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Layer V neurons in the primary motor cortex (M1) are important for motor skill learning. Since pretreatment of either CNQX or APV in rat M1 layer V impaired rotor rod learning, we analysed training‐induced synaptic plasticity by whole‐cell patch‐clamp technique in acute brain slices. Rats trained for 1 day showed a decrease in small inhibitory postsynaptic current (mIPSC) frequency and an increase in the paired‐pulse ratio of evoked IPSCs, suggesting a transient decrease in presynaptic GABA release in the early phase. Rats trained for 2 days showed an increase in miniature excitatory postsynaptic current (mEPSC) amplitudes/frequency and elevated AMPA/NMDA ratios, suggesting a long‐term strengthening of AMPA receptor‐mediated excitatory synapses. Importantly, rotor rod performance in trained rats was correlated with the mean mEPSC amplitude and the frequency obtained from that animal. In current‐clamp analysis, 1‐day‐trained rats transiently decreased the current‐induced firing rate, while 2‐day‐trained rats returned to pre‐training levels, suggesting dynamic changes in intrinsic properties. Furthermore, western blot analysis of layer V detected decreased phosphorylation of Ser408–409 in GABAA receptor β3 subunits in 1‐day‐trained rats, and increased phosphorylation of Ser831 in AMPA receptor GluA1 subunits in 2‐day‐trained rats. Finally, live‐imaging analysis of Thy1‐YFP transgenic mice showed that the training rapidly recruited a substantial number of spines for long‐term plasticity in M1 layer V neurons. Taken together, these results indicate that motor training induces complex and diverse plasticity in M1 layer V pyramidal neurons. Key points: Here we examined motor training‐induced synaptic and intrinsic plasticity of layer V pyramidal neurons in the primary motor cortex.The training reduced presynaptic GABA release in the early phase, but strengthened AMPA receptor‐mediated excitatory synapses in the later phase: acquired motor performance after training correlated with the strength of excitatory synapses rather than inhibitory synapses.As to the intrinsic property, the training transiently decreased the firing rate in the early phase, but returned to pre‐training levels in the later phase.Western blot analysis detected decreased phosphorylation of Ser408‐409 in GABAA receptor β3 subunits in the acute phase, and increased phosphorylation of Ser831 in AMPA receptor GluA1 subunits in the later phase.Live‐imaging analysis of Thy1‐YFP transgenic mice showed rapid and long‐term spine plasticity in M1 layer V neurons, suggesting training‐induced increases in self‐entropy per spine. [ABSTRACT FROM AUTHOR]

To determine the critical timing for learning and the associated synaptic plasticity, we analyzed developmental changes in learning together with training-induced plasticity. Rats were subjected to an inhibitory avoidance (IA) task prior to weaning. While IA training did not alter latency at postnatal day (PN) 16, there was a significant increase in latency from PN 17, indicating a critical day for IA learning between PN 16 and 17. One hour after training, acute hippocampal slices were prepared for whole-cell patch clamp analysis following the retrieval test. In the presence of tetrodotoxin (0.5 µM), miniature excitatory postsynaptic currents (mEPSCs) and inhibitory postsynaptic currents (mIPSCs) were sequentially recorded from the same CA1 neuron. Although no changes in the amplitude of mEPSCs or mIPSCs were observed at PN 16 and 21, significant increases in both excitatory and inhibitory currents were observed at PN 23, suggesting a specific critical day for training-induced plasticity between PN 21 and 23. Training also increased the diversity of postsynaptic currents at PN 23 but not at PN 16 and 21, demonstrating a critical day for training-induced increase in the information entropy of CA1 neurons. Finally, we analyzed the plasticity at entorhinal cortex layer III (ECIII)-CA1 or CA3-CA1 synapses for each individual rat. At either ECIII-CA1 or CA3-CA1 synapses, a significant correlation between mean α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid/N-methyl-D-aspartic acid (AMPA/NMDA) ratio and learning outcomes emerged at PN 23 at both synapses, demonstrating a critical timing for the direct link between AMPA receptor-mediated synaptic plasticity and learning efficacy. Here, we identified multiple critical periods with respect to training-induced synaptic plasticity and delineated developmental trajectories of learning mechanisms at hippocampal CA1 synapses.

Background: The intratumor heterogeneity (ITH) of cancer cells plays an important role in breast cancer resistance and recurrence. To develop better therapeutic strategies, it is necessary to understand the molecular mechanisms underlying ITH and their functional significance. Patient-derived organoids (PDOs) have recently been utilized in cancer research. They can also be used to study ITH as cancer cell diversity is thought to be maintained within the organoid line. However, no reports investigated intratumor transcriptomic heterogeneity in organoids derived from patients with breast cancer. This study aimed to investigate transcriptomic ITH in breast cancer PDOs., Methods: We established PDO lines from ten patients with breast cancer and performed single-cell transcriptomic analysis. First, we clustered cancer cells for each PDO using the Seurat package. Then, we defined and compared the cluster-specific gene signature (ClustGS) corresponding to each cell cluster in each PDO., Results: Cancer cells were clustered into 3-6 cell populations with distinct cellular states in each PDO line. We identified 38 clusters with ClustGS in 10 PDO lines and used Jaccard similarity index to compare the similarity of these signatures. We found that 29 signatures could be categorized into 7 shared meta-ClustGSs, such as those related to the cell cycle or epithelial-mesenchymal transition, and 9 signatures were unique to single PDO lines. These unique cell populations appeared to represent the characteristics of the original tumors derived from patients., Conclusions: We confirmed the existence of transcriptomic ITH in breast cancer PDOs. Some cellular states were commonly observed in multiple PDOs, whereas others were specific to single PDO lines. The combination of these shared and unique cellular states formed the ITH of each PDO., (© 2023. The Author(s).)

