and Fanselow, 1992; Phillips and LeDoux, 1992; Young et al., 1994; Maren and Fanselow, 1996; Maren et al., 1996,1997, 1998; Anagnostaras et al., 1999). Because the evidence that DH lesions produce a temporally graded retrograde amnesia selective for contextual Fear that accords well with declarative memory deficits in amnesic humans, we have further argued this may be a good model system with which to study the transformation of memory from a hippocampus-dependent to a hippocampus-independent (cortical) state (i.e., consolidation) (Scoville and Milner, 1957; Squire, 1992; Squire and Alvarez, 1995; Hodges and Graham, 1998; Squire et al., 2001; Murre et al., 2001; Frankland et al., 2001). In a letter to Hippocampus regarding our recent article, Bast et al. (2001b) expand on our review to discuss their recent data (and the data of others), focusing in particular on findings from lesions of the ventral hippocampus (VH) and discussing how these are problematic for the view we presented. Although a specific hypothesis on the role of the VH in Fear Conditioning has not yet been formulated, several interesting findings were reviewed, emphasizing, in particular, the effects of complete or VH lesions on both tone Fear Conditioning and on remotely acquired Fear (e.g.,Mumby et al., 1999; Sutherland et al., 2001). These findings are in contrast to DH lesions, in which a severe and selective deficit for recently acquired contextual Fear, but not for tone or remotely acquired Fear, is typically found (Kim and Fanselow, 1992; Phillips and LeDoux, 1992; Maren et al., 1997; Anagnostaras et al., 1999). In this reply, we address and expand on some of the issues raised by Bast et al. (2001b). Although this can help clarify where agreements lie in some of the empirical findings, we feel there is not yet enough experimental evidence to offer a specific role for the VH in Fear Conditioning, and it is not yet clear whether these findings challenge the views offered in our review. However, we agree that, as the interface between the DH and amygdala, future work in the area of VH will be essential to our understanding of the neural circuits involved in contextual Fear Conditioning:
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cholinergic modulation of Pavlovian Fear Conditioning effects of intrahippocampal scopolamine infusion
Hippocampus, 2001Co-Authors: Greg D Gale, Stephan G Anagnostaras, Michael S FanselowAbstract:Cholinergic neurotransmission has been implicated in the acquisition of a variety of tasks, including Pavlovian Fear Conditioning. To more precisely define the role of cholinergic modulation in this process, the effect of site-specific cholinergic antagonism was assessed. Male Long-Evans rats were implanted with chronic, bilateral cannulae aimed at the dorsal hippocampus. Infusions of scopolamine hydrobromide (50 mg bilaterally) or phosphate-buffered saline (PBS) were made immediately prior to a signaled Pavlovian Fear Conditioning procedure. On consecutive days following training, all rats were given independent tests assessing freezing to both the training context and the tone conditional stimulus (CS). Relative to PBS infused controls, rats that received intrahippocampal infusions of scopolamine showed a significant attenuation of contextual freezing but comparable levels of freezing to the tone CS. Neither shock sensitivity nor general activity levels differed between rats infused with scopolamine or PBS. These findings suggest that Fear Conditioning to context, but not discrete CS, requires intact cholinergic neurotransmis- sion in the hippocampus. Hippocampus 2001;11:371-376.
Stephen Maren - One of the best experts on this subject based on the ideXlab platform.
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making translation work harmonizing cross species methodology in the behavioural neuroscience of Pavlovian Fear Conditioning
Neuroscience & Biobehavioral Reviews, 2019Co-Authors: Jan Haaker, Stephen Maren, Marta Andreatta, Christian J Merz, Jan Richter, Helene S Richter, Shira Meir Drexler, Maren D Lange, Kay JunglingAbstract:Abstract Translational neuroscience bridges insights from specific mechanisms in rodents to complex functions in humans and is key to advance our general understanding of central nervous function. A prime example of translational research is the study of cross-species mechanisms that underlie responding to learned threats, by employing Pavlovian Fear Conditioning protocols in rodents and humans. Hitherto, evidence for (and critique of) these cross-species comparisons in Fear Conditioning research was based on theoretical viewpoints. Here, we provide a perspective to substantiate these theoretical concepts with empirical considerations of cross-species methodology. This meta-research perspective is expected to foster cross-species comparability and reproducibility to ultimately facilitate successful transfer of results from basic science into clinical applications.
