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Background: Although prognosis and treatments differ between small-cell- and nonsmall-cell carcinoma, comparisons of the histological types of NSCLC are uncommon. Thus, we investigated the oncological factors associated with the prognosis of early-stage adenocarcinoma and squamous cell carcinoma., Methods: We retrospectively compared the clinicopathological backgrounds and postoperative outcomes of patients diagnosed with pathological stage I-IIA adenocarcinoma and squamous cell carcinoma primary lung cancer completely resected at our department from January 2007 to December 2017. Multivariable Cox regression analysis for overall survival and recurrence-free survival was performed., Results: The median follow-up duration was 55.2 months. The cohort consisted of 532 adenocarcinoma and 96 squamous cell carcinoma patients. A significant difference in survival was observed between the two groups, with a 5-year overall survival rate of 90% (95% confidence interval 86-92%) for adenocarcinoma and 77% (95% CI 66-85%) for squamous cell carcinoma (P < 0.01) patients. Squamous cell carcinoma patients had worse outcomes compared to adenocarcinoma patients in stage IA disease, but there were no significant differences between the two groups in stage IB or IIA disease. In multivariate analysis, invasion diameter was associated with overall survival in adenocarcinoma (hazard ratio 1.76, 95% confidence interval 1.36-2.28), but there was no such association in squamous cell carcinoma (hazard ratio 0.73, 95% confidence interval 0.45-1.14)., Conclusions: The importance of tumor invasion diameter in postoperative outcomes was different between adenocarcinoma and squamous cell carcinoma. Thus, it is important to consider that nonsmall-cell carcinoma may have different prognoses depending on the histological type, even for the same stage., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Large language models (LLMs) have impacted advances in artificial intelligence. While LLMs have demonstrated high performance in general medical examinations, their performance in specialized areas such as nephrology is unclear. This study aimed to evaluate ChatGPT and Bard in their potential nephrology applications., Methods: Ninety-nine questions from the Self-Assessment Questions for Nephrology Board Renewal from 2018 to 2022 were presented to two versions of ChatGPT (GPT-3.5 and GPT-4) and Bard. We calculated the correct answer rates for the five years, each year, and question categories and checked whether they exceeded the pass criterion. The correct answer rates were compared with those of the nephrology residents., Results: The overall correct answer rates for GPT-3.5, GPT-4, and Bard were 31.3% (31/99), 54.5% (54/99), and 32.3% (32/99), respectively, thus GPT-4 significantly outperformed GPT-3.5 (p < 0.01) and Bard (p < 0.01). GPT-4 passed in three years, barely meeting the minimum threshold in two. GPT-4 demonstrated significantly higher performance in problem-solving, clinical, and non-image questions than GPT-3.5 and Bard. GPT-4's performance was between third- and fourth-year nephrology residents., Conclusions: GPT-4 outperformed GPT-3.5 and Bard and met the Nephrology Board renewal standards in specific years, albeit marginally. These results highlight LLMs' potential and limitations in nephrology. As LLMs advance, nephrologists should understand their performance for future applications., (© 2024. The Author(s), under exclusive licence to Japanese Society of Nephrology.)

Small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC) have recently been grouped as lung neuroendocrine carcinomas (NECs). Because these lung NECs are clinically malignant and their treatment strategies differ from those of non-SCLC, the quality of diagnosis has a significant prognostic impact. The diagnosis of LCNEC requires positive immunohistochemical staining with chromogranin A, synaptophysin, and CD56, along with a morphological diagnosis, and insulinoma-associated protein 1 (INSM1) has been proposed as an additional marker but is still not an ideal or better marker. We investigated Musashi-1 as a novel immunohistochemical marker in 42 patients with SCLCs and 44 with LCNECs who underwent lung resection between 1998 and 2020 at our institution. We found Musashi-1 expression in 98% (41/42) SCLC and in 90% (40/44) LCNEC. These findings were similar to CD56 expression and superior to synaptophysin, chromogranin A, and INSM1. Musashi-1 also tended to show more diffuse and intense staining, especially in LCNEC, with more cases staining > 10% than any other existing markers (Musashi-1, 77%; INSM1, 45%; chromogranin A, 34%; synaptophysin, 41%; and CD56, 66%). In conclusion, we identified Musashi-1 as a novel immunohistochemical staining marker to aid in the diagnosis of lung NEC.

Esophagogastroduodenoscopy (EGD) has become an indispensable examination to discover upper gastrointestinal diseases, including cancer, and perform endoscopic treatment. However, many individuals who undergo the procedure have feelings of anxiety and fear regarding EGD. Although the use of medication for sedation during EGD is useful for reducing anxiety and the stability of hemodynamics, sedation may increase the likelihood of complications. Several noninvasive distractions have been introduced to decrease pain and anxiety during endoscopic examinations;however, most assessments of these distractions evaluated subjective items such as impression. We herein add the results of our studies using objective items and review the effectiveness of distractions for EGD. J. Med. Invest. 69 : 8-18, February, 2022.

