記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: An assertive case management intervention program, ACTION-J, proved effective for preventing suicide attempters from reattempting suicide within 6 months. The ACTION-J randomized trial was conducted as part of the "National Strategic Research Projects." The program has been covered by the national medical payment system of Japan since 2016. The aim of the Post-ACTION-J Study (PACS) was to examine the current implementation status of assertive case management in a real-world clinical setting. METHODS: PACS was a prospective, multicenter registry cohort study. The participants were suicide attempters admitted to the emergency departments of 10 participating medical facilities from October 2016 to September 2018. The assertive case management intervention developed by the ACTION-J Study was offered to all patients, and the primary outcome was the duration and frequency of use of the intervention at 6 months. RESULTS: A total of 1159 patients were admitted to emergency departments after a suicide attempt during the study period, 144 of whom were included in our analysis. The proportion of participants who received the intervention for 6 months was 72.2% (104/144), and 63.9% (92/144) of the patients completed ≥7 case management interviews within 6 months. CONCLUSION: The findings of this study indicate successful implementation of an assertive case management intervention program based on the ACTION-J Study in a real-world clinical setting, following its integration with the national medical payment scheme in Japan. The study provided the useful information that could improve the implementation of assertive case management interventions in future.

DOI： 10.1002/pcn5.106

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Long interspersed nuclear element-1 (LINE-1, L1) affects the transcriptome landscape in multiple ways. Promoter activity within its 5'UTR plays a critical role in regulating diverse L1 activities. However, the epigenetic status of L1 promoters in adult brain cells and their relationship with psychiatric disorders remain poorly understood. Here, we examined DNA methylation and hydroxymethylation of the full-length L1s in neurons and nonneurons and identified "epigenetically active" L1s. Notably, some of epigenetically active L1s were retrotransposition competent, which even had chimeric transcripts from the antisense promoters at their 5'UTRs. We also identified differentially methylated L1s in the prefrontal cortices of patients with psychiatric disorders. In nonneurons of bipolar disorder patients, one L1 was significantly hypomethylated and showed an inverse correlation with the expression level of the overlapping gene NREP. Finally, we observed that altered DNA methylation levels of L1 in patients with psychiatric disorders were not affected by the surrounding genomic regions but originated from the L1 sequences. These results suggested that altered epigenetic regulation of the L1 5'UTR in the brain was involved in the pathophysiology of psychiatric disorders.

DOI： 10.1016/j.neures.2023.05.001

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記述言語：日本語   出版者・発行元：日本神経精神薬理学会・日本生物学的精神医学会・日本精神薬学会  

医中誌

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記述言語：日本語   出版者・発行元：(公社)日本精神神経学会  

医中誌

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: There has been number of studies suggesting experiences of adversity in early life interrelated subsequent brain development, however, neurobiological mechanisms confer risk for onset of psychiatric illness remains unclear. METHODS: In order to elucidate the pathogenic mechanisms underlying early life adversity-induced refractory depression in more detail, we administered corticosterone (CORT) to adolescent rats with or without prenatal ethanol exposure followed by an antidepressant or antipsychotic and examined alterations in depressive and social function behaviors and brain-derived neurotrophic factor (BDNF) levels in serum, the hippocampus, anterior cingulate cortex, and nucleus accumbens. RESULTS: The combined stress exposure of prenatal ethanol and adolescent CORT prolonged immobility times in the forced swim test (FST), and increased investigation times and numbers in the social interaction test (SIT). A treatment with escitalopram reversed depression-like behavior accompanied by reductions in BDNF levels in serum and the nucleus accumbens, while a treatment with blonanserin ameliorated abnormal social interaction behavior with reductions in serum BDNF levels. LIMITATIONS: Further studies are needed to clarify the clinical evinces responding to these results, and many questions remain regarding the mechanisms by which refractory depression and antidepressant/antipsychotic treatments cause changes in serum and brain regional BDNF levels. CONCLUSION: These results strongly implicate changes in BDNF levels in serum and the nucleus accumbens in the pathophysiology and treatment of early life combined stress-induced depression and highlight the therapeutic potential of escitalopram and new generation antipsychotic blonanserin for treatment-resistant refractory depression.

