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Memory retrieval is considered to have roles in memory enhancement. Recently, memory reconsolidation was suggested to reinforce or integrate new information into reactivated memory. Here, we show that reactivated inhibitory avoidance (IA) memory is enhanced through reconsolidation under conditions in which memory extinction is not induced. This memory enhancement is mediated by neurons in the amygdala, hippocampus, and medial prefrontal cortex (mPFC) through the simultaneous activation of calcineurin-induced proteasome-dependent protein degradation and cAMP responsive element binding protein-mediated gene expression. Interestingly, the amygdala is required for memory reconsolidation and enhancement, whereas the hippocampus and mPFC are required for only memory enhancement. Furthermore, memory enhancement triggered by retrieval utilizes distinct mechanisms to strengthen IA memory by additional learning that depends only on the amygdala. Our findings indicate that reconsolidation functions to strengthen the original memory and show the dynamic nature of reactivated memory through protein degradation and gene expression in multiple brain regions.DOI: http://dx.doi.org/10.7554/eLife.02736.001., (Copyright © 2014, Fukushima et al.)

cAMP response element-binding (CREB) has been known to be an essential transcription factor that activates gene expression required for the formation of long-term memory (LTM) in a wide range of animal models, from nematodes to higher animals such as Aplysia, Drosophila, and rodents. In mammals, various CREB mutant mice have been developed and analyzed. These studies have shown that gain or loss of CREB function improves and impairs, respectively, the formation of LTMs, enabling us to understand the roles of CREB in the formation and enhancement of memory. In this article, the analyses conducted on CREB mutant mice are reviewed with a particular focus on learning and memory formation. This article is part of a Special Issue entitled 'Memory enhancement'., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objectives: Assessment of physiologic renal motion in order to optimize abdominal intensity-modulated radiation therapy and stereotactic body radiation therapy., Methods and Materials: Twenty patients with a median age of 47 years underwent computed tomography simulation and four-dimensional computed tomography acquisition. Thirty-nine kidneys were contoured during ten phases of respiration to estimate renal motion., Results: Kidney motion was not related to age (p = 0.42), sex (p = 0.28), height (p = 0.75), or body weight (p = 0.63). The average +/- standard deviation (SD) of movement of the center of gravity for all subjects was 11.1 +/- 4.8 mm in the cranio-caudal (CC) direction (range, 2.5-20.5 mm), 3.6 +/- 2.1 mm in the anterior-posterior (AP) direction (range, 0.6-8.0 mm), and 1.7 +/- 1.4 mm in the right-left (RL) direction (range, 0.4-5.9 mm). Renal motion strongly correlated with the respiratory phases (r > 0.97 and p < 0.01 in all three directions)., Conclusions: Renal motion was independent of age, sex, height, or body weight. Renal motion in all directions was strongly respiration dependent, but motion in the cranio-caudal direction showed wide individual variation. In a clinical setting, it will be necessary to evaluate renal respiratory motion separately in each individual.

Our work on stereotactic body radiation therapy (SBRT) for primary and metastatic lung tumors will be described. The eligibility criteria for SBRT, our previous SBRT method, the definition of target volume, heterogeneity correction, the position adjustment using four-dimensional cone-beam computed tomography (4D CBCT) immediately before SBRT, volumetric modulated arc therapy (VMAT) method for SBRT, verifying of tumor position within internal target volume (ITV) using in-treatment 4D-CBCT during VMAT-SBRT, shortening of treatment time using flattening-filter-free (FFF) techniques, delivery of 4D dose calculation for lung-VMAT patients using in-treatment CBCT and LINAC log data with agility multileaf collimator, and SBRT method for centrally located lung tumors in our institution will be shown. In our institution, these efforts have been made with the goal of raising the local control rate and decreasing adverse effects after SBRT.

Linac parameters such as the multi-leaf collimator (MLC) position and jaw position, cumulative monitor units (MUs), and the corresponding gantry angle were recorded during the clinical delivery of volumetric modulated arc therapy for prostate, lung, and head/neck cancer patients. Then, linac parameters were converted into the beam-data format used in the treatment planning system, and the dose distribution was reconstructed. The dose-volume histogram and the dose difference (DD) were compared with the corresponding values in the treatment plan. A reproducible error of in-treatment linac parameters was observed when a sudden change of beam intensity or MLC/jaw speed occurred. The maximum cumulative MU error was more than 4 MU for lung cancer cases, and the maximum MLC position exceeded 5 mm for prostate and head/neck cancer patients. However, these errors were quickly compensated for at the next control point. All treatments analyzed in the present study were delivered within 0.4% accuracy at the planning target volume. The cumulative dose agreed with that of the plan within 3% of the prescribed dose. The 1% DD was 93.9, 99.9, and 93.4% of the prescription dose for prostate, lung, and head/neck cancer patients, respectively.