Background: The Japan Surveillance for Infection Prevention and Healthcare Epidemiology (J-SIPHE) system aggregates information related to antimicrobial resistance (AMR) measures in participating medical institutions nationwide and is intended to be used for promotion of AMR measures in participating facilities and their communities. This multicenter study aimed to determine the usefulness of the J-SIPHE system for evaluating the correlation between antibiotic use and antibiotic resistance in Hokkaido, Japan., Methods: Data on antibiotic use and detection rate of major resistant Gram-negative bacteria at 19 hospitals in 2020 were collected from the J-SIPHE system, and data correlations were analyzed using JMP Pro., Results: The detection rate of carbapenem-resistant Pseudomonas aeruginosa was significantly positively correlated with carbapenem use (Spearman's ρ = 0.551; P = .015). There were significant positive correlations between the detection rate of fluoroquinolone-resistant Escherichia coli and the use of piperacillin/tazobactam, carbapenems, and quinolones [ρ = 0.518 (P = .023), ρ = 0.76 (P < .001), and ρ = 0.502 (P = .029), respectively]., Conclusions: This is the first multicenter study to investigate the correlation between antibiotic use and antibiotic resistance using the J-SIPHE system. The results suggest that using this system may be beneficial for promoting AMR measures., (Copyright © 2022 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.)

Postnatal development of hippocampal function has been reported in many mammalian species, including humans. To obtain synaptic evidence, we analyzed developmental changes in plasticity after an inhibitory avoidance task in rats. Learning performance was low in infants (postnatal 2 weeks) but clearly improved from the juvenile period (3-4 weeks) to adulthood (8 weeks). One hour after the training, we prepared brain slices and sequentially recorded miniature excitatory postsynaptic currents (mEPSCs) and inhibitory postsynaptic currents (mIPSCs) from the same hippocampal CA1 neuron. Although the training failed to affect the amplitude of either mEPSCs or mIPSCs at 2 weeks, it increased mEPSC, but not mIPSC, amplitude at 3 weeks. At 4 weeks, the training had increased the amplitude of both mEPSCs and mIPSCs, whereas mIPSC, but not mEPSC, amplitude was increased at 8 weeks. Because early-life physiological functions can affect performance, we also evaluated sensory-motor functions together with emotional state and found adequate sensory/motor functions from infancy to adulthood. Moreover, by analyzing performance of rats in multiple hippocampal-dependent tasks, we found that the developmental changes in the performance are task dependent. Taken together, these findings delineate a critical period for learning and plastic changes at hippocampal CA1 synapses., (© 2022. The Author(s).)

The hippocampus is a primary area for contextual memory, known to process spatiotemporal information within a specific episode. Long-term strengthening of glutamatergic transmission is a mechanism of contextual learning in the dorsal cornu ammonis 1 (CA1) area of the hippocampus. CA1-specific immobilization or blockade of α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptor delivery can impair learning performance, indicating a causal relationship between learning and receptor delivery into the synapse. Moreover, contextual learning also strengthens GABA A (gamma-aminobutyric acid) receptor-mediated inhibitory synapses onto CA1 neurons. Recently we revealed that strengthening of GABA A receptor-mediated inhibitory synapses preceded excitatory synaptic plasticity after contextual learning, resulting in a reduced synaptic excitatory/inhibitory (E/I) input balance that returned to pretraining levels within 10 min. The faster plasticity at inhibitory synapses may allow encoding a contextual memory and prevent cognitive dysfunction in various hippocampal pathologies. In this review, we focus on the dynamic changes of GABA A receptor mediated-synaptic currents after contextual learning and the intracellular mechanism underlying rapid inhibitory synaptic plasticity. In addition, we discuss that several pathologies, such as Alzheimer's disease, autism spectrum disorders and epilepsy are characterized by alterations in GABA A receptor trafficking, synaptic E/I imbalance and neuronal excitability.

