Spaced conditioned stimulus presentation facilitates the extinction of strong fear memory in mice.

Inducing fear memory extinction by re-presenting a conditioned stimulus (CS) is the foundation of exposure therapy for post-traumatic stress disorder (PTSD). Investigating differences in the ability of different CS presentation patterns to induce extinction learning is crucial for improving this type of therapy. Using a trace fear conditioning paradigm in mice, we demonstrate that spaced presentation of the CS facilitated the extinction of a strong fear memory to a greater extent than continuous CS presentation. These results lay the groundwork for developing more effective exposure therapy techniques for PTSD.

[Retrograde Stanford Type A Aortic Dissection of Marfan Syndrome Long After Thoracic Endovascular Aortic Repair:Report of a Case].

A 52-year-old woman with Marfan syndrome developed Stanford type B aortic dissection and was treated with thoracic endovascular aortic repair. However, 29 months later, she presented with retrograde Stanford type A aortic dissection. We successfully performed aortic arch replacement with the frozen elephant trunk technique and valve-sparing aortic root replacement. The advantages of the frozen elephant trunk technique are that the distal anastomosis can be created without stent-graft resection and the cardiac arrest time is shortened. Therefore, the frozen elephant trunk technique was considered valuable and safe in this potentially lethal situation.

Fear generalization immediately after contextual fear memory consolidation in mice.

Fear generalization is a symptom of anxiety-related disorders, including acute stress disorder and post-traumatic stress disorder. Using a contextual fear conditioning paradigm, we found that mice exposed to a similar neutral context but not a different neutral context soon after training showed fear generalization immediately after contextual fear memory consolidation (i.e., 6 h after training). This fear generalization was reflected by a change not only in the total amount but also the pattern of freezing between conditioned and generalized contexts. These results provide insight into the factors that influence fear generalization and can facilitate future studies investigating the underlying pathophysiological mechanisms of anxiety-related disorders.

Remapping of Adult-Born Neuron Activity during Fear Memory Consolidation in Mice.

The mammalian hippocampal dentate gyrus is a unique memory circuit in which a subset of neurons is continuously generated throughout the lifespan. Previous studies have shown that the dentate gyrus neuronal population can hold fear memory traces (i.e., engrams) and that adult-born neurons (ABNs) support this process. However, it is unclear whether ABNs themselves hold fear memory traces. Therefore, we analyzed ABN activity at a population level across a fear conditioning paradigm. We found that fear learning did not recruit a distinct ABN population. In sharp contrast, a completely different ABN population was recruited during fear memory retrieval. We further provide evidence that ABN population activity remaps over time during the consolidation period. These results suggest that ABNs support the establishment of a fear memory trace in a different manner to directly holding the memory. Moreover, this activity remapping process in ABNs may support the segregation of memories formed at different times. These results provide new insight into the role of adult neurogenesis in the mammalian memory system.

Miniaturized microscope with flexible light source input for neuronal imaging and manipulation in freely behaving animals.

Simultaneous imaging and manipulation of a genetically defined neuronal population can provide a causal link between its activity and function. Here, we designed a miniaturized microscope (or 'miniscope') that allows fluorescence imaging and optogenetic manipulation at the cellular level in freely behaving animals. This miniscope has an integrated optical connector that accepts any combination of external light sources, allowing flexibility in the choice of sensors and manipulators. Moreover, due to its simple structure and use of open source software, the miniscope is easy to build and modify. Using this miniscope, we demonstrate the optogenetic silencing of hippocampal CA1 neurons using two laser light sources-one stimulating a calcium sensor (i.e., jGCaAMP7c) and the other serving as an optogenetic silencer (i.e., Jaws). This new miniscope can contribute to efforts to determine causal relationships between neuronal network dynamics and animal behavior.

Concise Review: Regulatory Influence of Sleep and Epigenetics on Adult Hippocampal Neurogenesis and Cognitive and Emotional Function.