The use of respiration-correlated cone-beam computed tomography (4D-CBCT) appears to be crucial for implementing precise radiation therapy of lung cancer patients. The reconstruction of 4D-CBCT images requires a respiratory phase. In this paper, we propose a novel method based on an image-based phase recognition technique using normalized cross correlation (NCC). We constructed the respiratory phase by searching for a region in an adjacent projection that achieves the maximum correlation with a region in a reference projection along the cranio-caudal direction. The data on 12 lung cancer patients acquired just prior to treatment and on 3 lung cancer patients acquired during volumetric modulated arc therapy treatment were analyzed in the search for the effective area of cone-beam projection images for performing NCC with 12 combinations of registration area and segment size. The evaluation was done by a "recognition rate" defined as the ratio of the number of peak inhales detected with our method to that detected by eye (manual tracking). The average recognition rate of peak inhale with the most efficient area in the present method was 96.4%. The present method was feasible even when the diaphragm was outside the field of view. With the most efficient area, we reconstructed in-treatment 4D-CBCT by dividing the breathing signal into four phase bins; peak exhale, peak inhale, and two intermediate phases. With in-treatment 4D-CBCT images, it was possible to identify the tumor position and the tumor size in moments of inspiration and expiration, in contrast to in-treatment CBCT reconstructed with all projections.

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.

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.

Volumetric modulated arc therapy (VMAT) is a rotational intensity-modulated radiotherapy (IMRT) technique capable of acquiring projection images for cone-beam computed tomography (CBCT). Respiratory-correlated cone-beam computed tomography, namely 4D-CBCT, serves to assess the displacement of a tumor position between planning and treatment due to organ motion and respiration, and is important for more accurate radiation therapy. On the other hand, recently, a 320-detector row CT scanner, namely 4D-CT, has become available that allows axial volumetric scanning of a 16-cm-long range in a patient without table movement. The goal of our research is to establish a new method of verification during treatment in stereotactic body radiotherapy. In this study, we compare the movement of the tumor between "before treatment" using 4D-CT and "in treatment" using 4D-CBCT. Three patients (55-68 years of age) with lung tumors underwent CT scans for radiotherapy planning using 4D-CT scans to analyze the movement of the tumor before treatment. The patients were treated by VMAT while acquiring projection images. 4D-CBCT datasets were reconstructed from the projection images using in-house programs. The tumor positions in 4D-CT and 4D-CBCT were detected and the movement of the tumor between "before treatment" and "in treatment" was similar. The movement of the tumors during treatment was predictable from 4D-CT before treatment. Furthermore, 4D-CBCT clarified the tumor position during treatment and could reevaluate the actual tumor position and dose distribution. We have successfully shown the movement of the tumor between "before treatment" using 4D-CT and "in treatment" using 4D-CBCT.

The teteracycline (Tc)-dependent and -inducible transcriptional activator (rtTA) system has been used to express regulated transgene expression in vitro and in vivo. However, previous reports have demonstrated that, even in the absence of Tc, the rtTA binds weakly to the tetracycline response element (TRE), leading to a low level of background activity. In order to reduce the leaky gene expression induced by rtTA, we previously established a tightly regulated system (A-IRES-R system) that makes use of both the rtTA (A) and a Tc-dependent repressor (TetR-Kruppel-associated box; KRAB) (R). In addition, others have described a transactivator rtTA2-M2 (M2) that displays higher sensitivity to Dox than rtTA. In this study, to further develop the A-IRES-R system, we generated a derivative Tc system (M2-IRES-R system) that co-expresses both rtTA-M2 and TetR-KRAB from a single vector. We show that compared to the A-IRES-R system, the M2-IRES-R system leads to a greater level of induced TRE-mediated transcription in the presence of doxycycline (Dox) and yet displays a similar level of basal TRE-mediated transcription in the absence of Dox. Furthermore, the M2-IRES-R system also displays less leaky gene expression in the absence of Dox compared to rtTA-M2 and rtTA systems. Taken together, our results suggest that the M2-IRES-R system enables to tightly regulate and highly induce the expression of transgene compared to other systems.