Adolescence is the critical postnatal stage for the action of androgen in multiple brain regions. Androgens can regulate the learning/memory functions in the brain. It is known that the inhibitory avoidance test can evaluate emotional memory and is believed to be dependent largely on the amygdala and hippocampus. However, the effects of androgen on inhibitory avoidance memory have never been reported in adolescent male rats. In the present study, the effects of androgen on inhibitory avoidance memory and on androgen receptor (AR)-immunoreactivity in the amygdala and hippocampus were studied using behavioral analysis, Western blotting and immunohistochemistry in sham-operated, orchiectomized, orchiectomized + testosterone or orchiectomized + dihydrotestosterone-administered male adolescent rats. Orchiectomized rats showed significantly reduced time spent in the illuminated box after 30 min (test 1) or 24 h (test 2) of electrical foot-shock (training) and reduced AR-immunoreactivity in amygdala/hippocampal cornu Ammonis (CA1) in comparison to those in sham-operated rats. Treatment of orchiectomized rats with either non-aromatizable dihydrotestosterone or aromatizable testosterone were successfully reinstated these effects. Application of flutamide (AR-antagonist) in intact adolescent rats exhibited identical changes to those in orchiectomized rats. These suggest that androgens enhance the inhibitory avoidance memory plausibly by binding with AR in the amygdala and hippocampus.

Androgen receptor (AR) is abundantly expressed in the preoptico-hypothalamic area, bed nucleus of stria terminalis, and medial amygdala of the brain where androgen plays an important role in regulating male sociosexual, emotional and aggressive behaviors. In addition to these brain regions, AR is also highly expressed in the hippocampus, suggesting that the hippocampus is another major target of androgenic modulation. It is known that androgen can modulate synaptic plasticity in the CA1 hippocampal subfield. However, to date, the effects of androgen on the intrinsic plasticity of hippocampal neurons have not been clearly elucidated. In this study, the effects of androgen on the expression of AR in the hippocampus and on the dynamics of intrinsic plasticity of CA1 pyramidal neurons were examined using immunohistochemistry, Western blotting and whole-cell current-clamp recording in unoperated, sham-operated, orchiectomized (OCX), OCX + testosterone (T) or OCX + dihydrotestosterone (DHT)-primed adolescent male rats. Orchiectomy significantly decreased AR-immunoreactivity, resting membrane potential, action potential numbers, afterhyperpolarization amplitude and membrane resistance, whereas it significantly increased action potential threshold and membrane capacitance. These effects were successfully reversed by treatment with either aromatizable androgen T or non-aromatizable androgen DHT. Furthermore, administration of the AR-antagonist flutamide in intact rats showed similar changes to those in OCX rats, suggesting that androgens affect the excitability of CA1 pyramidal neurons possibly by acting on the AR. Our current study potentially clarifies the role of androgen in enhancing the basal excitability of the CA1 pyramidal neurons, which may influence selective neuronal excitation/activation to modulate certain hippocampal functions., (Copyright © 2020 IBRO. Published by Elsevier Ltd. All rights reserved.)

Contextual learning requires the delivery of AMPA receptors to CA1 synapses in the dorsal hippocampus. However, proximodistal heterogeneity of pathway-specific plasticity remains unclear. Here, we examined the proximodistal heterogeneity in learning-induced plasticity at the CA1 synapses with inputs from the entorhinal cortex layer III (ECIII) or from CA3. We subjected male rats to an inhibitory avoidance task and prepared acute hippocampal slices for whole-cell patch clamp experiments, where we stimulated ECIII-CA1 or CA3-CA1 input fibers to analyze evoked excitatory postsynaptic currents (EPSCs). Compared to untrained controls, trained rats exhibited higher AMPA/NMDA current ratios at CA3-CA1 synapses of proximal and intermediate, but not distal CA1 neurons, which suggested that region-specific plasticity occurred after learning. Moreover, trained rats exhibited higher AMPA/NMDA current ratios at ECIII-CA1 synapses of intermediate and distal, but not proximal CA1 neurons. These findings suggested the presence of proximodistal heterogeneity in pathway-specific postsynaptic plasticity. Regarding presynaptic plasticity, training slightly, but significantly increased the paired-pulse ratios of CA3-CA1 synapses of proximal and intermediate, but not distal CA1 neurons. Moreover, trained rats exhibited higher paired-pulse ratios at ECIII-CA1 synapses of intermediate and distal, but not proximal CA1 neurons, which suggested region-specific presynaptic plasticity. Finally, learning was clearly prevented by the bilateral microinjection of a plasticity blocker in the proximal or intermediate, but not distal CA1 subfields, which suggested functional heterogeneity along the proximodistal axis. Understanding region- and pathway-specific plasticity at dorsal CA1 synapses could aid in controlling encoded memory., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The configural association theory and the conflict resolution model propose that hippocampal function is involved in learning negative patterning tasks (A+, B+, AB-). The first theory suggests a critical role of the hippocampus in the formation of configural representations of compound stimuli, in which stimuli A and B are presented simultaneously. The second theory hypothesizes that the hippocampus is important for inhibiting the response to a stimulus that is in conflict with response tendencies. Although these theories propose different interpretations of the link between hippocampal function and non-spatial discrimination tasks, they both predict that the hippocampus is involved in the information processing of compound stimuli in negative patterning tasks. Recently, our electrophysiological approach has shown that the hippocampal theta power correlate with response inhibition in a negative patterning task, positive patterning, simultaneous/serial feature negative task. These findings provide strong support for the assumption of the conflict resolution model that the role of the hippocampus in learning is to inhibit responses to conflicting stimuli during non-spatial stimulus discrimination tasks., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Although contextual learning requires plasticity at both excitatory and inhibitory ( E / I ) synapses in cornu ammonis 1 (CA1) neurons, the temporal dynamics across the neuronal population are poorly understood. Using an inhibitory avoidance task, we analyzed the dynamic changes in learning-induced E / I synaptic plasticity. The training strengthened GABA A receptor-mediated synapses within 1 min, peaked at 10 min, and lasted for over 60 min. The intracellular loop (Ser 408-409 ) of GABA A receptor β 3 subunit was also phosphorylated within 1 min of training. As the results of strengthening of α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor-mediated synapses, CA1 pyramidal neurons exhibited broad diversity of E / I synaptic currents within 5 min. Moreover, presynaptic glutamate release probability at basal dendrites also increased within 5 min. To further quantify the diversified E / I synaptic currents, we calculated self-entropy (bit) for individual neurons. The neurons showed individual levels of the parameter, which rapidly increased within 1 min of training and maintained for over 60 min. These results suggest that learning-induced synaptic plasticity is critical immediately following encoding rather than during the retrieval phase of the learning. Understanding the temporal dynamics along with the quantification of synaptic diversity would be necessary to identify a failure point for learning-promoted plasticity in cognitive disorders.-Sakimoto, Y., Kida, H., Mitsushima, D. Temporal dynamics of learning-promoted synaptic diversity in CA1 pyramidal neurons.

