• Korean Journal of Biological Psychiatry
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• v.28 no.2
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• pp.23-35
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• 2021

Fear conditioning and extinction, which are adaptive processes to learn and avoid potential threats, have essential roles in the pathophysiology of anxiety disorders. Experimental fear conditioning and extinction have been used to identify the mechanism of fear and anxiety in humans. However, the brain-based mechanisms of fear conditioning and extinction are yet to be established. In the current review, we summarized the results of neuroimaging studies that examined the brain changes-functional activity and structures-regarding fear conditioning or extinction in healthy individuals. The functional activity of the amygdala, insula, anterior cingulate gyrus, ventromedial prefrontal cortex, and hippocampus changed dynamically with both fear conditioning and extinction. This review may provide an up-to-date summary that may broaden our understanding of pathophysiological mechanisms of anxiety disorder. In addition, the brain regions that are involved in the fear conditioning and extinction may be considered as potential treatment targets in the future studies.

• Korean Journal of Biological Psychiatry
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• v.18 no.2
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• pp.80-89
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• 2011

Pavlovian fear conditioning has been extensively studied for the understanding of neurobiological basis of memory and emotion. Pavlovian fear conditioning is an associative memory which forms when conditioned stimulus (CS) is paired with unconditioned stimulus (US) once or repeatedly. This behavioral model is also important for the understanding of anxiety disorders such as posttraumatic stress disorder. Here we describe the neural circuitry involved in fear conditioning and the molecular mechanisms underlying fear memory formation. During consolidation some memories fade out but other memories become stable and concrete. Emotion plays an important role in determining which memories will survive. Memory becomes unstable and editable again immediately after retrieval. It opens the possibility for us of modulating the established fear memory. It provides us with very efficient tools to improve the efficacy of cognitive-behavior therapy and other exposure-based therapy treating anxiety disorders.

• Investigative Magnetic Resonance Imaging
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• v.26 no.2
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• pp.96-103
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• 2022

Purpose: The survival of organisms critically depends on avoidance responses to life-threatening stimuli. Information about dangerous situations needs to be remembered to produce defensive behavior. To investigate underlying brain regions to process information of danger, manganese-enhanced MRI (MEMRI) was used in olfactory fear-conditioned rats. Materials and Methods: Fear conditioning was conducted in male Sprague-Dawley rats. The animals received nasal injections of manganese chloride solution to monitor brain activation for olfactory information processing. Twenty-four hours after manganese injection, rats were exposed to electric foot shocks with odor cue for one hour. Control rats were exposed to the same odor cue without foot shocks. Forty-eight hours after the conditioning, rats were anesthetized and their brains were scanned with 9.4T MRI. Acquired images were processed and statistical analyses were performed using AFNI. Results: Manganese injection enhanced brain areas involved in olfactory information pathways in T1 weighted images. Rats that received foot shocks showed higher brain activation in the central nucleus of the amygdala, septum, primary motor cortex, and preoptic area. In contrast, control rats displayed greater signals in the orbital cortex and nucleus accumbens. Conclusion: Nasal delivery of manganese solution enhanced olfactory signal pathways in rats. Odor cue paired with foot shocks activated amygdala, the central brain region in fear, and related brain circuits. Use of MEMRI in fear conditioning provides a reliable monitoring technique of brain activation for fear learning.

• Proceedings of the Korean Society of Applied Pharmacology
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• 2008.04a
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• pp.33-45
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• 2008

Auditory fear memory is thought to be maintained by fear conditioning-induced potentiation of synaptic efficacy. The conditioning-induced potentiation has been shown to be maintained, at least in part, by enhanced expression of surface AMPA receptor (AMPAR) at excitatory synapses in the lateral amygdala (LA). Depotentiation, reversal of conditioning-induced potentiation, has been proposed as a cellular mechanism for fear extinction. However, a direct link between depotentiation and extinction has not yet been tested. To address this, we applied both ex vivo and in vivo approaches to rats in which fear memory had been consolidated. We found a novel form of ex vivo depotentiation; the depotentiation reversed conditioning-induced potentiation at thalamic input synapses onto the LA (T-LA synapses) ex vivo, and it could be induced only when both NMDA and metabotropic glutamate receptors were co-activated. Extinction returned the enhanced T-LA synaptic efficacy observed in conditioned rats to baseline and occluded the depotentiation. Consistently, extinction reversed conditioning-induced enhancement of surface expression of AMPAR subunits in LA synaptosomal preparations. A GluR2-derived peptide that blocks regulated AMPAR endocytosis inhibited depotentiation, and microinjection of a cell-permeable form of the peptide into the LA attenuated extinction. Our results are consistent with the use of depotentiation to weaken potentiated synaptic inputs onto the LA during extinction, and they provide strong evidence that AMPAR removal at excitatory synapses in the LA underlies extinction. The results described here are in line with previous findings. Neural activity in the LA has been shown to decrease after extinction in the rat and human. The NMDAR dependency of the depotentiation fits nicely with a large body of evidence that fear extinction depends upon amygdala NMDARs. Similarly, blockade of metabotropic glutamate recepotrs in the LA has recently been shown to attenuate fear extinction.