Neural stem and progenitor cells continue to generate new neurons in particular regions of the brain during adulthood. One of these neurogenic regions is the dentate gyrus (DG) of the hippocampus, which plays an important role in cognition and emotion. By exploiting this innate neuronal regeneration mechanism in the DG, new technologies have the potential to promote resistance to or recovery from brain dysfunction or degeneration. However, a deeper understanding of how adult DG neurogenesis is regulated by factors such as sleep and epigenetic modifications of gene expression could lead to further breakthroughs in the clinical application of neural stem and progenitor cells. In this review, we discuss the functions of adult-born DG neurons, describe the epigenetic regulation of adult DG neurogenesis, identify overlaps in how sleep and epigenetic modifications impact adult DG neurogenesis and memory consolidation, and suggest ways of using sleep or epigenetic interventions as therapies for neurodegenerative and psychiatric disorders. By knitting together separate strands of the literature, we hope to trigger new insights into how the functions of adult-generated neurons are directed by interactions between sleep-related neural processes and epigenetic mechanisms to facilitate novel approaches to preventing and treating brain disorders such as depression, post-traumatic stress disorder, and Alzheimer's disease. Stem Cells 2018;36:969-976.

[Congenital Unicuspid Aortic Valve Diagnosed by Intraoperative Findings].

A unicuspid aortic valve is an extremely rare congenital aortic valvular abnormality. We herein present 2 cases of unicuspid aortic valve diagnosed based on intraoperative findings. In case 1, a 75-year-old man was admitted to our hospital because of severe aortic regurgitation. We performed aortic valve replacement using a bioprosthetic valve, and a unicuspid aortic valve was definitively diagnosed according to the intraoperative findings. In case 2, a 54-year-old man developed dyspnea due to severe aortic stenosis. Aortic valve replacement using mechanical valve was performed, and we were able to diagnose unicuspid aortic valve intraoperatively. Achieving a preoperative definitive diagnosis of congenital unicuspid aortic valve by transthoracic echocardiography is reportedly difficult;however, transesophageal echocardiography may be effective for preoperative definitive diagnosis.

Unique activation of the quadriceps femoris during single- and multi-joint exercises.

PURPOSE: This study aimed to examine whether muscle activation of the quadriceps femoris differs between single- and multi-joint exercises, and to explore the factors resulting in muscle and exercise specificity in activation. METHODS: Eleven adults developed isometric hip extension torque gradually while maintaining submaximal isometric knee extension torque (Experiment 1). In Experiment 2, 15 men performed knee extension and leg press separately at intensities of 20, 40, 60 and 80 % of their one repetition maximum (1RM) load, and 14 men conducted leg press at intensities of 40 and 80 % of 1RM until exhaustion (Experiment 3). Muscle activation during exercises was measured using surface electromyography from the rectus femoris, vastus lateralis and medialis. RESULTS: The addition of isometric hip extension torque significantly decreased rectus femoris activation (Experiment 1). In Experiment 2, the rectus femoris activation was significantly higher during knee extension than during leg press, whereas no differences were observed in the vasti. The rectus femoris activation was not significantly different between leg press at 80 % and knee extension at 20 % of 1RM. The results of Experiment 3 showed significant increases in vasti activation at both intensities, whereas rectus femoris activation did not change at 80 % of 1RM. CONCLUSION: The results revealed that even at high intensity, the rectus femoris activation during multi-joint exercise is low and does not increase with fatigue, unlike the vasti, and that the inter-muscle and inter-exercise differences in activation depend on whether hip extension torque is exerted in the exercise.

Posttraining ablation of adult-generated olfactory granule cells degrades odor-reward memories.

Proliferation of neural progenitor cells in the subventricular zone leads to the continuous generation of new olfactory granule cells (OGCs) throughout life. These cells synaptically integrate into olfactory bulb circuits after ∼2 weeks and transiently exhibit heightened plasticity and responses to novel odors. Although these observations suggest that adult-generated OGCs play important roles in olfactory-related memories, global suppression of olfactory neurogenesis does not typically prevent the formation of odor-reward memories, perhaps because residual OGCs can compensate. Here, we used a transgenic strategy to selectively ablate large numbers of adult-generated OGCs either before or after learning in mice. Consistent with previous studies, pretraining ablation of adult-generated OGCs did not prevent the formation of an odor-reward memory, presumably because existing OGCs can support memory formation in their absence. However, ablation of a similar cohort of adult-generated OGCs after training impaired subsequent memory expression, indicating that if these cells are available at the time of training, they play an essential role in subsequent expression of odor-reward memories. Memory impairment was associated with the loss of adult-generated OGCs that were >10 d in age and did not depend on the developmental stage in which they were generated, suggesting that, once sufficiently mature, OGCs generated during juvenility and adulthood play similar roles in the expression of odor-reward memories. Finally, ablation of adult-generated OGCs 1 month after training did not produce amnesia, indicating that adult-generated OGCs play a time-limited role in the expression of odor-reward memories.

