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The family of epidermal growth factor (EGF) including neuregulin-1 are implicated in the neuropathology of schizophrenia. We established a rat model of schizophrenia by exposing perinatal rats to EGF and reported that the auditory pathophysiological traits of this model such as prepulse inhibition, auditory steady-state response, and mismatch negativity are relevant to those of schizophrenia. We assessed the activation status of the auditory cortex in this model, as well as that in patients with schizophrenia, by monitoring the three neural activity-induced proteins: EGR1 (zif268), c-fos, and Arc. Among the activity markers, protein levels of EGR1 were significantly higher at the adult stage in EGF model rats than those in control rats. The group difference was observed despite an EGF model rat and a control rat being housed together, ruling out the contribution of rat vocalization effects. These changes in EGR1 levels were seen to be specific to the auditory cortex of this model. The increase in EGR1 levels were detectable at the juvenile stage and continued until old ages but displayed a peak immediately after puberty, whereas c-fos and Arc levels were nearly indistinguishable between groups at all ages with an exception of Arc decrease at the juvenile stage. A similar increase in EGR1 levels was observed in the postmortem superior temporal cortex of patients with schizophrenia. The commonality of the EGR1 increase indicates that the EGR1 elevation in the auditory cortex might be one of the molecular signatures of this animal model and schizophrenia associating with hallucination. [ABSTRACT FROM AUTHOR]

The Nogo signal is involved in impairment of memory formation. We previously reported the lateral olfactory tract usher substance (LOTUS) as an endogenous antagonist of the Nogo receptor 1 that mediates the inhibition of axon growth and synapse formation. Moreover, we found that LOTUS plays an essential role in neural circuit formation and nerve regeneration. However, the effects of LOTUS on synapse formation and memory function have not been elucidated. Here, we clearly showed the involvement of LOTUS in synapse formation and memory function. The cultured hippocampal neurons derived from lotus gene knockout (LOTUS-KO) mice exhibited a decrease in synaptic density compared with those from wild-type mice. We also found decrease of dendritic spine formation in the adult hippocampus of LOTUS-KO mice. Finally, we demonstrated that LOTUS deficiency impairs memory formation in the social recognition test and the Morris water maze test, indicating that LOTUS is involved in functions of social and spatial learning and memory. These findings suggest that LOTUS affects synapse formation and memory function. [ABSTRACT FROM AUTHOR]

Cognitive performance in people varies according to time-of-day, with memory retrieval declining in the late afternoon-early evening. However, functional roles of local brain circadian clocks in memory performance remains unclear. Here, we show that hippocampal clock controlled by the circadian-dependent transcription factor BMAL1 regulates time-of-day retrieval profile. Inducible transgenic dominant negative BMAL1 (dnBMAL1) expression in mouse forebrain or hippocampus disrupted retrieval of hippocampal memories at Zeitgeber Time 8–12, independently of retention delay, encoding time and Zeitgeber entrainment cue. This altered retrieval profile was associated with downregulation of hippocampal Dopamine-cAMP signaling in dnBMAL1 mice. These changes included decreases in Dopamine Receptors (D1-R and D5-R) and GluA1-S845 phosphorylation by PKA. Consistently, pharmacological activation of cAMP-signals or D1/5Rs rescued impaired retrieval in dnBMAL1 mice. Importantly, GluA1 S845A knock-in mice showed similar retrieval deficits with dnBMAL1 mice. Our findings suggest mechanisms underlying regulation of retrieval by hippocampal clock through D1/5R-cAMP-PKA-mediated GluA1 phosphorylation. The neural mechanisms that lead to a relative deficit in memory retrieval in the afternoon are unclear. Here, the authors show that the circadian - dependent transcription factor BMAL1 regulates retrieval through dopamine and glutamate receptor phosphorylation. [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]

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]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The cAMP-responsive element binding protein (CREB) family of transcription factors is thought to be critical in memory formation. To define the role of CREB in distinct memory processes, we derived transgenic mice with an inducible and reversible CREB repressor by fusing CREBS133A to a tamoxifen (TAM)–dependent mutant of an estrogen receptor ligand-binding domain (LBD). We found that CREB is crucial for the consolidation of long-term conditioned fear memories, but not for encoding, storage or retrieval of these memories. Our studies also showed that CREB is required for the stability of reactivated or retrieved conditioned fear memories. Although the transcriptional processes necessary for the stability of initial and reactivated memories differ, CREB is required for both. The findings presented here delineate the memory processes that require CREB and demonstrate the power of LBD-inducible transgenic systems in the study of complex cognitive processes. [ABSTRACT FROM AUTHOR]

In this study, we developed the world's first artificial intelligence (AI) system that assesses the dysplasia of blood cells on bone marrow smears and presents the result of AI prediction for one of the most representative dysplasia—decreased granules (DG). We photographed field images from the bone marrow smears from patients with myelodysplastic syndrome (MDS) or non-MDS diseases and cropped each cell using an originally developed cell detector. Two morphologists labelled each cell. The degree of dysplasia was evaluated on a four-point scale: 0–3 (e.g., neutrophil with severely decreased granules were labelled DG3). We then constructed the classifier from the dataset of labelled images. The detector and classifier were based on a deep neural network pre-trained with natural images. We obtained 1797 labelled images, and the morphologists determined 134 DGs (DG1: 46, DG2: 77, DG3: 11). Subsequently, we performed a five-fold cross-validation to evaluate the performance of the classifier. For DG1–3 labelled by morphologists, the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were 91.0%, 97.7%, 76.3%, 99.3%, and 97.2%, respectively. When DG1 was excluded in the process, the sensitivity, specificity, PPV, NPV, and accuracy were 85.2%, 98.9%, 80.6%, and 99.2% and 98.2%, respectively. [ABSTRACT FROM AUTHOR]

Transcription factor CREB is believed to play essential roles in the formation of long-term memory (LTM), but not in learning and short-term memory (STM). Surprisingly, we previously showed that transgenic mice expressing a dominant active mutant of CREB (DIEDML) in the forebrain (DIEDML mice) demonstrated enhanced STM and LTM in hippocampal-dependent, rapid, one-trial learning tasks. Here we show that constitutive activation of CREB enhances hippocampal-dependent learning of temporal association in trace fear conditioning and delayed matching-to-place tasks. We then show that in DIEDML mice the apical tuft dendrites of hippocampal CA1 pyramidal neurons, required for temporal association learning, display increased spine density, especially of thin spines and of Homer1-negative spines. In contrast, the basal and apical oblique dendrites of CA1 neurons, required for rapid one-trial learning, show increased density of thin, stubby, and mushroom spines and of Homer1-positive spines. Furthermore, DIEDML mice showed increased dendritic complexity in the proximal portion of apical CA1 dendrites to the soma. In contrast, forebrain overexpression of CaMKIV, leading to enhanced LTM but not STM, show normal learning and CA1 neuron morphology. These findings suggest that dendritic region-specific morphological changes in CA1 neurons by constitutive activation of CREB may contribute to improved learning and STM. [ABSTRACT FROM AUTHOR]