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nmda receptor antagonism in the basolateral but not central amygdala blocks the extinction of Pavlovian Fear Conditioning in rats
European Journal of Neuroscience, 2010Co-Authors: Joshua M Zimmerman, Stephen MarenAbstract:Glutamate receptors in the basolateral complex of the amygdala (BLA) are essential for the acquisition, expression and extinction of Pavlovian Fear Conditioning in rats. Recent work has revealed that glutamate receptors in the central nucleus of the amygdala (CEA) are also involved in the acquisition of conditional Fear, but it is not known whether they play a role in Fear extinction. Here we examine this issue by infusing glutamate receptor antagonists into the BLA or CEA prior to the extinction of Fear to an auditory conditioned stimulus (CS) in rats. Infusion of the α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptor antagonist, 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione (NBQX), into either the CEA or BLA impaired the expression of conditioned freezing to the auditory CS, but did not impair the formation of a long-term extinction memory to that CS. In contrast, infusion of the N-methyl-d-aspartate (NMDA) receptor antagonist, d,l-2-amino-5-phosphonopentanoic acid (APV), into the amygdala, spared the expression of Fear to the CS during extinction training, but impaired the acquisition of a long-term extinction memory. Importantly, only APV infusions into the BLA impaired extinction memory. These results reveal that AMPA and NMDA receptors within the amygdala make dissociable contributions to the expression and extinction of conditioned Fear, respectively. Moreover, they indicate that NMDA receptor-dependent processes involved in extinction learning are localized to the BLA. Together with previous work, these results reveal that NMDA receptors in the CEA have a selective role acquisition of Fear memory.
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the amygdala is not necessary for unconditioned stimulus inflation after Pavlovian Fear Conditioning in rats
Learning & Memory, 2009Co-Authors: Christine A Rabinak, Caitlin A Orsini, Joshua M Zimmerman, Stephen MarenAbstract:The basolateral complex (BLA) and central nucleus (CEA) of the amygdala play critical roles in associative learning, including Pavlovian Conditioning. However, the precise role for these structures in Pavlovian Conditioning is not clear. Recent work in appetitive Conditioning paradigms suggests that the amygdala, particularly the BLA, has an important role in representing the value of the unconditioned stimulus (US). It is not known whether the amygdala performs such a function in aversive paradigms, such as Pavlovian Fear Conditioning in rats. To address this issue, Experiments 1 and 2 used temporary pharmacological inactivation of the amygdala prior to a US inflation procedure to assess its role in revaluing shock USs after either overtraining (Experiment 1) or limited training (Experiment 2), respectively. Inactivation of the BLA or CEA during the inflation session did not affect subsequent increases in conditioned freezing observed to either the tone conditioned stimulus (CS) or the Conditioning context in either experiment. In Experiment 3, NBQX infusions into the BLA impaired the acquisition of auditory Fear Conditioning with an inflation-magnitude US, indicating that the amygdala is required for associative learning with intense USs. Together, these results suggest that the amygdala is not required for revaluing an aversive US despite being required for the acquisition of Fear to that US.