Depression often first develops during adolescence, with its rate sharply increasing after puberty and often running a chronic, recurring course thereafter. The development of depression is associated with difficulties in the lives of adolescents and their families, reduced academic achievement, suicide, and increased socio-economic disadvantage in adulthood. Earlier and more effective interventions for depression in adolescents are required. This review describes the updated etiology and clinical features of adolescent depression, and focuses on appropriate therapeutic strategies to adopt in clinical practice. J. Med. Invest. 68 : 22-28, February, 2021.

Background: This study aimed to investigate the efficacy of the Deauville criteria, 5-point semiquantitative scale criteria to assess the maximum standardized uptake value of [18F]-fluoro-2-deoxy-d-glucose (FDG) on positron emission tomography (PET)-computed tomography (CT), in predicting lymph node metastasis and other pathological invasive characteristics of early-stage lung adenocarcinoma., Methods: In this retrospective study including 453 patients undergoing lobectomy or segmentectomy with lymph node dissection for clinical T1 or Tis N0 adenocarcinoma between April 2011 and March 2019, the FDG-PET/CT scans were evaluated using Deauville criteria to analyze the relationship of the Deauville score with the clinicopathological characteristics and prognosis., Results: The lymph node metastases were present in 0 (0%), 2 (1.1%), 6 (9.5%), 6 (15.8%), and 13 (15.7%) patients with Deauville scores of 1, 2, 3, 4, and 5, respectively. The pathological invasive characteristics (lymphatic, vascular, or visceral pleural invasion) were detected in 2 (2.4%), 17 (9.9%), 18 (28.6%), 23 (60.5%), and 54 (65.1%) patients with a Deauville score of 1, 2, 3, 4, and 5, respectively. The 3-year recurrence-free survival was longer in patients with a Deauville score of 1 to 2 (97.2%) than those with a Deauville score of 3 (86.2%; P < .001) or 4 to 5 (80.7%; P < .001)., Conclusions: The 5-point scale evaluation of the maximum standardized uptake value on FDG-PET/CT using the Deauville score was useful in predicting not only lymph node metastasis but also other malignant features of early-stage lung adenocarcinoma., (Copyright © 2020 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objective: Anatomical segmentectomy has the potential to replace lobectomy as the standard procedure for early stage non-small cell lung cancer. We investigated the safety and feasibility of robotic anatomical segmentectomy for non-small cell lung cancer., Methods: Overall 20 patients underwent robotic anatomical segmentectomy at Hiroshima University Hospital between January 2014 and January 2018. The clinicopathological characteristics, surgical outcomes, complications and prognosis were analyzed., Results: The median age was 68 (range 42-86) years, and 15 patients were female. Six patients were non-smokers. The most common clinical stage was IA1 (nine patients). Complex segmentectomies were performed in four patients (one right S3 segmentectomy, two right S8 segmentectomies and one left S8 + S9 segmentectomy). The median operation time was 163.5 (range, 114-314) minutes, and the median console time was 104 (range, 60-246) minutes. The median blood loss was 26.5 (range, 5-247) ml. The median resection margin and number of dissected lymph node were 15 (range, 2-60) mm and 5 (range, 1-15), respectively. Although five (25.0%) patients had grade IIIa complications (pleurodesis for prolonged air leakage) and one (5.0%) had a grade IIIb complication (reoperation for prolonged air leakage), no post-operative deaths occurred. The surgical outcomes were comparable with those of anatomical segmentectomy performed under hybrid video-assisted thoracoscopic surgery during the same period., Conclusion: In our initial experience of robotic anatomical segmentectomy for early stage non-small cell lung cancer, the procedure seems to be safe and feasible., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Objective : The purpose of the present study is to examine clinical factors related to life skills in people with schizophrenia. Method : The participants were 51 stabilized outpatients with schizophrenia. Their mean age was 38.91 (SD = 10.73) years. Life skills were assessed using the Life skills profile (LSP). Cognitive function was evaluated with the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery (MCCB). Clinical symptoms were assessed using the Positive and Negative Syndrome scale (PANSS), the Calgary Depression Scale for Schizophrenia (CDSS) and the Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS). Results : Cognitive function was not correlated with the LSP scores at all. Among clinical symptoms, scores of the PANSS positive and negative syndrome scales, the CDSS, and the DIEPSS had negative correlations with the LSP total score and the subscales. Stepwise regression analyses showed that the CDSS and PANSS negative syndrome scale scores were independent predictors of the LSP total score and two of the subscales. Conclusions : These results indicate that cognitive function is not associated with life skills but clinical symptoms such as depressive and negative symptoms have considerable impacts on life skills in people with schizophrenia. J. Med. Invest. 67 : 75-82, February, 2020.

We propose a fully quantum approach to nonperturbatively calculate the spin-split Landau levels and g factor of various spin-orbit coupled solids based on the k·p theory in the matrix mechanics representation. The new method considers the detailed band structure and the multiband effect of spin-orbit coupling irrespective of the magnetic-field strength. We show an application of this method to PbTe, a typical Dirac electron system. Contrary to popular belief, we show that the spin-splitting parameter M, which is the ratio of the Zeeman to cyclotron energy, exhibits a remarkable magnetic-field dependence. This field dependence can rectify the existing discrepancy between experimental and theoretical results. We also show that M evaluated from the fan diagram plot is different from that determined as the ratio of the Zeeman to cyclotron energy, which also overturns common belief.

