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Fear generalization is one of the main symptoms of posttraumatic stress disorder. In rodents, the anterior cingulate cortex (ACC) and the hippocampus (HPC) control the expression of contextual fear memory generalization. Consistently, ACC projections to the ventral HPC contribute to contextual fear generalization. However, the roles of ACC projections to the dorsal HPC (dHPC) in fear generalization are unclear, although the dHPC is required for the retrieval of recent contextual fear memory. To investigate these roles, we examined the effects of optogenetic silencing and stimulation of these projections in contextual fear generalization at the recent and remote time points. Mice underwent contextual fear conditioning and, at 1 or 28 d later, were tested in the conditioned chamber, a novel context, or a similar context. Optogenetic activation of these projections induced higher freezing in mice in the novel context compared with the control group at a recent (1-d), but not remote (28-d), time point following conditioning, suggesting that activation of this pathway enhances contextual fear generalization. In contrast, optogenetic inactivation of these projections induced lower freezing in the similar context compared with the control group at a recent, but not remote, time point, suggesting that inactivation of this pathway impaired contextual fear generalization. These observations suggest that the ACC to the dHPC projections positively regulate the expression of contextual fear generalization when contextual fear memory is recent.

Memory retrieval is not a passive process. When a memory is retrieved, it returns to a labile state and undergoes reconsolidation to be re-stored. The discovery of this memory reconsolidation has had a major impact on memory consolidation theory. In other words, it suggested that memory is more dynamic than expected and can be modified through reconsolidation. Conversely, a conditioned fear memory undergoes memory extinction after retrieval, and it is thought that extinction does not reflect its erasure, but rather new inhibitory learning of the original conditioned memory. We have investigated the relationship between memory reconsolidation and extinction by comparing their behavioral, cellular, and molecular mechanisms. Memory reconsolidation and extinction have opposite functions on contextual fear and inhibitory avoidance memories; reconsolidation maintains or strengthens fear memory, whereas extinction weakens it. Importantly, reconsolidation and extinction are contrasting memory processes not only at the behavioral level but also at cellular and molecular levels. Furthermore, our analysis revealed that reconsolidation and extinction are not independent processes, but interact with each other. Interestingly, we also found a "memory transition process" that switches the fear memory process from reconsolidation to extinction after retrieval. Investigating the mechanisms of reconsolidation and extinction will contribute to our understanding of the dynamic nature of memory. • Reconsolidation and extinction show opposite functions on fear memories. • Reconsolidation and extinction interact with each other. • The transition process switches memory phases from reconsolidation to extinction. [ABSTRACT FROM AUTHOR]

Aim: A reduced mismatch negativity (MMN) response is a promising electrophysiological endophenotype of schizophrenia that reflects neurocognitive impairment. Dopamine dysfunction is associated with symptoms of schizophrenia. However, whether the dopamine system is involved in MMN impairment remains controversial. In this study, we investigated the effects of the dopamine D2‐like receptor agonist quinpirole on mismatch responses to sound frequency changes in an animal model. Methods: Event‐related potentials were recorded from electrocorticogram electrodes placed on the auditory and frontal cortices of freely moving rats using a frequency oddball paradigm consisting of ascending and equiprobable (ie, many standards) control sequences before and after the subcutaneous administration of quinpirole. To detect mismatch responses, difference waveforms were obtained by subtracting nondeviant control waveforms from deviant waveforms. Results: Here, we show the significant effects of quinpirole on frontal mismatch responses to sound frequency deviations in rats. Quinpirole delayed the frontal N18 and P30 mismatch responses and reduced the frontal N55 MMN‐like response, which resulted from the reduction in the N55 amplitude to deviant stimuli. Importantly, the magnitude of the N55 amplitude was negatively correlated with the time of the P30 latency in the difference waveforms. In contrast, quinpirole administration did not clearly affect the temporal mismatch responses recorded from the auditory cortex. Conclusion: These results suggest that the disruption of dopamine D2‐like receptor signaling by quinpirole reduces frontal MMN to sound frequency deviations and that delays in early mismatch responses are involved in this MMN impairment. [ABSTRACT FROM AUTHOR]