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Pavlovian Fear Conditioning as a behavioral assay for hippocampus and amygdala function cautions and caveats
European Journal of Neuroscience, 2008Co-Authors: Stephen MarenAbstract:Pavlovian Fear Conditioning has become an important model for investigating the neural substrates of learning and memory in rats, mice and humans. The hippocampus and amygdala are widely believed to be essential for Fear Conditioning to contexts and discrete cues, respectively. Indeed, this parsing of function within the Fear circuit has been used to leverage Fear Conditioning as a behavioral assay of hippocampal and amygdala function, particularly in transgenic mouse models. Recent work, however, blurs the anatomical segregation of cue and context Conditioning and challenges the necessity for the hippocampus and amygdala in Fear learning. Moreover, nonassociative factors may influence the performance of Fear responses under a variety of conditions. Caution must therefore be exercised when using Fear Conditioning as a behavioral assay for hippocampal- and amygdala-dependent learning. When Estes and Skinner described the Conditioning of ‘anxiety’ in rats in 1941 (Estes & Skinner, 1941), they did not foresee that rodent models of aversive Conditioning would become one of the most ubiquitous behavioral paradigms to explore the neural substrates of learning and memory. Indeed, Pavlovian Fear Conditioning has become part of the standard arsenal of behavioral tasks used to interrogate the mnemonic capacities of rats, mice and humans. In Fear Conditioning, neutral stimuli (conditional stimuli or CSs) such as tones, lights, or places (contexts) are arranged to predict aversive outcomes such as footshock (an unconditional stimulus or US). After Conditioning, CSs come to evoke learned Fear responses (conditional responses or CRs) such as conditioned suppression, freezing and tachycardia. The explosion of scientific papers on this topic indexes the popularity of Fear Conditioning. A search of the Institute for Scientific Information Web of Science database reveals an enormous and exponential growth in publications on Fear Conditioning from a total of 17 papers in 1977, 12 papers in 1987, 138 papers in 1997 and 381 papers in 2007. The search terms were ‘Fear Conditioning’, ‘conditioned Fear’, ‘conditioned suppression’, ‘conditioned freezing’, or ‘Fear-potentiated startle’. The search revealed a total of 4207 hits over the history of the database
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hippocampus and Pavlovian Fear Conditioning in rats muscimol infusions into the ventral but not dorsal hippocampus impair the acquisition of conditional freezing to an auditory conditional stimulus
Behavioral Neuroscience, 2004Co-Authors: Stephen Maren, William HoltAbstract:The authors compared the effects of pharmacological inactivation of the dorsal hippocampus (DH) or ventral hippocampus (VH) on Pavlovian Fear Conditioning in rats. Freezing behavior served as the measure of Fear. Pretraining infusions of muscimol, a GABAA receptor agonist, into the VH disrupted auditory, but not contextual, Fear Conditioning; DH infusions did not affect Fear Conditioning. Pretesting inactivation of the VH or DH did not affect the expression of conditional freezing. Pretraining electrolytic lesions of the VH reproduced the effects of muscimol infusions, whereas posttraining VH lesions disrupted both auditory and contextual freezing. Hence, neurons in the VH are importantly involved in the acquisition of auditory Fear Conditioning and the expression of auditory and contextual Fear under some conditions. An abundance of evidence indicates that the hippocampus is importantly involved in associative learning and memory (Anagnostaras, Gale, & Fanselow, 2001; Douglas, 1967; Eichenbaum,
Joseph E Ledoux - One of the best experts on this subject based on the ideXlab platform.
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Acute restraint stress alters subsequent auditory Fear Conditioning in the rat
2020Co-Authors: David E. A. Bush, Luke R. Johnson, J. Choi, Joseph E LedouxAbstract:The neural basis of Pavlovian Fear Conditioning is well understood and depends upon neural processes within the amygdala. Stress is known to play a role in the modulation of Fear-related behavior, including Pavlovian Fear Conditioning. Chronic restraint stress has been shown to enhance Fear Conditioning to discrete and contextual stimuli; however, the time course and extent of restraint that is essential for this modulation of Fear learning remains unclear. Thus, we tested the extent to which a single exposure to 1 hr of restraint would alter subsequent auditory Fear Conditioning in rats.
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rethinking the Fear circuit the central nucleus of the amygdala is required for the acquisition consolidation and expression of Pavlovian Fear Conditioning
The Journal of Neuroscience, 2006Co-Authors: Ann E Wilensky, Glenn E Schafe, Morten P Kristensen, Joseph E LedouxAbstract:In the standard model of Pavlovian Fear learning, sensory input from neutral and aversive stimuli converge in the lateral nucleus of the amygdala (LA), in which alterations in synaptic transmission encode the association. During Fear expression, the LA is thought to engage the central nucleus of the amygdala (CE), which serves as the principal output nucleus for the expression of conditioned Fear responses. In the present study, we reexamined the roles of LA and CE. Specifically, we asked whether CE, like LA, might also be involved in Fear learning and memory consolidation. Using functional inactivation methods, we first show that CE is involved not only in the expression but also the acquisition of Fear Conditioning. Next, we show that inhibition of protein synthesis in CE after training impairs Fear memory consolidation. These findings indicate that CE is not only involved in Fear expression but, like LA, is also involved in the learning and consolidation of Pavlovian Fear Conditioning.