The events in the immune response to hepatitis B virus (HBV) remain unclear. We analyzed the direct influence of HBV on gene expression in human hepatocytes under immunodeficient conditions using a human hepatocyte chimeric mouse model. HBV-infected or non-infected chimeric mouse livers were collected, and gene expression profiles were compared. Since IL-8 was the most significantly up-regulated gene at 8 weeks after HBV infection, we focused on IL-8 and found that HBx and the large HBs (L-HBs) protein induce transcription of IL-8 via endoplasmic reticulum stress. This stress induces IL-8 transcription via NFAT activation and contributes to suppression of interferon responsiveness in HBV-infected human hepatocytes. In the present study, we identified a novel regulatory mechanism in which the L-HBs protein activates IL-8 via endoplasmic reticulum stress, suggesting a key role for IL-8 in the immune response to HBV and a potential new target for antiviral treatments of HBV infection., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: The purpose of the present study was to examine clinical factors related to social function in people with schizophrenia., Patients and Methods: The participants were 55 stabilized outpatients with schizophrenia. Their mean age was 39.36 (SD =10.65) years. Social function was assessed using the Quality of Life Scale (QLS). Cognitive function was evaluated with the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery (MCCB). Clinical symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS), the Calgary Depression Scale for Schizophrenia, and the Drug-Induced Extrapyramidal Symptoms Scale., Results: Neither the MCCB cognitive domain score nor composite score was correlated with the QLS scores. However, of the 10 MCCB subtests, the Trail Making Test Part A and the Brief Assessment of Cognition in Schizophrenia-Symbol Coding (BACS-SC) scores were positively correlated with the QLS scores. Among clinical variables, especially the PANSS negative syndrome scale score had a strong negative correlation with the QLS scores. Stepwise regression analyses showed that the PANSS negative syndrome scale score was an independent predictor of the QLS scores, and although the BACS-SC score predicted the QLS common objects and activities subscale score, the association was not so strong compared to the PANSS negative syndrome scale score., Conclusion: These results indicate that speed of processing evaluated by BACS-SC could predict some aspect of social function but negative symptoms have a much stronger impact on global social function in people with schizophrenia., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

The hippocampo-prefrontal pathway is a unique projection that connects distant ends of the cerebral cortex. The direct hippocampo-prefrontal projection arises from the ventral to intermediate third of the hippocampus, but not from the dorsal third. It forms a funnel-shaped structure that collects information from the large hippocampal area and projects it to the prefrontal cortex. The anatomical regional differentiation of the projection has not been described. The hippocampal region is differentiated into structural and behavioural roles. For example, it has been shown that the ventral, but not the dorsal, hippocampus reciprocally connects with the amygdala and influences emotional behaviours. These data imply that hippocampal variation along the dorso-ventral axis is contained within the hippocampo-prefrontal pathway. Here, we present electrophysiological studies that demonstrate regional differences in short- but not long-term plasticity in the intermediate/posterior-dorsal and ventral routes of the hippocampo-prefrontal pathway. Furthermore, behavioural studies revealed that each route appears to play a different role in working memory. These results suggest that hippocampal regional information is processed through different routes, with the integration of individual regulatory functions in the prefrontal convergent system., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

We recorded multiple unit activities of the CA1 region of the intermediate hippocampus and prelimbic area of the prefrontal cortex, and evoked responses in the prefrontal cortex by hippocampal stimulation in urethane-anesthetized rats. The multiple unit activities between these regions showed significant peaks of cross-correlograms, which indicated that firing initiated mainly from either the hippocampus (type HP) or the prefrontal cortex (type PH). In type HP, the slopes of evoked responses showed a significant inverse correlation with peak heights of cross-correlograms and number of bursts of multiple unit activities. These results suggest that multiple unit activity-based cross-correlograms (a measurement to test functional connectivity) are influenced by both evoked response (synaptic connectivity) and effects of local circuits.

We examined the effect of long-term potentiation (LTP) on paired-pulse responses across varied stimulus intensities and interstimulus intervals (ISIs), at ascending synapses from the intermediate and ventral hippocampus to the medial prefrontal cortex in urethane-anesthetized rats. LTP significantly shifted the median effective stimulus towards lower intensities in the intermediate route, and increased at 25-ms ISI the paired-pulse response, which was inversely proportional to the stimulus intensity. In the ventral route, the paired-pulse response varied with ISI rather than intensity, and increased at 50-ms and 100-ms ISI after LTP. The intermediate synaptic plasticity significantly exhibited total amplifier dynamics with wide ranges of frequency at lower intensity and intensity at 100-ms ISI in contrast to the ventral one.