Aims: Dietary Mg2+ deficiency (MgD) impairs hippocampus‐dependent memory in mice; however, the molecular mechanisms underlying MgD‐induced memory impairments are unclear. Here, we investigated the molecular signatures in the hippocampus of MgD mice by analyzing the hippocampal transcriptome. Methods: We performed RNA‐sequencing of the hippocampal transcriptome of MgD mice. We used gene ontology analyses and quantitative real‐time PCR to validate the RNA‐sequencing results. Results: mRNAs for neuroinflammation‐related genes were upregulated in the hippocampus and cortex of MgD mice. Conclusion: MgD induces neuroinflammation in the mouse brain, including the hippocampus and cortex. Our findings suggest that MgD‐induced neuroinflammation triggers the impairments of hippocampus‐dependent memory. [ABSTRACT FROM AUTHOR]

Abstract CREB has been reported to be activated by injury and is commonly used as marker for pain-related plasticity changes in somatosensory pathways, including spinal dorsal horn neurons and the anterior cingulate cortex (ACC). However no evidence has been reported to support the direct role of activated CREB in injury-related behavioral sensitization (or allodynia). Here we report that genetic enhancement of CREB-mediated transcription selectively in forebrain areas enhanced behavioral responses to non-noxious stimuli after chronic inflammation (CFA model) or nerve injury. In contrast, behavioral acute responses to peripheral subcutaneous injection of formalin did not show any significant difference. Furthermore, acute pain responses to noxious thermal stimuli were also not affected. Our results thus provide direct evidence that cortical CREB-mediated transcription contributes to behavioral allodynia in animal models of chronic inflammatory or neuropathic pain.

Memory reconsolidation is thought to maintain or enhance an original memory or add new information to the memory. Retrieved inhibitory avoidance (IA) memory is enhanced through memory reconsolidation by activating gene expression in the amygdala, medial prefrontal cortex (mPFC), and hippocampus. However, it remains unclear how these regions interact to reconsolidate/enhance IA memory. Here, we found the interactions between the amygdala and mPFC as upstream regulators of the hippocampus for IA memory reconsolidation. Pharmacological inactivation of the amygdala, mPFC, or hippocampus immediately after IA memory retrieval blocked IA memory enhancement. More importantly, inactivation of the amygdala or mPFC blocked the induction of c-Fos in the amygdala, mPFC, and hippocampus, whereas hippocampal blockade inhibited it only in the hippocampus. These observations suggest interactions between the amygdala and mPFC and they both function as upstream regulators of the hippocampus to reconsolidate IA memory. Our findings suggest circuitry mechanisms underlying IA memory enhancement through reconsolidation between the amygdala, mPFC, and hippocampus. [ABSTRACT FROM AUTHOR]

Abstract Background Fragile X syndrome is caused by lack of fragile X mental retardation protein (FMRP) due to silencing of the FMR1 gene. The metabotropic glutamate receptors (mGluRs) in the central nervous system contribute to higher brain functions including learning/memory, mental disorders and persistent pain. The transcription factor cyclic AMP-responsive element binding protein (CREB) is involved in important neuronal functions, such as synaptic plasticity and neuronal survival. Our recent study has shown that stimulation of Group I mGluRs upregulated FMRP and activated CREB in anterior cingulate cortex (ACC), a key region for brain cognitive and executive functions, suggesting that activation of Group I mGluRs may upregulate FMRP through CREB signaling pathway. Results In this study, we demonstrate that CREB contributes to the regulation of FMRP by Group I mGluRs. In ACC neurons of adult mice overexpressing dominant active CREB mutant, the upregulation of FMRP by stimulating Group I mGluR is enhanced compared to wild-type mice. However, the regulation of FMRP by Group I mGluRs is not altered by overexpression of Ca2+-insensitive mutant form of downstream regulatory element antagonist modulator (DREAM), a transcriptional repressor involved in synaptic transmission and plasticity. Conclusion Our study has provided further evidence for CREB involvement in regulation of FMRP by Group I mGluRs in ACC neurons, and may help to elucidate the pathogenesis of fragile X syndrome.