DOI： 10.1016/j.jad.2019.01.007

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: Suicide attempt is the most important risk factor for later suicide. A randomised-controlled, multicentre trial of postsuicide attempt case management for the prevention of further suicide attempts in Japan, named ACTION-J, has established effective interventions for prevention of suicide reattempts. The ACTION-J assertive case management intervention programme was adopted by the Japanese Ministry of Health, Labour and Welfare in 2016, when medical fees were revised. This nationwide programme is provided to patients who attempt suicide and who are admitted to emergency departments in Japan.The aim of the present study is to examine the current implementation status of the ACTION-J programme. The present study also aims to clarify which patients' and hospitals' factors affect the implementation of the programme. METHODS AND ANALYSIS: This is a prospective, multicentre, patient registry cohort study. Participants will be suicide attempters admitted to the emergency departments of medical facilities with both psychiatry and emergency departments. The assertive case management programme will be delivered to participants by a case manager for up to 24 weeks, based on psychiatric diagnoses, social risks and patient needs. The core feature of the programme is to encourage patients to participate in psychiatric treatment.The primary outcome will be the proportion of patients still participating in the case management intervention at 24 weeks after registration. The secondary outcomes will include measures of the fidelity of the case management intervention. The fidelity will be evaluated using a fidelity assessment manual developed by the study group. ETHICS AND DISSEMINATION: This observational study has been approved by the ethics board of Sapporo Medical University. Enrolment began in October 2016 and will continue until December 2018. Dissemination plans include presentations at scientific conferences and scientific publications. TRIAL REGISTRATION: UMIN000024474.

DOI： 10.1136/bmjopen-2017-020517

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Many patients with mental disorders visit emergency departments (EDs). However, the majority of these patients do not receive psychiatric assessment. In the present study, we investigated the detailed proportion of patients with mental disorders visiting an urban ED in the largest northern city in Japan. A retrospective chart review study was performed at a University Hospital from January 2012 to December 2015. The reasons for psychiatric consultations made by ED staff, and the primary psychiatric diagnoses were investigated. Among all living patients, 20% of them received consultations. The most common reason for consultation was suicide attempt followed by agitation or insomnia. Of all diagnoses, organic mental disorder was the most frequent and the mean age was significantly higher than the other diagnostic groups. Our study indicated that the frequency of psychiatric consultation was high. This indicates the high demand for mental health services at the ED. A thorough psychiatric assessment can provide adequate psychiatric services to acute patients; thereby possibly preventing suicide attempters from later actually dying by suicide.

DOI： 10.30773/pi.2018.04.04

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: Somatic mutations in the human brain are hypothesized to contribute to the functional diversity of brain cells as well as the pathophysiology of neuropsychiatric diseases. However, there are still few reports on somatic mutations in non-neoplastic human brain tissues. This study attempted to unveil the landscape of somatic mutations in the human brain. METHODS: We explored the landscape of somatic mutations in human brain tissues derived from three individuals with no neuropsychiatric diseases by whole-genome deep sequencing at a depth of around 100. The candidate mutations underwent multi-layered filtering, and were validated by ultra-deep target amplicon sequencing at a depth of around 200 000. RESULTS: Thirty-one somatic mutations were identified in the human brain, demonstrating the utility of whole-genome sequencing of bulk brain tissue. The mutations were enriched in neuron-expressed genes, and two-thirds of the identified somatic single nucleotide variants in the brain tissues were cytosine-to-thymine transitions, half of which were in CpG dinucleotides. CONCLUSION: Our developed filtering and validation approaches will be useful to identify somatic mutations in the human brain. The vulnerability of neuron-expressed genes to mutational events suggests their potential relevance to neuropsychiatric diseases.