We recorded spontaneous multiple unit activities (MUAs) of the hippocampus and prefrontal cortex in urethane-anesthetized rats and analyzed cross-correlograms between these MUAs to investigate the functional connectivity of neuronal activities. Results of these analyses reveal a significant correlation between MUAs in these regions, in which the firing initiated from either hippocampus (type H-P) or prefrontal cortex (type P-H) according to the significant peak of cross-correlograms. Furthermore, the MUA bursts were counted: a significant correlation was found between the peak height of cross-correlograms and MUA burst counts in type H-P, but not type P-H. These results suggest that the correlation between the hippocampus and prefrontal cortex MUAs that are related to the burst firing might reflect functional connectivity.

Aim: In recent years, greater attention has been given to quality of life (QOL) in schizophrenia and several studies reported that negative and depressive symptoms and cognitive dysfunction are related to patient QOL. But because a variety of QOL measures have been used in the previous studies, there seems to be no unanimous predictors for subjective and objective QOL. The purpose of the present study was to elucidate the relationship between clinical variables and subjective and objective QOL in outpatients with schizophrenia, using schizophrenia disease-specific QOL measures. Particular attention was paid to cognitive function as a predictor of QOL., Methods: Schizophrenia symptoms of the Positive and Negative Syndrome Scale (PANSS) were divided into five factors: positive factor, negative factor, cognitive factor, emotional discomfort, and hostility. The study sample consisted of 84 schizophrenia outpatients. Subjective and objective QOL were assessed with Schizophrenia Quality of Life Scale (SQLS) and the Quality of Life Scale (QLS), respectively., Results: Subjective QOL correlated significantly with emotional discomfort, positive factor, negative factor, extrapyramidal symptoms and cognitive factor, while objective QOL correlated with negative factor, cognitive factor, emotional discomfort, extrapyramidal symptoms, and dose of antipsychotics. Total score and three of four subscales in the QLS correlated significantly with cognitive factor, while cognitive factor had a significant correlation with only one of three scales of SQLS. Stepwise regression showed that subjective QOL was significantly predicted by emotional discomfort and extrapyramidal symptoms, while negative factor was the most important predictor of objective QOL., Conclusion: Cognitive dysfunction had a greater influence on objective QOL than subjective QOL. Treating depressive and negative symptoms and extrapyramidal symptoms might contribute to enhanced subjective and objective QOL.

Working memory in rats involves neural projections from the hippocampus (HP) to the prefrontal cortex (PFC), based on delayed task experiments in a radial-arm maze, in which the time span of working memory is longer than seconds. To determine whether the HP-PFC pathway is involved in short-term (on the order of seconds) working memory function, we lesioned the PFC and/or HP, and measured performance in an operant delayed alternation task. The posterior dorsal (pdHP) and ventral HP (vHP) were assessed separately. The bilateral PFC and bilateral pdHP ibotenate lesions produced significant working memory deficits, but the vHP lesion did not. Unilateral pdHP lesions combined with a PFC lesion in the opposite hemisphere reproduced the effects of bilaterally symmetrical lesions. By contrast, unilateral lesions of the pdHP combined with a PFC lesion in the same hemisphere had no effect on delayed alternation. These results indicate that the pdHP-PFC pathway is essential for working memory on the order of seconds in rats, and suggest that the pdHP and vHP pathways to the PFC play different behavioral roles.

To determine whether spontaneous local field potential (LFP) activities in the rat medial prefrontal cortex influence the responses evoked by hippocampal stimulation, we investigated the relationship between the evoked responses and the LFP powers immediately before the stimulation using anesthetized rats. We demonstrated that the degrees of evoked response showed significant inverse correlations with the prefrontal LFP powers in a specific frequency band (including the gamma band) immediately before the stimulation. The results indicate that the specific frequency band activities in the prefrontal LFPs may be involved in prefrontal responsiveness. Spontaneous LFP activities may have a role in information processing in the hippocampus-prefrontal cortex pathway.

Previously, we reported an elevation in the power of the medial prefrontal cortex (PFC) local field potential spontaneous gamma-band (40-100 Hz) after long-term depression (LTD) but not long-term potentiation (LTP) in the rat ventral hippocampus CA1 (vCA1)-PFC pathway. In the present study, we analyzed the PFC local field potential before and after the induction of posterior dorsal hippocampus CA1 (pdCA1)-PFC LTP/LTD in vivo. In contrast with vCA1-PFC, the present study found that gamma-band power elevation was associated with pdCA1-PFC LTP but not LTD, although we observed a correlation between LTD and the gamma-band power change. The differences between vCA1- and pdCA1-PFC pathways might be related to differences in synaptic plasticity and behavioral functions. Since the neural connection of the hippocampus and PFC is believed to be involved in the function of the working memory, sustained gamma-band power elevation in the PFC might be related to this function.

To determine whether the rat medial prefrontal cortex (PFC) is involved in delayed reinforcement operant behavior, we studied the effects of transient inactivation of the medial PFC (or the hippocampus as a control) during a delayed reinforcement lever-press task. We demonstrated the involvement of the PFC in this task: PFC inactivation but not hippocampal inactivation significantly impaired performance. In a separate experiment, we also recorded the prefrontal multiple unit activities during the task to determine the roles of the PFC in detail. Neuronal activity decreased during the delay period, suggesting that this decrease plays a role in delayed reinforcement operant behavior.