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systematic constellations of neurons are activated in lateral amygdala following Pavlovian Fear Conditioning
2006Co-Authors: Joseph E Ledoux, Neil Haranhalli, Lara W Massie, Justin P Little, Luke R. JohnsonAbstract:How memory is organized within neural networks is a fundamental question in neuroscience. We used Pavlovian Fear Conditioning to study the discrete organization patterns of neurons activated in an associative memory paradigm. In Pavlovian Fear Conditioning a neutral stimulus, such as an auditory tone, is temporally paired with an aversive unconditioned stimulus (US), such as a foot shock...
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memory consolidation of Pavlovian Fear Conditioning requires nitric oxide signaling in the lateral amygdala
European Journal of Neuroscience, 2005Co-Authors: Glenn E Schafe, Elizabeth P Bauer, Svetlana Rosis, Claudia R Farb, Sarina M Rodrigues, Joseph E LedouxAbstract:Nitric oxide (NO) has been widely implicated in synaptic plasticity and memory formation. In studies of long-term potentiation (LTP), NO is thought to serve as a ‘retrograde messenger’ that contributes to presynaptic aspects of LTP expression. In this study, we examined the role of NO signaling in Pavlovian Fear Conditioning. We first show that neuronal nitric oxide synthase is localized in the lateral nucleus of the amygdala (LA), a critical site of plasticity in Fear Conditioning. We next show that NO signaling is required for LTP at thalamic inputs to the LA and for the long-term consolidation of auditory Fear Conditioning. Collectively, the findings suggest that NO signaling is an important component of memory formation of auditory Fear Conditioning, possibly as a retrograde signal that participates in presynaptic aspects of plasticity in the LA.
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Pavlovian Fear Conditioning regulates thr286 autophosphorylation of ca2 calmodulin dependent protein kinase ii at lateral amygdala synapses
The Journal of Neuroscience, 2004Co-Authors: Sarina M Rodrigues, Joseph E Ledoux, Elizabeth P Bauer, Claudia R Farb, Glenn E SchafeAbstract:Ca2+/calmodulin-dependent protein kinase II (CaMKII) plays a critical role in synaptic plasticity and memory formation in a variety of learning systems and species. The present experiments examined the role of CaMKII in the circuitry underlying Pavlovian Fear Conditioning. First, we reveal by immunocytochemical and tract-tracing methods that αCaMKII is postsynaptic to auditory thalamic inputs and colocalized with the NR2B subunit of the NMDA receptor. Furthermore, we show that Fear Conditioning results in an increase of the autophosphorylated (active) form of αCaMKII in lateral amygdala (LA) spines. Next, we demonstrate that intra-amygdala infusion of a CaMK inhibitor, 1-[NO-bis-1,5-isoquinolinesulfonyl]- N -methyl-l-tyrosyl-4-phenylpiperazine, KN-62, dose-dependently impairs the acquisition, but not the expression, of auditory and contextual Fear Conditioning. Finally, in electrophysiological experiments, we demonstrate that an NMDA receptor-dependent form of long-term potentiation at thalamic input synapses to the LA is impaired by bath application of KN-62 in vitro . Together, the results of these experiments provide the first comprehensive view of the role of CaMKII in the amygdala during Fear Conditioning.
Glenn E Schafe - One of the best experts on this subject based on the ideXlab platform.
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The Fear Memory Network
Neuronal Networks in Brain Function CNS Disorders and Therapeutics, 2020Co-Authors: Glenn E SchafeAbstract:Pavlovian Fear Conditioning has become the paradigm of choice to study the mechanisms of mammalian associative memory and those of anxiety disorders that are characterized by persistent, unwanted Fear memories. In this chapter, I first review what is known about the neural network underlying simple forms of Pavlovian Fear Conditioning, including an in-depth look at the mechanisms underlying synaptic plasticity and memory formation in the amygdala and throughout the wider Fear network. Next, I review more complex aspects of Fear learning, including a discussion of the neural network and mechanisms underlying contextual Fear Conditioning and Fear extinction. Finally, I briefly summarize what is known about the Fear-learning system of the human brain and its relevance for understanding and treating anxiety disorders that are characterized by acquired Fears.