A 73-year-old woman had a history of medication, including methotrexate for rheumatoid arthritis, for 5 years. She had chronic epigastralgia for 2 weeks and found to have multiple submucosal tumors on upper gastrointestinal endoscopy in another hospital. She had a strong abdominal pain thereafter and diagnosed as having gastrointestinal perforation on the basis of CT scans. Abdominal examination revealed disseminated peritonitis, and emergency laparoscopic surgery was performed on the day of admission. A 1 cm perforation of the ileum was identified, and a 5 cm mass of the mesentery near the perforation was also identified. Small bowel partial resection, including both lesions, was performed. From the intraoperative findings, methotrexate-associated lymphoproliferative disorders(MTX-LPD)was suspected, and methotrexate was discontinued after the surgery. At a later date, the pathological result from both the surgical specimen and upper gastrointestinal endoscopy was diffuse large B cell lymphoma(DLBCL). CT scan, PET-CT scan, and upper gastrointestinal endoscopy were performed 1-2 months after surgery, and no tumor was identified. Currently, 6 months after the surgery, the patient is still alive without any progression of the lymphoma.

A man in the 60s visited our hospital with the complaints of epigastralgia and weight loss. Following an investigation, he was diagnosed with human epidermal growth factor receptor 2(HER2)-positive gastric cancer with invasion to the pancreas (T4b[pancreas], N2, M0, Stage ⅣA[Union for International Cancer Control 8th edition]). Preoperatively, he was administered a chemotherapeutic regimen of S-1 and cisplatin plus trastuzumab. After 2 courses of chemotherapy, computed tomography revealed invasion to the abdominal wall and pyloric stenosis; however, invasion to the pancreas was obscured, and the lymph node metastases had shrunk. He underwent laparoscopic gastro-jejunostomy. After 4 courses of chemotherapy, his condition was considered stable. A laparoscopic distal gastrectomy was performed together with resection of the abdominal wall invasion. The pathological stage was pT4b(abdominal wall), pN0, M0, Stage ⅢA, and R0 resection was achieved. The patient was administered 4 courses of adjuvant capecitabine plus oxaliplatin therapy and 4 courses of capecitabine monotherapy. He has been followed-up for 1.5 years since the curative resection and has not developed recurrences. This case suggests the usefulness of multimodal therapy for locally advanced gastric cancer.

The patient was a man in his 40s, who had undergone laparoscopic ileocecal resection with lymph node dissection(D3)for cecal cancer in January 2012. Histopathological examination of the resected specimens had revealed StageⅡ primary tumor with subserosal invasion and positive metastasis in 1-3 regional lymph nodes(pT2[SS]n1[+]). The pathological stage was Ⅲa(fStage Ⅲa), and the tumor showed RAS gene mutation. The patient was administered 5 cycles of postoperative adjuvant chemotherapy with oral tegafur/uracil(UFT)in combination with calcium folinate(UZEL). Abdominal computed tomography( CT)performed 1.5 years postoperatively revealed liver metastasis, and a laparoscopic partial hepatectomy was performed in August 2015. In addition, a node in the greater omentum, located in the inferior surface of the liver, was also resected. Histopathological examination of the resected specimens revealed peritoneal metastasis, based on the identification of the same type of adenocarcinoma as the colon cancer. The patient was given 8 cycles of adjuvant chemotherapy with capecitabine and oxaliplatin(CapeOX). Then, he presented with colonic ileus, caused by recurrent dissemination, and underwent a laparoscopic transverse colectomy in October 2015. Multiple perineal disseminations were found intraoperatively, and chemotherapy was initiated with irinotecan plus tegafur/gimeracil/oteracil(S-1)plus bevacizumab(IRIS/BV)for the recurrent and unresectable disease. After 27 cycles of this regimen, lung metastasis was detected; in addition, progression of the para-aortic node metastasis around the celiac plexus was also observed, and the patient was considered as having pro- gressive disease(PD). Treatment with trifluridine/tipiracil(TAS102)was started in September 2017. Prior to the initiation of this regimen, the dose of opioid rescue medication previously started for back and abdominal pain was rapidly increased. Accordingly, the base dose was increased, but the pain could not be controlled, and the major pain was consistently located along the area of innervation in the celiac plexus. Therefore, celiac plexus neurolysis(CPN)was performed as a local therapy. A CT-guided injection technique was used to administer urografin, bupivacaine, and absolute ethanol to complete the procedure. The patient was discharged without major complications, and the base opioid dose was gradually reduced. Since the patient did not require any rescue medication during daytime on some days, the reduction of the base opioid dose was significantly effective in improving the patient's quality of life(QOL). In patients with pain possibly caused by metastasis to the para-aortic nodes, this local therapy technique may be considered.