The differences in the waveform of Cerebral EP (Evoked Potential)s; SEP, VEP and AEP, among healthy subjects, schizophrenics, manic-depressives and epileptics were investigated. In 585 subjects of both sexes comprising these diagnostic groups, 6 channels of EPs, each 2 channels for each sensory modality, were recorded simultaneously/parallelly from each subject, without assigning a mental task. Then, waveforms of the g-m (group mean) EPs of each diagnostic group were superimposed for inspection. Peak latencies and inter-peak amplitudes of individual EPs were statistically tested among (ANCOVA) and between (Scheffe's multiple comparison test) these diagnostic groups for each channel (modality), and for each sex. The waveforms of g-m EPs of each diagnostic group differed from each other. The differences of latencies and inter-peak amplitudes among these diagnostic groups attained to the significant level (P<0.05), with more significant differences between healthy subjects and each of these pathological diagnostic groups than between each of these pathological diagnostic groups, for each sex. Thus the differences in the waveform of EPs among these diagnostic groups were confirmed even taking the effect of medication on EPs into consideration. These results might suggest the existence of a waveform for individual EPs specific to each of these diagnostic groups, for each sex.

Anatomical evidence suggests that rat CA1 hippocampal afferents collaterally innervate excitatory projecting pyramidal neurons and inhibitory interneurons, creating a disynaptic, feed-forward inhibition microcircuit in the medial prefrontal cortex (mPFC). We investigated the temporal relationship between the frequency of paired synaptic transmission and gamma-aminobutyric acid (GABA)ergic receptor-mediated modulation of the microcircuit in vivo under urethane anesthesia. Local perfusions of a GABAa antagonist (-)-bicuculline into the mPFC via microdialysis resulted in a statistically significant disinhibitory effect on intrinsic GABA action, increasing the first and second mPFC responses following hippocampal paired stimulation at interstimulus intervals of 100-200 ms, but not those at 25-50 ms. This (-)-bicuculline-induced disinhibition was compensated by the GABAa agonist muscimol, which itself did not attenuate the intrinsic oscillation of the local field potentials. The perfusion of a sub-minimal concentration of GABAb agonist (R)-baclofen slightly enhanced the synaptic transmission, regardless of the interstimulus interval. In addition to the tonic control by spontaneous fast-spiking GABAergic neurons, it is clear the sequential transmission of the hippocampal-mPFC pathway can phasically drive the collateral feed-forward inhibition system through activation of a GABAa receptor, bringing an active signal filter to the various types of impulse trains that enter the mPFC from the hippocampus in vivo.

The hippocampal-medial prefrontal cortex (mPFC) pathway provides highly convergent input to the mPFC in rats and shows two types of short-term plasticity in terms of paired-pulse facilitation (PPF) of the field potential under urethane anesthesia. We now report that stimulating either the dorsal or ventral subregions of the posterior hippocampus elicited PPF (by about 335 and 120%, respectively) of field potentials recorded in the mPFC at 100 ms interpulse interval. This PPF-like interaction occurred when projections were stimulated in the ventral-dorsal order (by about 200% of the single-pulsed response), but not vice versa. When weak long-term potentiation (LTP) of the dorsal projection was evoked simultaneously with strong LTP of the ventral projection, an associative effect was revealed (about +55%), although the magnitudes of LTP in each projection were not correlated. Even when the impermutable PPF-like facilitation was further enhanced (by about +120%), the enhancement was not correlated with either form of LTP, but exhibited the interaction of changes in the dorsal PPF, rather than in the heterotopic priming effect through the ventral projection. Moreover, this change was correlated with the associated LTP ratio of dorsal to ventral projection LTP (i.e., LTP associativity). Larger increases in LTP associativity correlated with greater impermutable PPF-like facilitation; in addition, there was hardly attenuation of the response to the dorsal projection by subsequent electrolytic lesions of the ventral subregion. These results indicate that the mPFC functionally integrates discrete sources of hippocampal information via cooperativity between short- and long-term plasticity.

Young and old rats, aged 3 and 24 months old, respectively, were conditioned to press a lever under lamp-on conditions for reward acquisition and lamp-off for no reward using a variable interval reinforcement schedule that averaged 15 s; i.e., the minimal requirement was 4 responses/min. Over a 30-day period, young and old groups showed increased response to lamp-on from 22 to 35/min and from 10 to 23/min, respectively, and shortened response to lamp-off after initial training. Response to lamp-on as a percentage of total response to lamp-on and -off (the discrimination ratio) was over 80%. For the next 30 days, reversal learning was imposed to reinforce discrimination of the lamp-off state. Young rats showed a steadily increasing discrimination ratio from 40% to 70%, and old rats from 30% to 60%. In comparison with the initial training, young rats showed a total response increase from 50% to 60%, while old rats showed an approximately 5% decrease without loss of reward-obtaining efficiency. In vivo microdialysis during reversal revealed that young rats had higher dopamine transmission in the basolateral amygdala than old rats. The dopamine level was positively correlated with the number of responses to state of reward in young rats and negatively with the numbers of both NRF and RF responses to lamp-on and -off states in old rats. These results suggest that in reversal discrimination, basolateral amygdalar dopamine efflux correlates with the manner of age-related conditioned response rather than the ability to learn.