Purpose: To investigate the three-dimensional movement of internal fiducial markers placed near esophageal cancers using 320-multislice CT., Methods and Materials: This study examined 22 metal markers in the esophageal wall near the primary tumors of 12 patients treated with external-beam photon radiotherapy. Motion assessment was analyzed in 41 respiratory phases during 20 s of cine CT in the radiotherapy position., Results: Motion in the cranial-caudal (CC) direction showed a strong correlation (R(2) > 0.4) with the respiratory curve in most markers (73%). The average absolute amplitude of the marker movement was 1.5 ± 1.6 mm, 1.6 ± 1.7 mm, and 3.3 ± 3.3 mm in the left-right (LR), anterior-posterior (AP), and CC directions, respectively. The average marker displacements in the CC direction between peak exhalation and inhalation for the 22 clips were 1.1 mm (maximum, 5.5 mm), 3.0 mm (14.5 mm), and 5.1 mm (16.3 mm) for the upper, middle, and lower thoracic esophagus, respectively., Conclusions: Motion in primary esophagus tumor was evaluated with 320-multislice CT. According to this study, 4.3 mm CC, 1.5 mm AP, and 2.0 mm LR in the upper, 7.4 mm CC, 3.0 mm AP, and 2.4 mm LR in the middle, and 13.8 mm CC, 6.6 mm AP, and 6.8 mm LR in the lower thoracic esophagus provided coverage of tumor motion in 95% of the cases in our study population., (Copyright © 2011 Elsevier Inc. All rights reserved.)

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.

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.

Reconsolidation and extinction of fear memories are induced by re-exposure to the conditioned stimulus (CS) but they appear to be opposite processes; as the fear memory is maintained or inhibited through reconsolidation and extinction, respectively. More importantly, reconsolidation and extinction are thought to be potential targets for the treatment of Post Traumatic Stress Disorder (PTSD). From this view, it is important to understand mechanisms by which reactivated fear memories are reconsolidated or extinguished. Here, we review processes for fear memory regulation including consolidation, reconsolidation and extinction, and discuss implications of fear memory regulation with PTSD.

Long-term potentiation (LTP) is a key cellular model for studying mechanisms for learning and memory. Previous studies reported that the Ca(2+)/calmodulin-dependent protein kinase IV (CaMKIV) is critical for gene regulation, and behavioral learning and memory. Less is known about the roles of CaMKIV in cortical plasticity and trace fear memory. Here we have found that LTP was significantly enhanced in the anterior cingulate cortex (ACC) of the mice overexpressing CaMKIV. By contrast, neither alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated basal excitatory synaptic transmission nor N-methyl-d-aspartate (NMDA) receptor-mediated excitatory postsynaptic currents were affected. Furthermore, paired-pulse ratio in the transgenic mice is normal. In behavioral tests, we found that the CaMKIV transgenic mice exhibited significant enhancement in trace fear memory, while the acute sensory thresholds were not affected. Our results provide strong evidence that forebrain CaMKIV contributes to trace fear memory by enhancing synaptic potentiation in the ACC.

Acute depletion of brain tryptophan (TRP) levels in humans has been used as a biochemical model of depression. In this study, we examined the effects of consumption of a diet low in TRP on emotional behavior in mice. Specifically, we assessed various parameters of emotional behavior in mice fed a TRP-limited diet for at least 1 mo. TRP-limited mice showed increased defensive, but not offensive, aggression in the resident-intruder test. In the social dominance tube test, these mice showed enhanced social dominance. Since defensive aggression is thought to be a reflection of not only aggression but also fear, these changes in the social behavior of TRP-limited mice are thought to reflect changes in their emotional status. TRP-limited mice also showed increased locomotor activity and mobility in the open field and forced swim tests, respectively, suggesting that their stress/emotional responsiveness was enhanced. Importantly, these mice displayed normal levels of anxiety and motor performance as determined by the elevated zero maze and open field tests, and the rotarod test, respectively, suggesting that their hyperactivity was not due to a reduction in anxiety levels or to enhancement of their motor performance. Thus, dietary TRP restriction appears to result in alterations in the emotional response to stress, in mice.