The slice patch clamp technique is a powerful tool for investigating learning-induced neural plasticity in specific brain regions. To analyze motor-learning induced plasticity, we trained rats using an accelerated rotor rod task. Rats performed the task 10 times at 30-s intervals for 1 or 2 days. Performance was significantly improved on the training days compared to the first trial. We then prepared acute brain slices of the primary motor cortex (M1) in untrained and trained rats. Current-clamp analysis showed dynamic changes in resting membrane potential, spike threshold, afterhyperpolarization, and membrane resistance in layer II/III pyramidal neurons. Current injection induced many more spikes in 2-day trained rats than in untrained controls. To analyze contextual-learning induced plasticity, we trained rats using an inhibitory avoidance (IA) task. After experiencing foot-shock in the dark side of a box, the rats learned to avoid it, staying in the lighted side. We prepared acute hippocampal slices from untrained, IA-trained, unpaired, and walk-through rats. Voltage-clamp analysis was used to sequentially record miniature excitatory and inhibitory postsynaptic currents (mEPSCs and mIPSCs) from the same CA1 neuron. We found different mean mEPSC and mIPSC amplitudes in each CA1 neuron, suggesting that each neuron had different postsynaptic strengths at its excitatory and inhibitory synapses. Moreover, compared with untrained controls, IA-trained rats had higher mEPSC and mIPSC amplitudes, with broad diversity. These results suggested that contextual learning creates postsynaptic diversity in both excitatory and inhibitory synapses at each CA1 neuron. AMPA or GABAA receptors seemed to mediate the postsynaptic currents, since bath treatment with CNQX or bicuculline blocked the mEPSC or mIPSC events, respectively. This technique can be used to study different types of learning in other regions, such as the sensory cortex and amygdala.

It is believed that a transient decline in hippocampal theta power is induced by behavioral inhibition during a go/no-go stimulus discrimination task. In a previously reported positive patterning (PP) task, rats learn to lever press when a compound stimulus, both tone and light, is presented and inhibit their lever press when a single stimulus, tone or light, is presented. In this task, rats were required to inhibit their response to the single stimulus in a task where both compound and single stimuli were presented with an overlapping element. Thus, we hypothesized that there would be a transient decline in hippocampal theta power induced by behavioral inhibition to the presence of a single stimuli in the PP task. The result of this study showed that a decline in hippocampal theta power occurred during response inhibition to the presence of a single tone stimulus in the PP task, supporting our hypothesis. However, we did not observe any decline in hippocampal theta power during response inhibition to the presence of a single light stimulus. We found that the error response rate for the tone stimulus was slightly lower than that for light stimulus in the PP task. Thus, we proposed that the decline in hippocampal theta power related to more accurate response inhibition to the stimulus that had an overlapping element.

Although it has been shown that hippocampal theta power transiently declines during response inhibition in a simultaneous feature negative (FN: A+, AB-) task, observations of additional changes after this initial decline have been inconsistent across subjects. We hypothesized that the cause of these inconsistencies might be that variations in the learning speed for the FN task differentially affect the changes in hippocampal theta activity observed during the task. In this study, we classified rats into three groups (fast, intermediate, and slow FN-learning groups) based on the number of sessions required to complete learning of the FN task. We then examined whether there was a difference in hippocampal theta power among the fast, intermediate, and slow FN-learning groups, and rats that learned a simple discrimination task (SD group). We observed that compared to the SD group, the slow FN-learning group, but not the fast FN-learning group, showed an increase in hippocampal theta power. In addition, a transient decline of hippocampal theta power occurred in the fast FN-learning group, but not in the slow FN-learning group. These results indicate that the hippocampal theta activity during response inhibition in the FN task differed between fast- and slow-learning rats. Thus, we propose that a difference in learning speed affected hippocampal theta activity during response inhibition under a conflict state., (Copyright © 2015 Elsevier B.V. All rights reserved.)