We examined the effect of long-term potentiation or depression (LTP or LTD) on the local field potential, focusing on the gamma-band (40-100 Hz) power, in the ventral hippocampus CA1 of anesthetized rats. LTP and LTD induction in the CA3-CA1 pathway increased the CA1 spontaneous gamma-band power by around 40 and 80-100 Hz, respectively, while neither changed the evoked levels significantly. These results suggest that the ventral CA1 local field potential can maintain bidirectional plasticity in the steady state for the long term. Given the involvement of synaptic plasticity in learning and memory, the gamma-band power change associated with LTP/LTD may relate to ventral hippocampal functions. The LTP increased the spontaneous power at around 40 Hz of the gamma-band frequency in the ventral CA1, and the LTD did the same at 80-100 Hz. The biphasic increase may distribute the subsequent input appropriately to regulate the relevant synaptic history in the ventral CA1 and anatomically related structures in vivo., (Copyright 2004 Springer-Verlag)

We studied the interaction between paired-pulse facilitation (PPF) and long-term potentiation (LTP) in the hippocampo-prefrontal cortex (PFC, prelimbic area) pathway, stimulating the ventral or posterior dorsal CA1 region (vCA1 or pdCA1). In the vCA1-PFC, the group averaged PPF did not change after the LTP induction, and there was a negative correlation between the post-LTP PPF change and LTP magnitude. In contrast, the post-LTP PPF of the pdCA1-PFC appeared to decrease significantly, and the PPF change was independent of the LTP magnitude. We found that there were at least two mechanisms of PPF regulation following LTP induction in the pathway resulting from extensive CA1 projections into the prelimbic area. The results imply that the CA1-PFC pathway regulates the PFC PPF quantitatively in LTP-dependent and independent manners, which depend on the local properties of the CA1 regions.

To determine the relationship between cholinergic modulation within the rat medial prefrontal cortex (mPFC) and the progress of lever-press extinction, we conducted an experiment in which muscarinic and nicotinic acetylcholine (ACh) receptor antagonists were microinjected into the mPFC. The muscarinic antagonist injected immediately before the initial extinction training did not affect the progress of extinction during the training (no within-session effect), but disrupted a second re-training session the next day (across-session effect). By contrast, the nicotinic antagonist disrupted the progress of extinction both within and across training sessions. These results confirm that ACh in the mPFC modulates lever-press extinction and suggest that nicotinic and muscarinic receptors are involved in short- and long-term memory processes.

The hippocampo-prefrontal cortex pathway reportedly expresses long-term potentiation (LTP) and depression (LTD) in anesthetized rats. We examined whether there were any effects governing the induction of LTD after prior induction of LTP, or vice versa. Induction in sequence of LTP and LTD resulted in significantly stable changes of about 140 and 70% of a common control for 1 h each. The reversed sequence, LTD and LTP, showed a mirror image of about 65 and 135% of control, which were not different from the respective changes in the first sequence (P>0.3 for each). The correlation coefficient between changes was significantly positive in the first sequence and weakly negative in the reverse. These results indicate that this pathway can express compatibility of bidirectional synaptic plasticity while historical changes remain covert.

We previously reported a difference in short-term synaptic plasticity between the rat posterior dorsal CA1 (pdCA1)-prefrontal cortex (PFC) and ventral CA1 (vCA1)-PFC pathways. Here, to determine the effects of hippocampal train stimulation on the local field potential in the medial PFC, we recorded the PFC field potential with brief 250-Hz train stimulation (1, 3, 5, 7, and 9 pulses) of pdCA1 or vCA1 in anesthetized rats. Analysis of the gamma-band (40-100 Hz) power revealed stimulation-evoked gamma oscillation in the pdCA1-PFC, but not in the vCA1-PFC. These results indicate that these pathways have different responses to train stimulation. The function of the pdCA1-PFC may differ from that of the vCA1-PFC, a well-known hippocampus-PFC pathway.

To determine whether long-term depression (LTD) affects cortical gamma-band local field potential (40-100 Hz), we conducted a LTD induction experiment in the hippocampus-prefrontal cortex (PFC) pathway of an anesthetized rat. The LTD induction increased the spontaneous level of PFC gamma-band power of 70-100 Hz, which was not affected after the long-term potentiation (LTP) induction in our previous experiment. In addition, the LTD induction increased the evoked PFC gamma-band power at 900 ms after hippocampal test stimulation; this latency appeared to differ from that (500-700 ms) observed in our previous LTP experiment. The results indicate that the PFC field potential increases its gamma-band power following both LTP and LTD in the hippocampus-PFC pathway, which is involved in working memory. Particularly, the sustained increase by LTD may reflect a representation of working memory.

We studied paired-pulse facilitation and long-term potentiation/depression in anesthetized rats to determine whether the hippocampal CA1 region inhibits local differences in short-term and long-term synaptic plasticity in its projections to the prefrontal cortex. We compared projections with the PFC from the posterior dorsal and ventral hippocampal CA1 regions (pdCA1 and vCA1 respectively). The two pathways displayed similar properties. However, the PPF properties of the pdCA1, projections differed dramatically from those of the pdCA1 projections. The pdCA1 projections showed the opposite of facilitation (i.e. suppression) at 25-50 ms intervals and more pronounced facilitation at 100-400 ms intervals. These results suggest that there are functional differences between these pathways.