Abstract Background During permanent memory formation, recall of acquired place memories initially depends on the hippocampus and eventually become hippocampus-independent with time. It has been suggested that the quality of original place memories also transforms from a precise form to a less precise form with similar time course. The question arises of whether the quality of original place memories is determined by brain regions on which the memory depends. Results To directly test this idea, we introduced a new procedure: a non-associative place recognition memory test in mice. Combined with genetic and pharmacological approaches, our analyses revealed that place memory is precisely maintained for 28 days, although the recall of place memory shifts from hippocampus-dependent to hippocampus-independent with time. Moreover, the inactivation of the hippocampal function does not inhibit the precision of remote place memory. Conclusion These results indicate that the quality of place memories is not determined by brain regions on which the memory depends.

Abstract Background Retinoid signaling pathways mediated by retinoic acid receptor (RAR)/retinoid × receptor (RXR)-mediated transcription play critical roles in hippocampal synaptic plasticity. Furthermore, recent studies have shown that treatment with retinoic acid alleviates age-related deficits in hippocampal long-term potentiation (LTP) and memory performance and, furthermore, memory deficits in a transgenic mouse model of Alzheimer's disease. However, the roles of the RAR/RXR signaling pathway in learning and memory at the behavioral level have still not been well characterized in the adult brain. We here show essential roles for RAR/RXR in hippocampus-dependent learning and memory. In the current study, we generated transgenic mice in which the expression of dominant-negative RAR (dnRAR) could be induced in the mature brain using a tetracycline-dependent transcription factor and examined the effects of RAR/RXR loss. Results The expression of dnRAR in the forebrain down-regulated the expression of RARβ, a target gene of RAR/RXR, indicating that dnRAR mice exhibit dysfunction of the RAR/RXR signaling pathway. Similar with previous findings, dnRAR mice displayed impaired LTP and AMPA-mediated synaptic transmission in the hippocampus. More importantly, these mutant mice displayed impaired hippocampus-dependent social recognition and spatial memory. However, these deficits of LTP and memory performance were rescued by stronger conditioning stimulation and spaced training, respectively. Finally, we found that pharmacological blockade of RARα in the hippocampus impairs social recognition memory. Conclusions From these observations, we concluded that the RAR/RXR signaling pathway greatly contributes to learning and memory, and LTP in the hippocampus in the adult brain.

Abstract Background Memory retrieval is not a passive process. Recent studies have shown that reactivated memory is destabilized and then restabilized through gene expression-dependent reconsolidation. Molecular studies on the regulation of memory stability after retrieval have focused almost exclusively on fear memory, especially on the restabilization process of the reactivated fear memory. We previously showed that, similarly with fear memories, reactivated spatial memory undergoes reconsolidation in the Morris water maze. However, the underlying molecular mechanisms by which reactivated spatial memory is destabilized and restabilized remain poorly understood. In this study, we investigated the molecular mechanism that regulates the stability of the reactivated spatial memory. Results We first showed that pharmacological inactivation of the N-methyl-D-aspartate glutamate receptor (NMDAR) in the hippocampus or genetic inhibition of cAMP-responsible element binding protein (CREB)-mediated transcription disrupted reactivated spatial memory. Finally, we showed that pharmacological inhibition of cannabinoid receptor 1 (CB1) and L-type voltage gated calcium channels (LVGCCs) in the hippocampus blocked the disruption of the reactivated spatial memory by the inhibition of protein synthesis. Conclusions Our findings indicated that the reactivated spatial memory is destabilized through the activation of CB1 and LVGCCs and then restabilized through the activation of NMDAR- and CREB-mediated transcription. We also suggest that the reactivated spatial memory undergoes destabilization and restabilization in the hippocampus, through similar molecular processes as those for reactivated contextual fear memories, which require CB1 and LVGCCs for destabilization and NMDAR and CREB for restabilization.