It is believed that a decline in hippocampal theta power is induced by response inhibition for a conflict stimulus having an overlapping element. This study used a simultaneous feature positive (simul FP: A-, AX+) task and a serial FP (A-, X→A+) task. In these tasks, the compound and single stimuli have an overlapping element, and rats are required to exhibit response inhibition for the single stimulus A. We examined hippocampal theta activity during simul FP (A-, AX+), serial FP (A-, X→A+), and simple discrimination (SD; A-, X+) tasks and revealed that the transient decrease in hippocampal theta power occurred during response inhibition for the single stimulus A in simul FP tasks, which provides evidence that a transient decline in hippocampal theta power is induced by behavioral inhibition of conflict stimuli having an overlapping element. Thus, we concluded that the transient decline in hippocampal theta power was induced by behavioral inhibition for the conflict stimulus having an overlapping element., (Copyright © 2014 Elsevier B.V. All rights reserved.)

A recent behavioral inhibitory theory proposed that the hippocampus plays an important role in response inhibition to conflicting stimuli composed of simple inhibitory associations between events embedded in concurrent simple excitatory associations. In addition, the theory states that a serial feature negative (FN) task is a hippocampal-dependent task requiring the formation of a simple inhibitory association; on the other hand, a simple discrimination (SD) task is a typical hippocampus-independent task. In the present study, we recorded hippocampal theta activity from rats during FN and SD tasks to identify any potential differences. In the FN (A+, B→A-) task used in this study, rats were required to press a lever to present stimulus A (A+) and avoid pressing a lever to present a serial compound stimulus (B→A-). In the simple discrimination task (A+, B-), rats were required to press a lever to present stimulus A (A+) and avoid pressing a lever to present stimulus B (B-). We observed a transient decline of hippocampal theta power during response inhibition for a serial compound stimulus in the FN task. Thus, we conclude that the transient decline in hippocampal theta power reflects response inhibition for a conflicting stimulus. The results of the present study strongly support the behavioral inhibition theory., (Copyright © 2014 Elsevier B.V. All rights reserved.)

It was showed that solving a simple discrimination task (A+, B-) and a simultaneous feature-negative (FN) task (A+, AB-) used the hippocampal-independent strategy. Recently, we showed that the number of sessions required for a rat to completely learn a task differed between the FN and simple discrimination tasks, and there was a difference in hippocampal theta activity between these tasks. These results suggested that solving the FN task relied on a different strategy than the simple discrimination task. In this study, we provided supportive evidence that solving the FN and simple discrimination tasks involved different strategies by examining changes in performance and hippocampal theta activity in the FN task after transfer from the simple discrimination task (A+, B- → A+, AB-). The results of this study showed that performance on the FN task was impaired and there was a difference in hippocampal theta activity between the simple discrimination task and FN task. Thus, we concluded that solving the FN task uses a different strategy than the simple discrimination task.

To determine the developmental trajectory of hippocampal function in rats, we examined 24-h changes in extracellular acetylcholine (ACh) levels and contextual learning performance. Extracellular ACh significantly correlated with spontaneous behavior, exhibiting a 24-h rhythm in juvenile (4-week-old), pubertal (6-week-old), and adult (9- to 12-week-old) rats. Although juveniles of both sexes exhibited low ACh levels, adult males had higher ACh levels than adult females. Moreover, juveniles exhibited much more spontaneous activity than adults when they showed equivalent ACh levels. Similarly, juveniles of both sexes exhibited relatively low contextual learning performance. Because contextual learning performance was significantly increased only in males, adult males exhibited better performance than adult females. We also observed a developmental relationship between contextual learning and ACh levels. Scopolamine pretreatment blocked contextual learning and interrupted the correlation. Since long-term scopolamine treatment after weaning impaired contextual learning in juveniles, the cholinergic input may participate in the development of hippocampus.

A 44-year-old woman with a history of transient right hemiparesis presented with personality change. One year later, she was admitted with ophthalmoparesis, dysarthria and regression phenomenon. MRI indicated acute infarction of the paramedian region of the midbrain and a nodular lesion in the interpeduncular fossa with contrast enhancement. Two years later, the patient was admitted with sudden onset of right hemiplegia. MRI showed acute infarction in the left side of the pons, diffuse brain atrophy, and abnormal contrast enhancement in the nodular lesion of interpeduncular fossa and leptomeninges of the ventral pons. MR angiography revealed that cerebral main tracts were intact, and cerebrospinal fluid analysis revealed mild pleocytosis and slightly elevated protein levels. Cervical lymph node biopsy demonstrated caseating granuloma with acid-fast bacilli. The patient was diagnosed with chronic tuberculous meningitis, even though tuberculous bacilli were not detected on polymerase chain reaction (PCR) or in culture. Antituberculous medication resulted in radiological resolution and neurological improvement. Although the patient had mild headache and pyrexia at the first admission, no signs of meningeal irritation were confirmed throughout the clinical course. We suspect that a paucity of tuberculous bacilli released from the tuberculous foci in the meninges to the subarachnoid space caused prolonged clinical course and lack of meningeal irritation signs.

In experiment 1 of this study, we compared hippocampal theta activity between negative patterning and simple discrimination tasks. Our results demonstrated a transient decline in theta activity during response inhibition for a compound stimulus in the negative patterning task. In experiment 2 of this study, we compared hippocampal theta activity among simultaneous feature-negative, compound stimulus discrimination, and simple discrimination tasks in order to determine the cause of the decline in hippocampal theta activity during negative patterning tasks. Our results revealed that the decline in hippocampal theta activity occurred during the response inhibition for a compound stimulus in the simultaneous feature-negative task but not during the compound stimulus discrimination or simple discrimination tasks. Thus, we conclude that the transient decline in hippocampal theta activity is related to the inhibition in response to a compound stimulus that has an element that overlaps with a single stimulus., (Crown Copyright © 2013. Published by Elsevier B.V. All rights reserved.)