To determine the involvement of the medial prefrontal cortex (mPFC) in operant-type delayed alternation, microinjections of muscimol into the mPFC were used for temporal inactivation during behavioral tests in rats. The temporal mPFC inactivation showed effects related to both dorsal (decreased delay-dependent correct ratio, indicating working memory-related deficits) and ventral hippocampus inactivation (increased tendency to repeat errors) reported in our recent paper, without motor or sensory effects. These findings suggest that the mPFC integrates information from different hippocampal regions during a delayed alternation task.

To investigate whether changes occur in acetylcholine (ACh) levels in the rat medial prefrontal cortex (mPFC) during initial lever-press extinction training, in vivo microdialysis was used to measure mPFC ACh. Elevated ACh was found during this training period. Furthermore, this elevation significantly correlated with the number of responses found in the re-training session the next day, but not with that in the initial training. These results suggest that the mPFC ACh elevation during the initial training period enhances the progress of lever-press extinction across sessions.

We examined whether long-term potentiation (LTP) affects cortical gamma-band electroencephalograms (EEG) in the hippocampo-prefrontal cortex (PFC) pathway of anesthetized rats. The LTP induction increased the evoked PFC gamma-band EEG power (40-100 Hz) to 120-135% at 500-700 ms after test stimulation. A simple increment of stimulus intensity, instead of LTP induction, did not reveal this evoked increase. Neither LTP induction nor the intensity increment changed significantly the magnitude of an evoked decrease at around 100 ms or the spontaneous prestimulation gamma-band power. These results indicate that LTP in PFC specifically increases the evoked gamma-band EEG power, which may reflect a phasic mode of plastic neurotransmission through the hippocampo-PFC pathway in vivo.

To investigate the relationship between the prefrontal and hippocampal acetylcholine (ACh) systems and working memory, an in vivo microdialysis study was conducted. A group of rats was trained to perform a working memory task, delayed alternation, in an operant chamber for food reinforcement. The rats had to choose one of two response levers in an alternative manner in each trial, with a certain interval between trials. They had to remember which lever they chose in the previous trial without the assistance of external cues. Another group was trained to perform a reference memory task, cued alternation, in which the behavioral sequence was identical, but an external cue was provided. After stable behavior was established, a dialysis probe was implanted into the prefrontal cortex or the hippocampus of each rat. The extracellular concentration of ACh in the dialysates from the prefrontal cortex increased during performance of the delayed alternation task, while the hippocampal ACh showed a more distinct increase during performance of the cued alternation task. These results suggest that the prefrontal ACh is mainly related to working memory, whereas the hippocampal ACh is mainly related to reference memory.

To confirm neural plasticity of the mouse hippocampo-prefrontal cortex (PFC) pathway, paired-pulse facilitation (PPF) and long-term potentiation (LTP) induction were determined in the pathway. In addition, we tested whether the plasticity differs in projections of the pathway from the dorsal (upper) and ventral (lower) parts of the temporal hippocampus. The results showed PPF and LTP of this pathway, and these differed between the projections. The projection from the upper part showed stronger PPF and weaker LTP compared with that from the lower part. These results suggest that the mouse hippocampo-PFC pathway is involved in learning and memory, and contains projections related to different functions.

To determine the involvement of the hippocampal regions in a operant-type delayed alternation task of short delay or long delay, microinjections of muscimol into the hippocampus were used for temporal inactivation during the behavioral test in each rat. Dorsal hippocampal inactivation impaired the correct ratio of long delay. Ventral hippocampal inactivation showed no changes in the correct ratio, however, it increased the tendency of perseveration in long delay. These findings suggest hippocampus has regional differentiation in delayed alternation task.

To clarify hippocampal regional differences in synaptic plasticity, paired-pulse facilitation (PPF, a form of short-term plasticity), long-term potentiation (LTP, a form of long-term plasticity), and their interactions were studied in the dorsal and ventral hippocampal CA1 regions of anesthetized rats. Baseline PPF and post-LTP PPF experiments were conducted at interstimulus intervals (ISIs) of 20-320 ms. A general protocol (100 Hz, 1 s) and a stronger protocol (250-Hz pulse series) were applied for LTP induction. PPF were observed in both regions; however, the degree was lower and the range of ISIs was narrower in the ventral region compared with the dorsal region. The degree of ventral LTP was lower than that of the dorsal LTP. The interaction between PPF and LTP was observed in both regions (PPF change correlated inversely with degree of baseline PPF). However, this was also different in each region. Dorsal PPF increased or decreased; in contrast, ventral PPF of short ISIs after LTP only decreased. These regional differences in short-term and long-term synaptic plasticity may explain a consequence of different afferent inputs and information processing.