[Risk Factors in Surgical Intervention for Prosthetic Valve Endocarditis].

The aim of this retrospective study was to detect the risk factors for in-hospital mortality after surgery for active prosthetic valve endocarditis ( PVE). We reviewed 35 operations for active PVE, including 6 cases of early PVE. Seven patients were New York Heart Association (NYHA) functional class IV. Preoperative mechanical ventilation was necessary in 3 patients, 1 patient required intra-aortic balloon pumping, and another needed percutaneous cardiopulmonary support. Preoperatively, cerebrovascular events were observed in 13 patients, annular abscess in 12, and perivalvular leakage in 14. Valve replacement was performed in 24 patients and aortic root replacement in 11. Annular reconstruction was required in 18 patients. There were 6 hospital deaths (17.1%). The results of risk factor analysis showed that early PVE, NYHA functional class IV, and preoperative mechanical ventilation were independent risk factors for in-hospital death after surgery. In conclusion, surgical treatment of PVE should be performed before hemodynamic deterioration.

Planar polarity of multiciliated ependymal cells involves the anterior migration of basal bodies regulated by non-muscle myosin II.

Motile cilia generate constant fluid flow over epithelial tissue, and thereby influence diverse physiological processes. Such functions of ciliated cells depend on the planar polarity of the cilia and on their basal bodies being oriented in the downstream direction of fluid flow. Recently, another type of basal body planar polarity, characterized by the anterior localization of the basal bodies in individual cells, was reported in the multiciliated ependymal cells that line the surface of brain ventricles. However, little is known about the cellular and molecular mechanisms by which this polarity is established. Here, we report in mice that basal bodies move in the apical cell membrane during differentiation to accumulate in the anterior region of ependymal cells. The planar cell polarity signaling pathway influences basal body orientation, but not their anterior migration, in the neonatal brain. Moreover, we show by pharmacological and genetic studies that non-muscle myosin II is a key regulator of this distribution of basal bodies. This study demonstrates that the orientation and distribution of basal bodies occur by distinct mechanisms.

Roles of planar cell polarity signaling in maturation of neuronal precursor cells in the postnatal mouse olfactory bulb.

Neuronal precursor cells generated by stem cells in the subventricular zone (SVZ) migrate and differentiate into mature interneurons in the olfactory bulb (OB). The mechanisms responsible for the dynamic morphological changes in cells during this process are largely unknown. Wnt/planar cell polarity (PCP) signaling regulates various developmental events, including neuronal migration and neurite formation. Here, we studied the function of two components of the PCP pathway, Dishevelled2 and Van Gogh like-2, in the newborn neurons in the postnatal mouse OB. Electroporation- or lentivirus-mediated introduction of vectors carrying a knockdown or dominant-negative construct of these genes into the SVZ altered the distribution and dendrite formation of newborn neurons in the OB, suggesting that PCP signaling is involved in regulating the maturation of new neurons in the OB.

Fully automatic REM sleep stage-specific intervention systems using single EEG in mice.

Sleep stage-specific intervention is widely used to elucidate the functions of sleep and their underlying mechanisms. For this intervention, it is imperative to accurately classify rapid-eye-movement (REM) sleep. However, the proof of fully automatic real-time REM sleep classification in vivo has not been obtained in mice. Here, we report the in vivo implementation of a system that classifies sleep stages in real-time from a single-channel electroencephalogram (EEG). It enabled REM sleep-specific intervention with 90 % sensitivity and 86 % precision without prior configuration to each mouse. We further derived systems capable of classification with higher frequency sampling and time resolution. This attach-and-go sleep staging system provides a fully automatic accurate and scalable tool for investigating the functions of sleep.

Posttraining ablation of adult-generated neurons degrades previously acquired memories.

New neurons are continuously generated in the subgranular zone of the adult hippocampus and, once sufficiently mature, are thought to integrate into hippocampal memory circuits. However, whether they play an essential role in subsequent memory expression is not known. Previous studies have shown that suppression of adult neurogenesis often (but not always) impairs subsequent hippocampus-dependent learning (i.e., produces anterograde effects). A major challenge for these studies is that these new neurons represent only a small subpopulation of all dentate granule cells, and so there is large potential for either partial or complete compensation by granule cells generated earlier on during development. A potentially more powerful approach to investigate this question would be to ablate adult-generated neurons after they have already become part of a memory trace (i.e., retrograde effects). Here we developed a diphtheria toxin-based strategy in mice that allowed us to selectively ablate a population of predominantly mature, adult-generated neurons either before or after learning, without affecting ongoing neurogenesis. Removal of these neurons before learning did not prevent the formation of new contextual fear or water maze memories. In contrast, removal of an equivalent population after learning degraded existing contextual fear and water maze memories, without affecting nonhippocampal memory. Ablation of these adult-generated neurons even 1 month after learning produced equivalent memory degradation in the water maze. These retrograde effects suggest that adult-generated neurons form a critical and enduring component of hippocampal memory traces.