DOI： 10.1111/pcn.12632

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記述言語：日本語   出版者・発行元：札幌医科大学医療人育成センター  

医中誌

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.4172/2378-5756.1000444

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Current antipsychotics reduce positive symptoms and reverse negative symptoms in conjunction with cognitive behavioral issues with the goal of restoring impaired occupational and social functioning. However, limited information is available on their influence on gliogenesis or their neurogenic properties in adult schizophrenia brains, particularly on GABAergic interneuron production. In the present study, we used young adult subventricular zone (SVZ)-derived progenitor cells expressing proteoglycan NG2 cultures to examine the oligodendrocyte and GABAergic interneuron genesis effects of several kinds of antipsychotics on changes in differentiation function induced by exposure to the NMDA receptor antagonist MK-801. We herein demonstrated that antipsychotics promoted or restored changes in the oligodendrocyte/GABAergic interneuron differentiation functions of NG2(+) cells induced by the exposure to MK-801, which was considered to be one of the drug-induced schizophrenia model. We also demonstrated that antipsychotics restored heat-shock protein (HSP) production in NG2(+) cells with differentiation impairment. The antipsychotics olanzapine, aripiprazole, and blonanserin, but not haloperidol increased HSP90 levels, which were reduced by the exposure to MK-801. Our results showed that antipsychotics, particularly those recently synthesized, exerted similar GABAergic interneuron genesis effects on NG2(+) neuronal/glial progenitor cells in the adult rat brain by increasing cellular HSP production, and also suggest that HSP90 may play a crucial role in the pathophysiology of schizophrenia and is a key target for next drug development.

DOI： 10.1016/j.jpsychires.2017.03.008

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Current diagnostic criteria recommend neuroimaging as a diagnostic support tool for the clinical diagnosis of dementia with Lewy bodies (DLB). Because DLB causes characteristic impairments and disabilities, such as neuroleptic hypersensitivity, which may significantly increase morbidity and mortality, its prompt and correct diagnosis is very important. The aim of this study was to evaluate the extent to which diagnostic accuracy can be increased by using different combinations of brain perfusion single-photon emission computed tomography (bp-SPECT), 123 I-metaiodobenzylguanidine myocardial scintigraphy (MIBG scintigraphy), and DAT-SPECT. Taking finances and patient burden into consideration, we compared the tests to determine priority. METHODS: Thirty-four patients with probable DLB (75.0 ± 8.3 years old; 14 men, 20 women) underwent bp-SPECT, MIBG scintigraphy, and DAT-SPECT. RESULTS: Our comparison of three functional imaging techniques indicated that MIBG scintigraphy (79%) and Dopamine-transporter (DAT) SPECT (79%) had better sensitivity for characteristic abnormalities in DLB than bp-SPECT (53%). The combination of the three modalities could increase sensitivity for diagnosis of DLB to 100%. Additionally, the ratio of patients with rapid eye movement sleep behaviour disorder was significantly higher in the positive finding group on MIBG scintigraphy than in the negative finding group. CONCLUSIONS: In terms of stand-alone diagnostic means, priority should be placed on MIBG scintigraphy or DAT-SPECT for the diagnosis of DLB. However, our results suggest that the combination of bp-SPECT, MIBG scintigraphy, and DAT-SPECT increased the accuracy of the clinical diagnosis of DLB.

DOI： 10.1111/psyg.12227

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Suicide is one of the common severe accidents occurring in hospitals. This study aimed to investigate inpatient suicides simultaneously in medical and psychiatric settings in a large number of hospitals and to examine the prevalence of common suicide risk factors, related symptoms in inpatients who had died by suicide and the differences in inpatient suicides between both settings. We conducted a survey of hospitals in Japan that belonged to the nationwide standard-setting and accrediting body. The questionnaire covered the: 1) presence or absence of inpatient suicides in each hospital from 2012 to 2015; 2) number of inpatient suicides; 3) method, location, and timing of inpatient suicides; and 4) characteristics of inpatients who died by suicide. In total, 529 hospitals reported 262 inpatient suicides during the 3-year period: 131 were in medical settings and 131 were in psychiatric settings. The prevalence of common suicide risk factors was frequent in inpatient suicides. Inpatients had characteristics and suicide risk factors specific to those settings such as worsening of physical health in medical settings. Therefore, recognizing common suicide risk factors and understanding differences in inpatient suicides between both settings are important to prevent inpatient suicides.

DOI： 10.1016/j.psychres.2017.01.076

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記述言語：英語  

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記述言語：英語  

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記述言語：日本語   出版者・発行元：(株)響文社  

医中誌

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Future Medicine Ltd.  