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identification of plasticity associated genes regulated by Pavlovian Fear Conditioning in the lateral amygdala
Journal of Neurochemistry, 2010Co-Authors: Jonathan E Ploski, Kevin W Park, Junli Ping, Melissa S Monsey, Glenn E SchafeAbstract:J. Neurochem. (2010) 112, 636–650. Abstract Most recent studies aimed at defining the cellular and molecular mechanisms of Pavlovian Fear Conditioning have focused on protein kinase signaling pathways and the transcription factor cAMP-response element binding protein (CREB) that promote Fear memory consolidation in the lateral nucleus of the amygdala (LA). Despite this progress, there still remains a paucity of information regarding the genes downstream of CREB that are required for long-term Fear memory formation in the LA. We have adopted a strategy of using microarray technology to initially identify genes induced within the dentate gyrus following in vivo long-term potentiation (LTP) followed by analysis of whether these same genes are also regulated by Fear Conditioning within the LA. In the present study, we first identified 34 plasticity-associated genes that are induced within 30 min following LTP induction utilizing a combination of DNA microarray, qRT-PCR, and in situ hybridization. To determine whether these genes are also induced in the LA following Pavlovian Fear Conditioning, we next exposed rats to an auditory Fear Conditioning protocol or to control conditions that do not support Fear learning followed by qRT-PCR on mRNA from microdissected LA samples. Finally, we asked whether identified genes induced by Fear learning in the LA are downstream of the extracellular-regulated kinase/mitogen-activated protein kinase signaling cascade. Collectively, our findings reveal a comprehensive list of genes that represent the first wave of transcription following both LTP induction and Fear Conditioning that largely belong to a class of genes referred to as ‘neuronal activity dependent genes’ that are likely calcium, extracellular-regulated kinase/mitogen-activated protein kinase, and CREB-dependent.
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The Activity-Regulated Cytoskeletal-Associated Protein (Arc/Arg3.1) Is Required for Memory Consolidation of Pavlovian Fear Conditioning in the Lateral Amygdala
The Journal of Neuroscience, 2008Co-Authors: Jonathan E Ploski, Kevin W Park, Melissa S Monsey, Vicki J. Pierre, Jason Smucny, Kathie A. Overeem, Glenn E SchafeAbstract:The activity-regulated cytoskeletal-associated protein (Arc/Arg3.1) is an immediate early gene that has been widely implicated in hippocampal-dependent learning and memory and is believed to play an integral role in synapse-specific plasticity. Here, we examined the role of Arc/Arg3.1 in amygdala-dependent Pavlovian Fear Conditioning. We first examined the regulation of Arc/Arg3.1 mRNA and protein after Fear Conditioning and LTP-inducing stimulation of thalamic inputs to the lateral amygdala (LA). Quantitative real-time PCR, in situ hybridization, Western blotting and immunohistochemistry revealed a significant upregulation of Arc/Arg3.1 mRNA and protein in the LA relative to controls. In behavioral experiments, intra-LA infusion of an Arc/Arg3.1 antisense oligodeoxynucleotide (ODN) was observed to be anatomically restricted to the LA, taken up by LA cells, and to promote significant knockdown of Arc/Arg3.1 protein. Rats given intra-LA infusions of multiple doses of the Arc/Arg3.1 ODN showed an impairment of LTM (tested ∼24 later), but no deficit in STM (tested 3 h later) relative to controls infused with scrambled ODN. Finally, to determine whether upregulation of Arc/Arg3.1 occurs downstream of ERK/MAPK activation, we examined Arc/Arg3.1 expression in rats given intra-LA infusion of the MEK inhibitor U0126. Relative to vehicle controls, infusion of U0126 impaired training-induced increases in Arc/Arg3.1 expression. These findings suggest that Arc/Arg3.1 expression in the amygdala is required for Fear memory consolidation, and further suggest that Arc/Arg3.1 regulation in the LA is downstream of the ERK/MAPK signaling pathway.