Hippocampal function is important in the acquisition of negative patterning but not of simple discrimination. This study examined rat hippocampal theta activity during the acquisition stages (early, middle, and late) of the negative patterning task (A+, B+, AB-). The results showed that hippocampal theta activity began to decline transiently (for 500 ms after non-reinforced stimulus presentation) during the late stage of learning in the negative patterning task. In addition, this transient decline in hippocampal theta activity in the late stage was lower in the negative patterning task than in the simple discrimination task. This transient decline during the late stage of task acquisition may be related to a learning process distinctive of the negative patterning task but not the simple discrimination task. We propose that the transient decline of hippocampal theta activity reflects inhibitory learning and/or response inhibition after the presentation of a compound stimulus specific to the negative patterning task.

The hippocampus is important in learning during a discrimination-reversal task. In this task, animals first learn to emit the go response to one stimulus and the no-go response to another stimulus (S1+, S2-) during the discrimination phase, and then they learn to reverse these relationships between stimulus and response during the reversal phase (S1-, S2+). To emit a no-go response for non-reinforced trial during the reversal phase, animals needed to inhibit the previously learned response pattern. This study examined the relationship between the reversal phase of the discrimination-reversal task and hippocampal electric activity in operant conditioning. The results revealed that hippocampal theta power transiently declined during the non-reinforced trial in the reversal phase compared with that during the discrimination phase. This decrease was observed during the 400-600-ms epoch after the onset of stimulus presentation. This study suggested that transient decline in hippocampal theta power is related to negative memory retrieval., (Copyright © 2013 Elsevier B.V. All rights reserved.)

This study examined hippocampal theta power during configural and non-configural tasks in rats. Experiment 1 compared hippocampal theta power during a negative patterning task (A+, B+, AB-) to a configural task and a simple discrimination task (A+, B-) as a non-configural task. The results showed that hippocampal theta power during the non-reinforcement trial (non-RFT) of the negative patterning task was higher than that during the simple discrimination task. However, this hippocampal power may reflect sensory processing for compound stimuli that have cross-modality features (the non-RFT of the negative patterning task was presented together with visual and auditory stimuli, but the non-RFT of the simple discrimination task was presented with visual or auditory stimulus alone). Thus, in experiment 2, we examined whether the experiment 1 results were attributable to sensory processing of a compound stimulus by comparing hippocampal theta power during negative patterning (A+, B+, AB-), simultaneous feature-negative (A+, AB-), and simple discrimination tasks (A+, B-). Experiment 2 showed that hippocampal theta activity during the non-RFT in the negative patterning task was higher than that in the simultaneous feature-negative and simple discrimination tasks. Thus, we showed that hippocampal theta activity increased during configural tasks but not during non-configural tasks.

This study examined configural association theory and conflict resolution models in relation to hippocampal neural activity during positive patterning tasks. According to configural association theory, the hippocampus is important for responses to compound stimuli in positive patterning tasks. In contrast, according to the conflict resolution model, the hippocampus is important for responses to single stimuli in positive patterning tasks. We hypothesized that if configural association theory is applicable, and not the conflict resolution model, the hippocampal theta power should be increased when compound stimuli are presented. If, on the other hand, the conflict resolution model is applicable, but not configural association theory, then the hippocampal theta power should be increased when single stimuli are presented. If both models are valid and applicable in the positive patterning task, we predict that the hippocampal theta power should be increased by presentation of both compound and single stimuli during the positive patterning task. To examine our hypotheses, we measured hippocampal theta power in rats during a positive patterning task. The results showed that hippocampal theta power increased during the presentation of a single stimulus, but did not increase during the presentation of a compound stimulus. This finding suggests that the conflict resolution model is more applicable than the configural association theory for describing neural activity during positive patterning tasks., (Copyright © 2012 Elsevier B.V. All rights reserved.)

We report a case of isolated hypoglossal nerve palsy with acute lymphoblastic leukemia. A 47-year-old woman had fever unknown origin during two months. Her tongue bent to the right and cephalalgia developed. She complained unable to speech and swallow. On admission, right isolated hypoglossal nerve palsy presented. Blood examination showed the mild elevation of CRP and soluble IL2 receptor. Examination of cerebrospinal fluid was negative. Gadolinium enhanced magnetic resonance imaging (MRI) of brain showed abnormal intensity on sphenoid bone. 2-[(18)F] fluoro-2-deoxy-D-glucose (FDG)-positron emission tomography (PET) showed abnormal accumulation on sphenoid bone, spleen, the left supraclavicular node, mesenteric lymph node. Blast cells appeared in peripheral blood afterwards. Acute lymphatic leukemia (ALL) was diagnosed by bone marrow biopsy. The central nervous system disorder by ALL tends to the invasion to meninges or cerebrovascular disorder. This is the first case report that isolated hypoglossal nerve paralysis resulted from ALL.