DOI： 10.4172/Neuropsychiatry.1000119

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

To better understand the relationship of repeated exposure to adversity during early development as a risk factor for refractory depression, we exposed pregnant female rats to ethanol and the resulting pups to corticosterone during adolescence. A stressful forced swim test was then used to induce depression-like behavior. The adolescent rat brains were examined for the possible therapeutic benefit of a combination of sertraline, an antidepressant, and neural stem cells (NSCs) complexed with atelocollagen in relation to the level of GABAergic interneuron and synaptic protein density in different brain regions. The combined exposures of prenatal and adolescent stress resulted in a reduction in parvalbumin (PV)-positive phenotype of GABAergic interneurons and reduced postsynaptic density protein 95 (PSD-95) levels in the anterior cingulate cortex, amygdala, and hippocampus. Treatments with sertraline and NSCs reversed the reductions in PV-positive cells and PSD-95 levels. Furthermore, the combined treatment of sertraline and NSCs resulted in reduced depressive-like behaviors. These experiments underscore a potentially important role for synaptic remodeling and GABAergic interneuron genesis in the treatment of refractory depression and highlight the therapeutic potential of stem cell and pharmacological combination treatments for refractory depression.

DOI： 10.1007/s00702-014-1194-2

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Recent reports suggest a lifetime suicide risk for schizophrenia patients of approximately 5%. This figure is significantly higher than the general population suicide risk consequently, detection of those at risk is clinically important. This study was undertaken to define the characteristics of suicide attempts by schizophrenia patients compared with attempts by patients with mood disorders. All patients were diagnosed using the ICD-10 criteria. The study population comprised 65 patients with F2 disorders (schizophrenia, schizotypal and delusional disorders), i.e., "the F2 group", and 94 patients with F3 disorders (mood disorders), i.e., "the F3 group", who presented in the clinical setting of consultation-liaison psychiatry. The F2 group had a significantly younger mean age and significantly higher ratios of 'past/present psychiatric treatment' and 'more than 3 months interruption of psychiatric treatment'. In contrast, the ratios of 'physical disorder comorbidity', 'alcohol intake at suicide attempt' and 'suicide note left behind' were significantly higher in the F3 group. The F2 group attempted suicide by significantly more serious methods. Furthermore, 'hallucination-delusion' was the most prevalent motive in the F2 group and was the only factor that showed a significant association with the seriousness of the method of suicide attempt (OR = 3.36, 95% CI: 1.05-11.33).

DOI： 10.1371/journal.pone.0096272

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記述言語：英語  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Stem cell therapy is well proposed as a potential method for the improvement of neurodegenerative damage in the brain. Among several different procedures to reach the cells into the injured lesion, the intravenous (IV) injection has benefit as a minimally invasive approach. However, for the brain disease, prompt development of the effective treatment way of cellular biodistribution of stem cells into the brain after IV injection is needed. Atelocollagen has been used as an adjunctive material in a gene, drug and cell delivery system because of its extremely low antigenicity and bioabsorbability to protect these transplants from intrabody environment. However, there is little work about the direct effect of atelocollagen on stem cells, we examined the functional change of survival, proliferation, migration and differentiation of cultured neural stem cells (NSCs) induced by atelocollagen in vitro. By 72-h treatment 0.01-0.05% atelocollagen showed no significant effects on survival, proliferation and migration of NSCs, while 0.03-0.05% atelocollagen induced significant reduction of neuronal differentiation and increase of astrocytic differentiation. Furthermore, IV treated NSCs complexed with atelocollagen (0.02%) could effectively migrate into the brain rather than NSC treated alone using chronic alcohol binge model rat. These experiments suggested that high dose of atelocollagen exerts direct influence on NSC function but under 0.03% of atelocollagen induces beneficial effect on regenerative approach of IV administration of NSCs for CNS disease.

DOI： 10.1007/s00702-013-1010-4

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記述言語：日本語   出版者・発行元：日本臨床精神神経薬理学会・日本神経精神薬理学会  

医中誌

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記述言語：日本語   出版者・発行元：(株)アークメディア  

医中誌

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記述言語：日本語   出版者・発行元：(一社)日本アルコール・アディクション医学会  

医中誌

J-GLOBAL

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記述言語：日本語   出版者・発行元：(株)アークメディア  

医中誌

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記述言語：日本語   出版者・発行元：(一社)日本アルコール・アディクション医学会  