Abstract Background Memory consolidation is a process to stabilize short-term memory, generating long-term memory. A critical biochemical feature of memory consolidation is a requirement for gene expression. Previous studies have shown that fear memories are consolidated through the activation of gene expression in the amygdala and hippocampus, indicating essential roles of these brain regions in memory formation. However, it is still poorly understood whether gene expression in brain regions other than the amygdala/hippocampus is required for the consolidation of fear memory; however, several brain regions are known to play modulatory roles in fear memory formation. Results To further understand the mechanisms underlying the formation of fear memory, we first identified brain regions where gene expression is activated after learning inhibitory avoidance (IA) by analyzing the expression of the immediately early genes c-fos and Arc as markers. Similarly with previous findings, the induction of c-fos and Arc expression was observed in the amygdala and hippocampus. Interestingly, we also observed the induction of c-fos and Arc expression in the medial prefrontal cortex (mPFC: prelimbic (PL) and infralimbic (IL) regions) and Arc expression in the anterior cingulate cortex (ACC). We next examined the roles of these brain regions in the consolidation of IA memory. Consistent with previous findings, inhibiting protein synthesis in the hippocampus blocked the consolidation of IA memory. More importantly, inhibition in the mPFC or ACC also blocked the formation of IA memory. Conclusion Our observations indicated that the formation of IA memory requires gene expression in the ACC and mPFC as well as in the amygdala and hippocampus, suggesting essential roles of the ACC and mPFC in IA memory formation.

Abstract Calcium/calmodulin-dependent kinase IV (CaMKIV) phosphorylates the major transcription factor, cyclic AMP-responsive element binding protein (CREB), which plays key roles in synaptic plasticity and memory consolidation. Our previous study showed that long-term potentiation (LTP) in the anterior cingulate cortex (ACC) was significantly enhanced in transgenic mice overexpressing CaMKIV. Considering that the CaMKIV-CREB pathway plays a central role in the protein synthesis-dependent LTP, it is possible that upregulation of CaMKIV contributes to enhancement of LTP by promoting protein synthesis. To test this possibility, we examined the effects of transcription and translation inhibitors on synaptic potentiation induced by pairing of synaptic activity with postsynaptic depolarization (paired training) in ACC pyramidal neurons of wild-type and CaMKIV transgenic mice. We found that synaptic potentiation induced by paired training was partially inhibited by transcription or translation inhibitors both in wild-type and CaMKIV transgenic mice; the extent of inhibition was markedly larger in the CaMKIV transgenic mice than in the wild-type mice. Biochemical and immunohistochemical studies revealed that CaMKIV was distributed in the membrane, cytosol and nucleus of ACC neurons. Our results reveal in the first time a transcription- and translation-dependent component of early synaptic LTP in adult ACC synapses, and demonstrate that CaMKIV enhances early synaptic potentiation by activating new protein synthesis.

Abstract Mounting evidence suggests that neural oscillations are related to the learning and consolidation of newly formed memory in the mammalian brain. Four to seven Hertz (4-7 Hz) oscillations in the prefrontal cortex are also postulated to be involved in learning and attention processes. Additionally, slow delta oscillations (1-4 Hz) have been proposed to be involved in memory consolidation or even synaptic down scaling during sleep. The molecular mechanisms which link learning-related oscillations during wakefulness to sleep-related oscillations remain unknown. We show that increasing the expression of calcium/calmodulin dependent protein kinase IV (CaMKIV), a key nucleic protein kinase, selectively enhances 4-7.5 Hz oscillation power during trace fear learning and slow delta oscillations during subsequent sleep. These oscillations were found to be boosted in response to the trace fear paradigm and are likely to be localized to regions of the prefrontal cortex. Correlation analyses demonstrate that a proportion of the variance in 4-7.5 Hz oscillations, during fear conditioning, could account for some degree of learning and subsequent memory formation, while changes in slow delta power did not share this predictive strength. Our data emphasize the role of CaMKIV in controlling learning and sleep-related oscillations and suggest that oscillatory activity during wakefulness may be a relevant predictor of subsequent memory consolidation.