A 20-year-old female patient was presented with a 1-year history of progressive weakness of the left hand. Examination on admission showed atrophy of the muscles of the left forearm, cold paralysis and minipolymyoclonus. MR images of the cervical cord showed anterior transfer of the cervical cord on anterior flexion and cervical cord compression at the site of cervical kyphosis, confirming the diagnosis of Hirayama disease. Many features of the present case are unusual: the patient is a female (who are rarely afflicted by this disease), with cervical kyphosis and a history of exercise involving cervical vertebral loading, suggesting a potential involvement of the latter two factors in the disease onset. The findings suggest that cervical vertebral dysplasia and intervertebral disc degeneration may influence cervical kyphosis, and be involved in the onset of Hirayama disease.

GGA (geranylgeranoic acid) is a natural polyprenoic acid, derivatives of which has been shown to prevent second primary hepatoma. GGA induces mitochondria-mediated PCD (programmed cell death), which may be relevant to cancer prevention. To gain further insights into GGA-induced PCD, autophagy processes were examined in human hepatoma-derived HuH-7 cells. Treatment of HuH-7/GFP (green fluorescent protein)-LC3 cells with GGA induced green fluorescent puncta in the cytoplasm within 30 min and their massive accumulation at 24 h. After 15 min of GGA treatment, a burst of mitochondrial superoxide production occurred and LC3β-I was appreciably converted into LC3β-II. GGA-induced early stages of autophagy were unequivocally confirmed by electron-microscopic observation of early/initial autophagic vacuoles. On the other hand, LC3β-II as well as p62/SQSTM1 (sequestosome 1) continuously accumulated and co-localized in the cytoplasmic puncta after GGA treatment. Furthermore, GGA treatment of HuH-7/mRFP (monomeric red fluorescent protein)-GFP-LC3 cells showed yellow fluorescent puncta, whereas glucose deprivation of the cells gave red fluorescent puncta. These results strongly suggest that GGA induces the initial phase of autophagy, but blocks the maturation process of autolysosomes or late stages of autophagy, insomuch that GGA provides substantial accumulation of autophagosomes under serum-starvation conditions in human hepatoma cells.

Neuroactive steroids are synthesized in the central and peripheral nervous systems. The purpose of this study was to analyze the effects of environmental enrichment on neuroactive steroidogenesis in the rat hippocampus. Environmental enrichment rats were housed in a group of nine in a large cage and three groups of pair-housed rats were housed in a standard cage for 8 weeks. The levels of mRNAs for steroidogenic enzymes and proteins in hippocampus were quantified by real-time RT-PCR. Environmental enrichment increased the mRNA expression levels of 5α-reductase-1 and 3α-hydroxysteroid dehydrogenase, which catalyze synthesis of allopregnanolone from progesterone. Hence, environmental enrichment appears to affect allopregnanolone synthesis., (Copyright © 2010 Elsevier Inc. All rights reserved.)

17beta-estradiol is synthesized de novo in the rat hippocampus. However, the regulatory mechanism of hippocampal estradiol synthesis has remained unclear. We investigated the effects of social isolation on rat hippocampal estradiol synthesis. Rats were divided into two groups: social isolation and pair housed group. Socially isolated rats were housed individually while pair housed rats were housed two per cage for 8 weeks. Social isolation activated the transcription of neurosteroidogenic molecules, including steroidogenic acute regulatory protein (StAR) and CYP19 (cytochrome P450arom). These two molecules are involved in the regulatory step for steroidogenesis and final step of estradiol synthesis. In contrast, the mRNA levels were not affected in rat olfactory bulb. The hippocampal estradiol content was increased in accordance with the increased mRNA levels. The hippocampal estradiol content exhibited correlations with the StAR and P450arom mRNA levels. These data suggest that social isolation may enhance de novo estradiol synthesis in the hippocampus.

Purpose: Bladder cancer is a common malignancy in which local recurrence and distant failure contribute to poor patient outcome. The search for improved therapies remains a high priority in this disease. For most experimental therapies animal tumor models represent an important step between in vitro testing and clinical trials. A useful animal model of bladder cancer involves the orthotopic implantation of bladder tumor cells in sygeneic animals. This model offers the opportunity to test the efficacy of therapies administered systemically or intravesically. However, quantitation of tumor growth has been difficult., Materials and Methods: To allow the quantitative assessment of tumor mass in this model and differentiate tumor cells from normal bladder epithelium at early stages of tumor growth we transfected cells of the MBT2 murine bladder cancer cell line with a vector encoding enhanced green fluorescent protein and devised an enzyme-linked immunosorbent assay that enables the detection of green fluorescent protein in cells at the pg. level., Results: Using this assay tumor growth can be detected 7 days after implantation and by 14 days levels of green fluorescent protein are more than 500-fold greater than in controls., Conclusions: Combined with the enzyme-linked immunosorbent assay use of this MBT2 green fluorescent protein transfectant allows tumor cell growth to be monitored with sensitivity and reproducibility. It reduces the time required to measure effects on tumor growth to 2 weeks, while preserving the advantages of this orthotopic tumor model.