医中誌

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記述言語：英語  

Web of Science

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/tp.2012.111

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記述言語：英語  

Web of Science

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記述言語：日本語   出版者・発行元：(一社)日本アルコール・アディクション医学会  

医中誌

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Genetic influences on the predisposition to complex behavioral or physiological traits can reflect genetic polymorphisms that lead to altered gene product function, and/or variations in gene expression levels. We have explored quantitative variations in an animal's alcohol consumption, using a genetical genomic/phenomic approach. In our studies, gene expression is correlated with amount of alcohol consumed, and genomic regions that regulate the alcohol consumption behavior and the quantitative levels of gene expression (behavioral and expression quantitative trait loci [QTL]) are determined and used as a filter to identify candidate genes predisposing the behavior. We determined QTLs for alcohol consumption using the LXS panel of recombinant inbred mice. We then identified genes that were: 1) differentially expressed between five high and five low alcohol-consuming lines or strains of mice; and 2) were physically located in, or had an expression QTL (eQTL) within the alcohol consumption QTLs. Comparison of mRNA and protein levels in brains of high and low alcohol consuming mice led us to a bioinformatic examination of potential regulation by microRNAs of an identified candidate transcript, Gnb1 (G protein beta subunit 1). We combined our current analysis with our earlier work identifying candidate genes for the alcohol consumption trait in mice, rats and humans. Our overall analysis leads us to postulate that the activity of the GABAergic system, and in particular GABA release and GABA receptor trafficking and signaling, which involves G protein function, contributes significantly to genetic variation in the predisposition to varying levels of alcohol consumption. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'.

DOI： 10.1016/j.neuropharm.2010.12.019

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Brain-derived neurotrophic factor (BDNF) belongs to the neurotrophin family, and enhances the growth and maintenance of several neuronal systems. In addition, BDNF may promote neurogenesis and protect against hippocampal volume loss in depressive disorders. Although first detected in brain, BDNF also exists in peripheral tissues and is mainly stored in platelets and circulates in blood. Recent reports indicate that serum BDNF levels in depressive patients are lower than in control subjects, and antidepressant treatment increases serum BDNF levels in responders. A single report suggests that decreased serum BDNF in major depression is related to mechanisms of platelet BDNF release; however, the mechanisms of changes in BDNF blood levels are still poorly understood. In the present study, we investigated the direct influence of antidepressants on BDNF release from platelets and their effects on serum levels. We used samples of washed platelets prepared from rat blood, and investigated the platelet BDNF release and serum BDNF concentration changes in response to adding antidepressants. We found that BDNF was dose-dependently released from platelets by direct treatment with various kinds of antidepressants in vitro, and serum BDNF concentration was also increased by intravenous antidepressant treatment. These results confirm that BDNF release from platelets is affected by antidepressants, which may relate to the circulating BDNF level change in peripheral blood. The response of BDNF release differs depending on the type and amount of antidepressants, making BDNF a serious candidate as a predictor of antidepressant treatment response.

DOI： 10.1016/j.pnpbp.2010.07.036

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Recent neuroimaging studies have revealed progressive morphological brain changes during the course of schizophrenia, and the neurotrophic and neurogenetic effects of atypical antipsychotics are believed to prevent or retard these brain volume reductions. In addition to drug-induced neural stem cell (NSC) activation, transplantation of exogenous NSCs has been proposed as a possible approach to repair the damaged brain in psychiatric disease. NSC transplantation embraces not only neuron replacement but also enhanced neuroprotection of existing neurons with the goal of restoring the impaired brain. However, little is known about the cell-cell interactions of exogenous NSCs with existing neurons, or about their neuroprotective actions especially in psychiatric diseases. In the present study, we used cortical neuron cultures to examine the neurotrophism and neuroprotection of exogenous NSCs against the neuronal damage induced by exposure to the NMDA receptor antagonist, MK-801. We also investigated their role in serum/nutrient deprivation stress. The exogenous NSCs exerted neuroprotective effects against both types of apoptotic injuries considered as in vitro schizophrenic disease models. Exogenous NSCs also altered cellular survival signaling in injured neurons by indirect cell-cell contact in an injury-dependent manner. In MK-801 exposure, NSCs increased phosphorylated Akt (p-Akt) and ERK (p-ERK), both of which were reduced by this stress. While, in serum/nutrient deprivation, NSCs increased p-Akt, but decreased p-ERK which was increased by this damage. Our results demonstrate that exogenous NSCs have anti-apoptotic activities and can rescue cortical neurons by directing cellular survival signaling of neurons into the proper direction, without cell contact.