• Korean Journal of Biological Psychiatry
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• v.15 no.4
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• pp.254-264
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• 2008

Objectives : The neural substrate of fear is thought to be highly conserved among species including human. The purpose of this review was to address the neural substrates of fear based on recent findings obtained from animal and human studies. Methods : Recent studies on brain regions related to fear, particularly fear conditioning in rodents and humans, were extensively reviewed. Results : This paper suggests high consistency in anatomical structure and physiological mechanisms for fear perception, response, learning and modulation in animals and humans. Conclusions : Fear is manifested and modulated by well conserved neural circuits among species interconnected with the amygdala, such as the hippocampus and the ventromedial prefrontal cortex. Further research is required to incorporate findings from animal studies into a better understanding of neural circuitry of fear in human in a translational approach.

• BMB Reports
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• v.49 no.1
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• pp.1-2
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• 2016

Of the numerous events that occur in daily life, we readily remember salient information, but do not retain most less-salient events for a prolonged period. Although some of the episodes contain putatively emotional aspects, the information with lower saliency is rarely stored in neural circuits via an unknown mechanism. We provided substantial evidence indicating that synaptic plasticity in the dorsal ITC of amygdala allows for selective storage of salient emotional experiences, while it deters less-salient experience from entering long-term memory. After activation of D4R or weak fear conditioning, STDP stimulation induces LTD in the LA-ITC synapses. This form of LTD is dependent upon presynaptic D4R, and is likely to result from enhancement of GABA release. Both optogenetic abrogation of LTD and ablation of D4R at the dorsal ITC in vivo lead to heightened and over-generalized fear responses. Finally, we demonstrated that LTD was impaired at the dorsal ITC of PTSD model mice, which suggests that maladaptation of GABAergic signaling and the resultant LTD impairment contribute to the endophenotypes of PTSD. [BMB Reports 2016; 49(1): 1-2]

• The Korean Journal of Physiology and Pharmacology
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• v.16 no.5
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• pp.293-296
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• 2012

Memory reconsolidation is ubiquitous across species and various memory tasks. It is a dynamic process in which memory is modified and/or updated. In experimental conditions, memory reconsolidation is usually characterized by the fact that the consolidated memory is disrupted by a combination of memory reactivation and inhibition of protein synthesis. However, under some experimental conditions, the reactivated memory is not disrupted by inhibition of protein synthesis. This so called "boundary condition" of reconsolidation may be related to memory strength. In Pavlovian fear conditioning, the intensity of unconditional stimulus (US) determines the strength of the fear memory. In this study, we examined the effect of the intensity of US on the reconsolidation of contextual fear memory. Strong contextual fear memory, which is conditioned with strong US, is not disrupted by inhibition of protein synthesis after its reactivation; however, a weak fear memory is often disrupted. This suggests that a US of strong intensity can inhibit reconsolidation of contextual fear memory.

• Molecules and Cells
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• v.37 no.1
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• pp.24-30
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• 2014

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

• The Korean Journal of Physiology and Pharmacology
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• v.6 no.6
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• pp.299-304
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• 2002

Calcitonin gene-related peptide (CGRP) expressing neurons are distributed widely throughout the central and peripheral nervous systems. Due to its distribution and pharmacological studies, CGRP has been implicated to be involved in anxiety, fear and depression. In this study, ${\alpha}CGRP-knockout$ mice were used to assess the consequences of removing this neuropeptide to the mice behaviors. ${\alpha}CGRP-knockout$ mice performed equally as well as wild type mice in the light-dark transition test and in the elevated plus maze test of anxiety. ${\alpha}CGRP-null$ mice behaved similarly as wild-type mice in the Porsolt swim test of depression. They also exhibited normal learning and memory in the fear conditioning tasks. It is concluded that ${\alpha}CGRP$ is not essential for mice to be able to perform these tests, despite the presence of ${\alpha}CGRP$ in the relevant regions of the brain.

• Journal of Ginseng Research
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• v.40 no.1
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• pp.55-61
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• 2016

Background: A number of neurological and neurodegenerative diseases share impaired cognition as a common symptom. Therefore, the development of clinically applicable therapies to enhance cognition has yielded significant interest. Previously, we have shown that activation of lysophosphatidic acid receptors (LPARs) via gintonin application potentiates synaptic transmission by the blockade of $K^+$ channels in the mature hippocampus. However, whether gintonin may exert any beneficial impact directly on cognition at the neural circuitry level and the behavioral level has not been investigated. Methods: In the current study, we took advantage of gintonin, a novel LPAR agonist, to investigate the effect of gintonin-mediated LPAR activation on cognitive performances. Hippocampus-dependent fear memory test, synaptic plasticity in the hippocampal brain slices, and quantitative analysis on synaptic plasticity-related proteins were used. Results: Daily oral administration of gintonin for 1 wk significantly improved fear memory retention in the contextual fear-conditioning test in mice.We also found that oral administration of gintonin for 1 wk increased the expression of learning and memory-related proteins such as phosphorylated cyclic adenosine monophosphate-response element binding (CREB) protein and brain-derived neurotrophic factor (BDNF). In addition, prolonged gintonin administration enhanced long-term potentiation in the hippocampus. Conclusion: Our observations suggest that the systemic gintonin administration could successfully improve contextual memory formation at the molecular and synaptic levels as well as the behavioral level. Therefore, oral administration of gintonin may serve as an effective noninvasive, nonsurgical method of enhancing cognitive functions.