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the activity regulated cytoskeletal associated protein arc arg3 1 is required for memory consolidation of Pavlovian Fear Conditioning in the lateral amygdala
The Journal of Neuroscience, 2008Co-Authors: Jonathan E Ploski, Kevin W Park, Melissa S Monsey, Vicki J. Pierre, Jason Smucny, Kathie A. Overeem, Glenn E SchafeAbstract:The activity-regulated cytoskeletal-associated protein (Arc/Arg3.1) is an immediate early gene that has been widely implicated in hippocampal-dependent learning and memory and is believed to play an integral role in synapse-specific plasticity. Here, we examined the role of Arc/Arg3.1 in amygdala-dependent Pavlovian Fear Conditioning. We first examined the regulation of Arc/Arg3.1 mRNA and protein after Fear Conditioning and LTP-inducing stimulation of thalamic inputs to the lateral amygdala (LA). Quantitative real-time PCR, in situ hybridization, Western blotting and immunohistochemistry revealed a significant upregulation of Arc/Arg3.1 mRNA and protein in the LA relative to controls. In behavioral experiments, intra-LA infusion of an Arc/Arg3.1 antisense oligodeoxynucleotide (ODN) was observed to be anatomically restricted to the LA, taken up by LA cells, and to promote significant knockdown of Arc/Arg3.1 protein. Rats given intra-LA infusions of multiple doses of the Arc/Arg3.1 ODN showed an impairment of LTM (tested ∼24 later), but no deficit in STM (tested 3 h later) relative to controls infused with scrambled ODN. Finally, to determine whether upregulation of Arc/Arg3.1 occurs downstream of ERK/MAPK activation, we examined Arc/Arg3.1 expression in rats given intra-LA infusion of the MEK inhibitor U0126. Relative to vehicle controls, infusion of U0126 impaired training-induced increases in Arc/Arg3.1 expression. These findings suggest that Arc/Arg3.1 expression in the amygdala is required for Fear memory consolidation, and further suggest that Arc/Arg3.1 regulation in the LA is downstream of the ERK/MAPK signaling pathway.
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rethinking the Fear circuit the central nucleus of the amygdala is required for the acquisition consolidation and expression of Pavlovian Fear Conditioning
The Journal of Neuroscience, 2006Co-Authors: Ann E Wilensky, Glenn E Schafe, Morten P Kristensen, Joseph E LedouxAbstract:In the standard model of Pavlovian Fear learning, sensory input from neutral and aversive stimuli converge in the lateral nucleus of the amygdala (LA), in which alterations in synaptic transmission encode the association. During Fear expression, the LA is thought to engage the central nucleus of the amygdala (CE), which serves as the principal output nucleus for the expression of conditioned Fear responses. In the present study, we reexamined the roles of LA and CE. Specifically, we asked whether CE, like LA, might also be involved in Fear learning and memory consolidation. Using functional inactivation methods, we first show that CE is involved not only in the expression but also the acquisition of Fear Conditioning. Next, we show that inhibition of protein synthesis in CE after training impairs Fear memory consolidation. These findings indicate that CE is not only involved in Fear expression but, like LA, is also involved in the learning and consolidation of Pavlovian Fear Conditioning.
Stephan G Anagnostaras - One of the best experts on this subject based on the ideXlab platform.
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sleep deprivation and Pavlovian Fear Conditioning
Learning & Memory, 2009Co-Authors: Tristan Shuman, Elizabeth M Harrison, Jennifer R Sage, Stephan G AnagnostarasAbstract:Sleep has been suggested to play a role in memory consolidation. Prior rodent studies have used sleep deprivation to examine this relationship. First, we reexamined the effects of sleep deprivation on Pavlovian Fear Conditioning. We found that the deprivation method itself (i.e., gentle handling) induced deficits independent of sleep. Second, we examined an alternative method of sleep deprivation using amphetamine and found that this method failed to induce amnesia. These data indicate that sleep deprivation is a problematic way to examine the role of sleep in memory consolidation, and an alternative paradigm is proposed. Language: en
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modafinil and memory effects of modafinil on morris water maze learning and Pavlovian Fear Conditioning
Behavioral Neuroscience, 2009Co-Authors: Tristan Shuman, Suzanne C Wood, Stephan G AnagnostarasAbstract:Modafinil has been shown to promote wakefulness and some studies suggest the drug can improve cognitive function. Because of many similarities, the mechanism of action may be comparable to classical psychostimulants, although the exact mechanisms of modafinil’s actions in wakefulness and cognitive enhancement are unknown. The current study aims to further examine the effects of modafinil as a cognitive enhancer on hippocampus-dependent memory in mice. A high dose of modafinil (75 mg/kg ip) given before training improved acquisition on a Morris water maze. When given only before testing, modafinil did not affect water maze performance. We also examined modafinil (0.075 to 75 mg/kg) on Pavlovian Fear Conditioning. A low dose of pretraining modafinil (0.75 mg/kg) enhanced memory of contextual Fear Conditioning (tested off-drug 1 week later) whereas a high dose (75 mg/kg) disrupted memory. Pretraining modafinil did not affect cued Conditioning at any dose tested, and immediate posttraining modafinil had no effect on either cued or contextual Fear. These results suggest that modafinil’s effects of memory are more selective than amphetamine or cocaine and specific to hippocampus-dependent memory.