Efficacy of landiolol hydrochloride for prevention of atrial fibrillation after heart valve surgery.

The goal of this prospective study was to examine the effects of landiolol hydrochloride on prevention of atrial fibrillation and on hemodynamics in the acute postoperative phase after heart valve surgery. The subjects were 60 patients who underwent valve surgery at our hospital from April 2008 to July 2010. The patients were randomly divided into two groups: the landiolol group (30 patients) and the control (no landiolol) group (30 patients). In the landiolol group, continuous intravenous landiolol was initiated immediately on admission to the intensive care unit at a dose of 10 µg/kg/ minute. Occurrence of atrial fibrillation was compared between the groups over an observation period of 72 hours after surgery. Atrial fibrillation occurred in 6 patients (20%) in the landiolol group and 16 (53.3%) in the control group during the observation period. Landiolol hydrochloride significantly reduced the occurrence of atrial fibrillation in the acute postoperative phase after heart valve surgery. Heart rate was significantly decreased by landiolol, but aggravation of hemodynamics was not observed. These results suggest that landiolol is a useful drug for prevention of atrial fibrillation after valve surgery.

[Papillary fibroelastoma of the left ventricular outflow tract].

Cardiac papillary fibroelastoma is an uncommon tumor, and especially the one located in the left ventricular outflow tract wall is rare. The patient is a 69-year-old female. Multi-detector-row computed tomography (MDCT) revealed a 20×15 mm tumor attached to the left ventricular outflow tract wall under the left coronary cusp. The tumor was surgically removed with a slight margin. The tumor was milk-white in color, and had an egg-like appearance. The histological findings revealed papillary fibroelastoma. The postoperative course was uneventful.

Functional convergence of developmentally and adult-generated granule cells in dentate gyrus circuits supporting hippocampus-dependent memory.

In the hippocampus, the production of dentate granule cells (DGCs) persists into adulthood. As adult-generated neurons are thought to contribute to hippocampal memory processing, promoting adult neurogenesis therefore offers the potential for restoring mnemonic function in the aged or diseased brain. Within this regenerative context, one key issue is whether developmentally generated and adult-generated DGCs represent functionally equivalent or distinct neuronal populations. To address this, we labeled separate cohorts of developmentally generated and adult-generated DGCs and used immunohistochemical approaches to compare their integration into circuits supporting hippocampus-dependent memory in intact mice. First, in the water maze task, rates of integration of adult-generated DGCs were regulated by maturation, with maximal integration not occurring until DGCs were five or more weeks in age. Second, these rates of integration were equivalent for embryonically, postnatally, and adult-generated DGCs. Third, these findings generalized to another hippocampus-dependent task, contextual fear conditioning. Together, these experiments indicate that developmentally generated and adult-generated DGCs are integrated into hippocampal memory networks at similar rates, and suggest a functional equivalence between DGCs generated at different developmental stages.

Expression and proliferation-promoting role of Diversin in the neuronally committed precursor cells migrating in the adult mouse brain.

The subventricular zone (SVZ) is the largest neurogenic region in the adult rodent brain. In the adult SVZ, unlike in the embryonic brain, neuronally committed precursor cells (neuroblasts) maintain their proliferative activity while migrating toward the olfactory bulb (OB), suggesting that they are inhibited from exiting the cell cycle. Little is known about the mechanisms underlying the unique ability of adult neuroblasts to proliferate during migration. Here, we studied the expression and function of Diversin, a component of the Wnt signaling pathways. In the neonatal and adult mouse brain, Diversin expression was observed in neuroblasts and mature neurons in the SVZ and hippocampus. Retrovirus-mediated overexpression of Diversin promoted the proliferation of neuroblasts and increased the number of neuroblasts that reached the OB. Conversely, the knockdown of Diversin decreased the proliferation of neuroblasts. Our results indicate that Diversin plays an important role in the proliferation of neuroblasts in the SVZ of the adult brain.