We studied whether a protocol reported as in vivo prefrontal long-term depression (LTD) induction protocol, also induced LTD in the anesthetized rat hippocampal CA1, and whether differences in LTD induction existed between dorsal and ventral CA1, by low-frequency stimulation (LFS) (1 Hz, 900) or low-frequency burst stimulation (LFBS) (5-pulse burst at 4 ms interpulse intervals at 1 Hz, 900), hippocampo-prefrontal LTD induction protocol. Though LFS failed to induce stable LTD in dorsal or ventral CA1, LFBS reliably induced LTD in the ventral not dorsal CA1. This similarity between ventral hippocampal and hippocampo-prefrontal LTD induction thus implies their serial integration process, ventral CA3-CA1-prefrontal cortex pathway and observed dorsal and ventral differences involved in behavioral functions such as learning.

To determine whether the medial prefrontal cortex (PFC), ventral hippocampus and hippocampo-PFC pathway are involved in operant lever-press learning, we conducted lidocaine injections to these brain sites. Rats were injected immediately after lever-press acquisition in the first training, and the second 5-min test the next day. Results showed the response rate of either PFC- or ventral hippocampus-inactivated rats to be lower than that of control rats in the test the next day. Rats having lidocaine injected into the unilateral ventral hippocampus combined with contralateral medial PFC also showed lower response rate in their tests. These results suggest that hippocampo-PFC disconnection disturbs operant learning.

We studied excitatory field potentials in the medial prefrontal cortex (mPFC, prelimbic area) to electrostimulation of the ventral hippocampus (CA1/subicular region) in the anaesthetized rat. Nine hundred stimulus trains (5 pulses at 250 Hz) applied at 1 Hz to the ventral hippocampus significantly and persistently depressed the amplitude and maximal slope ( approximately 55% for each index) of the prelimbic field potentials, but did not change the latency of the maximal slope or peak negativity. Twelve stimulus trains (50 pulses at 250 Hz) applied subsequently at 0.1 Hz restored the depression back to control level, and this reversible depression was maintained for at least 13 h. Cumulative depressive effects on the prelimbic field potential amplitude and maximal slope were observed upon addition of stimulus trains in the hippocampus. An important implication of the results is that the direct pathway from the hippocampus to the mPFC in the rat retains long-term depression (LTD) as a neuroplastic form in vivo. This form could cooperate with long-term potentiation (LTP) and such a bi-directional synaptic plasticity in the prefrontal cortex contributes to how cortical neural networks store information.

We reported previously that administration of 1-oleoyl-2-docosahexaenoyl-sn-glycero-3-phosphorylcholine (ODHPC), a kind of phosphatidylcholine, enhanced discriminatory shock avoidance learning in rats. Since long-term potentiation (LTP) of the hippocampus has been suggested to be a physiological substrate of some forms of memory, we investigated the effects of ODHPC on LTP in the rat hippocampal CA1 region. LTP in the amplitude of population spikes in the CA1 region was induced by tetanic stimulation in anesthetized rats. ODHPC significantly increased magnitudes of LTP in a dose-dependent manner when injected intraperitoneally 20 min before inducing LTP. However, administration of 1,2-dioleoyl-sn-glycero-3-phosphorylcholine, in which only docosahexaenoyl residue of ODHPC was replaced with oleoyl residue, did not affect LTP. These results suggest that ODHPC enhances hippocampal LTP by its specific conformation.

To determine whether the rat medial prefrontal cortex (PFC) is involved in acquiring operant learning, we observed changes in extracellular concentration of dopamine (DA) and acetylcholine (ACh) in the rat medial PFC during lever-press acquisition (acquisition group) or retrieval (retention group) using in vivo microdialysis. We found that DA or ACh elevation related to acquisition occurred. DA elevation was observed in the acquisition group only. These results indicate that the medical PFC is related to acquisition, and suggest that interaction between DA and ACh may be involved in learning acquisition.

Our previous study showed that active oxygen radicals generated from a Fenton system and a xanthine plus xanthine oxidase system caused serious loss of in vivo bioactivity of recombinant human erythropoietin (EPO), a highly glycosylated protein. In the present study, we characterized the oxidative modifications to the protein and carbohydrate moiety of EPO, which lead to a reduction of its bioactivity. In vitro bioactivity was reduced when EPO was treated with oxygen radicals generated from a Fenton system in the presence of 0.016 mM H2O2, and the reduction was directly proportional to the loss of in vivo bioactivity. SDS-PAGE analysis showed that dimer formation and degradation was observed under more severe conditions (Fenton reaction with 0.16 mM H2O2). The tryptophan destruction was detected at 0.016 mM H2O2 and well correlated with the loss of in vitro bioactivity, whereas loss of other amino acids were occurred under more severe conditions. Treatment with the Fenton system did not result in any specific damage on the carbohydrate moiety of EPO, except a reduction of sialic acid content under severe condition. These results suggest that active oxygen radicals mainly react with the protein moiety rather than the carbohydrate moiety of EPO. Destruction of tryptophan residues is the most sensitive marker of oxidative damage to EPO, suggesting the importance of tryptophan in the active EPO structure. Deglycosylation of EPO caused an increased of susceptibility to oxygen radicals compared to intact EPO. The role of oligosaccharides in EPO may be to protect the protein structure from active oxygen radicals.