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Memory and psychostimulants: modulation of Pavlovian Fear Conditioning by amphetamine in C57BL/6 mice.
Psychopharmacology, 2008Co-Authors: Suzanne C Wood, Stephan G AnagnostarasAbstract:With the use of prescription stimulants on the rise, it is important to examine the cognitive effects of low and moderate doses of stimulants rather than only those typical of addicts. The present study examined the effects a range of doses (0.005-8 mg/kg) of D: -amphetamine sulfate on cued and contextual Pavlovian Fear Conditioning in mice. In agreement with previous research, subjects administered with a moderately high dose of amphetamine (8 mg/kg) pre-training, typical of what addicts might take, displayed impaired conditioned freezing when tested off-drug. Alternately, subjects injected with a very low dose of amphetamine (0.005, 0.025, or 0.05 mg/kg) pre-training, similar to the therapeutic doses for attention deficit hyperactivity disorder, displayed enhanced memory when tested off-drug. A control study showed that these effects were not due to state-dependent learning. Thus, dose is a critical determinant of the cognitive effects of psychostimulants.
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cocaine and Pavlovian Fear Conditioning dose effect analysis
Behavioural Brain Research, 2007Co-Authors: Suzanne C Wood, Jennifer R Sage, Stephan G AnagnostarasAbstract:Emerging evidence suggests that cocaine and other drugs of abuse can interfere with many aspects of cognitive functioning. The authors examined the effects of 0.1 – 15 mg/kg of cocaine on Pavlovian contextual and cued Fear Conditioning in mice. As expected, pre-training cocaine dose-dependently produced hyperactivity and disrupted freezing. Surprisingly, when the mice were tested off-drug later, the group pre-treated with a moderate dose of cocaine (15 mg/kg) displayed significantly less contextual and cued memory, compared to saline control animals. Conversely, mice pre-treated with a very low dose of cocaine (0.1 mg/kg) showed significantly enhanced Fear memory for both context and tone, compared to controls. These results were not due to cocaine’s anesthetic effects, as shock reactivity was unaffected by cocaine. The data suggest that despite cocaine’s reputation as a performance-enhancing and anxiogenic drug, this effect is seen only at very low doses, whereas a moderate dose disrupts hippocampus and amygdala-dependent Fear Conditioning.
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Cocaine and Pavlovian Fear Conditioning: Dose–effect analysis
Behavioural Brain Research, 2006Co-Authors: Suzanne C Wood, Jennifer R Sage, Stephan G AnagnostarasAbstract:Emerging evidence suggests that cocaine and other drugs of abuse can interfere with many aspects of cognitive functioning. The authors examined the effects of 0.1 – 15 mg/kg of cocaine on Pavlovian contextual and cued Fear Conditioning in mice. As expected, pre-training cocaine dose-dependently produced hyperactivity and disrupted freezing. Surprisingly, when the mice were tested off-drug later, the group pre-treated with a moderate dose of cocaine (15 mg/kg) displayed significantly less contextual and cued memory, compared to saline control animals. Conversely, mice pre-treated with a very low dose of cocaine (0.1 mg/kg) showed significantly enhanced Fear memory for both context and tone, compared to controls. These results were not due to cocaine’s anesthetic effects, as shock reactivity was unaffected by cocaine. The data suggest that despite cocaine’s reputation as a performance-enhancing and anxiogenic drug, this effect is seen only at very low doses, whereas a moderate dose disrupts hippocampus and amygdala-dependent Fear Conditioning.