DOI： 10.1016/j.schres.2010.05.008

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Recent biological studies suggest the existence of the common pathophysiological aspects in alcoholism and depression. Postmortem studies have revealed the impairment of cAMP signaling in the patients with alcoholism. The similar alteration of cAMP signaling was also reported in postmortem brains of depressed patients. In this study, we supported the notion that neurogenesis would be essential in pathophysiology of both alcoholism and depression. Alcohol affected the function of neural stem cells (NSCs) and decreased neurogenesis at doses which did not affects cell survival, and treatment of antidepressant or moodstabilizer rescued the alcohol-induced suppression of neurogenesis. As the key mechanism of NSC differentiation change by ethanol and psychotropics, we focused on the transcriptional repressor, NRSF/REST activity change. Our in vitro studies demonstrated the NRSF/REST activation by ethanol and suppressive effect of antidepressants and lithium against its activation by ethanol. We further described the ERK reduction and ER stress in the cellular mechanism of NRSF/REST activation. All these findings suggested that cAMP-CREB cascade reduction and NRSF/REST activation may be common underlying mechanisms in the pathophysiology of alcoholism and depression.

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

Recent clinical neuroimaging studies have suggested the morphological brain changes occur and progress in the course of alcoholism and depression. The abnormality of neurogenesis has emerged as a potential epidemiological mechanism of these diseases. Previously, we have indicated the low dose of ethanol that could not influence on the survival of neurons and neural stem cell (NSC) suppress differentiation to neurons but glias through activation of neuron-restrictive silencing factor/repressor element-1 silencing transcription factor (NRSF/REST). We revealed the endoplasmic reticulum function and trophic factor signaling change implicated in this mechanism of ethanol action on NSC differentiation change. The analysis of potentials of psychotropic drugs on the ethanol-induced NSC function change may reveal the possible biological way of neural network impairment and its repair. Furthermore, the approach of using stem cells such as intravenous NSC transplantation can be a useful method to clarify the neural network reconstruction damaged by ethanol. The importance of interactive analysis of in vitro to in vivo should be documented for the pathophysiological understanding and new therapy development against alcohol-induced brain damage.

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記述言語：英語  

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

Ethanol is a deleterious agent that causes various kinds of neuronal damage to both the developing and adult brain. Recent research on alcoholism implicates impaired function of neural stem cell (NSC) in the pathogenesis of ethanol-induced brain dysfunction. We previously reported that the differentiation of NSCs into neurons was significantly influenced by ethanol. We also found that neuron-restrictive silencer factor/repressor element 1-silencing transcription factor (NRSF/ REST) binding activity potentiated by ethanol underlies the mechanism of ethanol inhibition of neuronal differentiation. Epigenetics refers to post-translational modifications of DNA and nuclear proteins that produce lasting alterations in patterns of gene expression. Epigenetic mechanism plays a critical role of neuronal plasticity and there is clear evidence that dysfunction of epigenetic mechanism also contributes to neurological and psychiatric illness. We will review epigenetic regulation in pathogenesis of psychiatric illness including alcoholism. We also demonstrated that trichostatin A, histone deacetylase inhibitor, reduced the ethanol-induced suppression of neuronal differentiation of NSCs. We suggest that ethanol alters the function of neural differentiation through the mechanism of potentiation of NRSF/REST binding and histone modifications.

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Lithium, a mood-stabilizing drug, is widely used to treat bipolar affective disorder. Recent studies have demonstrated that lithium has neuroprotective and neurotrophic properties, which may relate to its clinical effectiveness. Ethanol is a deleterious agent that causes various kinds of neuronal damage to both the developing and adult brain. In this study, we investigated the potential of lithium to produce recovery of ethanol-induced suppressed neuronal differentiation at ethanol concentrations lower than those that affect the viability of neural stem cells (NSCs). We evaluated the effect of lithium on neuronal differentiation of NSCs obtained from rat embryos. To elucidate the molecular mechanisms underlying the altered neuronal differentiation induced by lithium and ethanol, we focused on neuron-restrictive silencer factor (NRSF), which represses transcription of neuronal genes in the terminal stage of NSC differentiation. Lithium increased neuronal differentiation and decreased ethanol-induced suppression of neuronal differentiation of NSCs. Furthermore, lithium reduced the DNA binding activity and protein level of NRSF enhanced by ethanol. Based on our findings, we speculate that lithium may be efficacious in the treatment of ethanol-induced neurological deficits.