Abstract Background Previous studies have demonstrated tissue-specific regulation of the rhythm of circadian transcription, suggesting that transcription factor complex CLOCK/BMAL1, essential for maintaining circadian rhythm, regulates transcription in a tissue-specific manner. To further elucidate the mechanism of the cell type-specific regulation of transcription by CLOCK/BMAL1 at the molecular level, we investigated roles of CBP/p300 and tissue-specific cofactors in CLOCK/BMAL1-mediated transcription. Results As shown previously, CBP/p300 stimulates CLOCK/BMAL1-mediated transcription in COS-1 cells. However, CBP/p300 repressed CLOCK/BMAL1-mediated transcription in NIH3T3 cells and knockdown of CBP or p300 expression by siRNA enhanced this transcription. Studies using GAL4-fusion proteins suggested that CBP represses CLOCK/BMAL1-mediated transcription by targeting CLOCK. We further investigated mechanisms of this cell type-specific modulation of CLOCK/BMAL1-mediated transcription by CBP by examining roles of co-repressor HDAC3 and co-activator pCAF, which are highly expressed in NIH3T3 and COS cells, respectively. CBP repressed CLOCK/BMAL1-mediated transcription in COS-1 cells when HDAC3 was overexpressed, but activated it in NIH3T3 cells when pCAF was overexpressed. CBP forms a complex with CLOCK by interacting with HDAC3 or pCAF; however, direct interaction of CBP with CLOCK was not observed. Conclusion Our findings indicate possible mechanisms by which CBP/p300 tissue-specifically acts cooperatively with pCAF and HDAC3 either as a co-activator or co-repressor, respectively, for CLOCK/BMAL1.

Abstract Background Previous studies have demonstrated essential roles for alpha-calcium/calmodulin-dependent protein kinase II (alpha-CaMKII) in learning, memory and long-term potentiation (LTP). However, previous studies have also shown that alpha-CaMKII (+/-) heterozygous knockout mice display a dramatic decrease in anxiety-like and fearful behaviors, and an increase in defensive aggression. These findings indicated that alpha-CaMKII is important not only for learning and memory but also for emotional behaviors. In this study, to understand the roles of alpha-CaMKII in emotional behavior, we generated transgenic mice overexpressing alpha-CaMKII in the forebrain and analyzed their behavioral phenotypes. Results We generated transgenic mice overexpressing alpha-CaMKII in the forebrain under the control of the alpha-CaMKII promoter. In contrast to alpha-CaMKII (+/-) heterozygous knockout mice, alpha-CaMKII overexpressing mice display an increase in anxiety-like behaviors in open field, elevated zero maze, light-dark transition and social interaction tests, and a decrease in locomotor activity in their home cages and novel environments; these phenotypes were the opposite to those observed in alpha-CaMKII (+/-) heterozygous knockout mice. In addition, similarly with alpha-CaMKII (+/-) heterozygous knockout mice, alpha-CaMKII overexpressing mice display an increase in aggression. However, in contrast to the increase in defensive aggression observed in alpha-CaMKII (+/-) heterozygous knockout mice, alpha-CaMKII overexpressing mice display an increase in offensive aggression. Conclusion Up-regulation of alpha-CaMKII expression in the forebrain leads to an increase in anxiety-like behaviors and offensive aggression. From the comparisons with previous findings, we suggest that the expression levels of alpha-CaMKII are associated with the state of emotion; the expression level of alpha-CaMKII positively correlates with the anxiety state and strongly affects aggressive behavior.

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Abstract Understanding basic neuronal mechanisms hold the hope for future treatment of brain disease. The 1st international conference on synapse, memory, drug addiction and pain was held in beautiful downtown Toronto, Canada on August 21–23, 2006. Unlike other traditional conferences, this new meeting focused on three major aims: (1) to promote new and cutting edge research in neuroscience; (2) to encourage international information exchange and scientific collaborations; and (3) to provide a platform for active scientists to discuss new findings. Up to 64 investigators presented their recent discoveries, from basic synaptic mechanisms to genes related to human brain disease. This meeting was in part sponsored by Molecular Pain, together with University of Toronto (Faculty of Medicine, Department of Physiology as well as Center for the Study of Pain). Our goal for this meeting is to promote future active scientific collaborations and improve human health through fundamental basic neuroscience researches. The second international meeting on Neurons and Brain Disease will be held in Toronto (August 29–31, 2007).

Purpose: Cone‐beam computed tomography (CBCT) offers advantages over conventional fan‐beam CT in that it requires a shorter time and less exposure to obtain images. However, CBCT images suffer from low soft‐tissue contrast, noise, and artifacts compared to conventional fan‐beam CT images. Therefore, it is essential to improve the image quality of CBCT. Methods: In this paper, we propose a synthetic approach to translate CBCT images with deep neural networks. Our method requires only unpaired and unaligned CBCT images and planning fan‐beam CT (PlanCT) images for training. The CBCT images and PlanCT images may be obtained from other patients as long as they are acquired with the same scanner settings. Once trained, three‐dimensionally reconstructed CBCT images can be directly translated into high‐quality PlanCT‐like images. Results: We demonstrate the effectiveness of our method with images obtained from 20 prostate patients, and provide a statistical and visual comparison. The image quality of the translated images shows substantial improvement in voxel values, spatial uniformity, and artifact suppression compared to those of the original CBCT. The anatomical structures of the original CBCT images were also well preserved in the translated images. Conclusions: Our method produces visually PlanCT‐like images from CBCT images while preserving anatomical structures. [ABSTRACT FROM AUTHOR]

Since the advent of deep convolutional neural networks (DNNs), computer vision has seen an extremely rapid progress that has led to huge advances in medical imaging. Every year, many new methods are reported at conferences such as the International Conference on Medical Image Computing and Computer-Assisted Intervention and Machine Learning for Medical Image Reconstruction, or published online at the preprint server arXiv. There is a plethora of surveys on applications of neural networks in medical imaging (see [1] for a relatively recent comprehensive survey). This article does not aim to cover all aspects of the field, but focuses on a particular topic, image-to-image translation. Although the topic may not sound familiar, it turns out that many seemingly irrelevant applications can be understood as instances of image-to-image translation. Such applications include (1) noise reduction, (2) super-resolution, (3) image synthesis, and (4) reconstruction. The same underlying principles and algorithms work for various tasks. Our aim is to introduce some of the key ideas on this topic from a uniform viewpoint. We introduce core ideas and jargon that are specific to image processing by use of DNNs. Having an intuitive grasp of the core ideas of applications of neural networks in medical imaging and a knowledge of technical terms would be of great help to the reader for understanding the existing and future applications. Most of the recent applications which build on image-to-image translation are based on one of two fundamental architectures, called pix2pix and CycleGAN, depending on whether the available training data are paired or unpaired (see Sect. 1.3). We provide codes ([2-3]) which implement these two architectures with various enhancements. Our codes are available online with use of the very permissive MIT license. We provide a hands-on tutorial for training a model for denoising based on our codes (see Sect. 6). We hope that this article, together with the codes, will provide both an overview and the details of the key algorithms and that it will serve as a basis for the development of new applications. [ABSTRACT FROM AUTHOR]

Aims: Lactobacillus species are used widely as various food and supplements to improve health. Previous studies have shown that heat‐killed Lactobacillus brevis SBC8803 induces serotonin release from intestinal cells and affects sleep rhythm and the autonomic nervous system. However, the effect of SBC8803 on cognitive function remains unknown. Here, we examined the effects of dietary heat‐killed SBC8803 on hippocampus‐dependent memory and adult hippocampal neurogenesis. Methods: Hippocampus‐dependent memory performance was assessed in mice fed heat‐killed SBC8803 using social recognition and contextual fear conditioning tasks. Adult hippocampal neurogenesis was evaluated before, during, and after feeding heat‐killed SBC8803 by measuring the number of 5‐bromo‐2‐deoxyuridine (BrdU)‐positive cells following systemic injections of BrdU using immunohistochemistry. Results: Mice fed a heat‐killed SBC8803 diet showed an improvement of hippocampus‐dependent social recognition and contextual fear memories and enhanced adult hippocampal neurogenesis by increasing the survival, but not proliferation, of newborn neurons. Conclusion: Dietary heat‐killed SBC8803 functions as memory and neurogenesis enhancers. [ABSTRACT FROM AUTHOR]

The bHLH-PAS transcription factors clock circadian regulator (CLOCK) and brain and muscle ARNT-like protein 1 (BMAL1) play essential roles in the generation of circadian gene expression rhythms through the activation of E-box-mediated transcription. Importantly, circadian transcriptional rhythms mediated by CLOCK/BMAL1 are observed in peripheral tissues as well as in the suprachiasmatic nucleus and contribute to tissue-specific functions. These findings suggest that CLOCK/BMAL1 have roles in many biological phenomena by interacting with various cellular regulators. In the present study, to understand the mechanisms underlying the multiple functional roles of CLOCK, we tried to identify new proteins that interact with CLOCK using a yeast two-hybrid system. We identified neuroendocrine-specific protein (NSP)-C, which is highly expressed in the brain, as a positive regulator of CLOCK/BMAL1-mediated transcription. We found that NSP-C interacted with CLOCK in mammalian cells. Co-expression of NSP-C with CLOCK/BMAL1 enhanced the transcriptional activation by CLOCK/BMAL1. Furthermore, knockdown of endogenous NSP-C by small interfering RNA (siRNA) suppressed E-box-mediated transcription, while this reduction of transcription was rescued by the expression of NSP-C protected from the action of siRNA. These observations suggest that NSP-C contributes to the upregulation of CLOCK/BMAL1-mediated transcription. [ABSTRACT FROM AUTHOR]

Post-traumatic stress disorder (PTSD) is a psychiatric disorder associated with memories of traumatic experiences. Conditioned fear memory, a representative model of traumatic memories, is observed across species from lower to higher animals, including humans. Numerous studies have investigated the mechanisms of conditioned fear memory and have led to the identification of the underlying processes involved in fear memory regulation, including cellular and systems consolidation of fear conditioning, destabilization/reconsolidation and extinction after fear memory retrieval, and forgetting of fear memory. These studies suggested that mechanisms for fear memory regulation are shared by humans and other higher animals. Additionally, rodent studies have identified the mechanisms of fear memory at the molecular, cellular, and circuit levels. Findings from these studies in rodents have been applied to facilitate the development and improvement of PTSD intervention. For instance, reconsolidation and extinction of fear memories have been applied for PTSD treatment to improve prolonged exposure (PE) therapy, an effective psychotherapy for PTSD. Combination of medications weakening retrieved traumatic memory (e.g., by facilitating both destabilization and extinction) with PE therapy may contribute to improvement of PTSD. Interestingly, a recent study in mice identified forgetting of fear memory as another potential therapeutic target for PTSD. A better understanding of the mechanisms involved in fear memory processes is likely to facilitate the development of better treatments for PTSD. This review describes fear memory processes and their mechanisms and discusses the pros and cons of applying how this knowledge can be applied in the development of interventions for PTSD. [ABSTRACT FROM AUTHOR]