DOI： 10.1016/j.ejphar.2008.07.021

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

Recent clinical neuroimaging studies have revealed the possible relation between morphological brain changes, and memory, cognitive impairment in the course of alcoholism and depression. In the previous studies, we have been analyzing the mechanism of neural network disruption by ethanol using postmortem human brain and cultured cells, and identified the sensitive effect of ethanol on the neural stem cell (NSC) differentiation rather than the influence on neuronal cell survival. Furthermore, to develop a novel method for reconstruction of the neural network damaged by ethanol, we tried to analyze the usefulness of intravenous NSC transplantation in fetal alcohol syndrome spectrum disorder (FASD) model rats. In the in vitro studies, we have found the suppressive effect of ethanol on NSC differentiation to neurons, through alteration of transcription factor, CREB and NRSF/REST activities, by the cellular signaling cascade changes including trophic factors and endoplasmic reticulum (ER) function. In the in vivo studies, we have shown the effective migration of labeled NSCs into the brain of FASD model rats, and revealed the therapeutic potential of this transplantation for the treatment of anxiety/cognitive dysfunction and behavioral abnormalities in alcohol-induced brain neural network damage. We are going to the next step for analysis of transplanted NSC dynamics in the brain, which must play a pivotal role in the effective induction of behavioral recoveries.

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記述言語：日本語   出版者・発行元：札幌医科大学医学部  

DOI： 10.15114/smj.76.7

医中誌

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記述言語：日本語   出版者・発行元：日本生物学的精神医学会  

医中誌

J-GLOBAL

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記述言語：日本語   出版者・発行元：(株)先端医学社  

医中誌

J-GLOBAL

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記述言語：日本語   出版者・発行元：(公財)先進医薬研究振興財団  

医中誌

J-GLOBAL

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記述言語：英語   出版者・発行元：(一社)日本神経精神薬理学会  

医中誌

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記述言語：英語  

Web of Science

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記述言語：英語  

Web of Science

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記述言語：英語  

Web of Science

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記述言語：英語  

Web of Science

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記述言語：日本語   出版者・発行元：(株)響文社  

医中誌

J-GLOBAL

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記述言語：英語  

Web of Science

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記述言語：英語   出版者・発行元：日本神経化学会  

医中誌

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記述言語：日本語   出版者・発行元：日本神経化学会  

医中誌

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記述言語：英語   出版者・発行元：日本神経化学会  

医中誌

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記述言語：日本語   出版者・発行元：日本神経化学会  

医中誌

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記述言語：英語  

Web of Science

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記述言語：日本語   出版者・発行元：(一社)日本アルコール・アディクション医学会  

医中誌

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記述言語：日本語   出版者・発行元：(公社)日本精神神経学会  

医中誌

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記述言語：日本語   出版者・発行元：(公財)先進医薬研究振興財団  

医中誌

J-GLOBAL

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

PubMed

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記述言語：英語   出版者・発行元：日本神経化学会  

医中誌

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記述言語：英語   出版者・発行元：日本神経化学会  

医中誌

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記述言語：日本語   出版者・発行元：(公財)先進医薬研究振興財団  

医中誌

J-GLOBAL

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記述言語：日本語   出版者・発行元：(一社)日本神経精神薬理学会  

医中誌

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記述言語：日本語   出版者・発行元：(一社)日本神経精神薬理学会  

医中誌

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記述言語：日本語   出版者・発行元：(公社)日本精神神経学会  

医中誌

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記述言語：日本語   出版者・発行元：(公社)日本精神神経学会  

医中誌

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記述言語：日本語   出版者・発行元：(一社)日本総合病院精神医学会  

医中誌

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記述言語：日本語   出版者・発行元：(一社)日本総合病院精神医学会  

医中誌

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記述言語：日本語   出版者・発行元：(一社)日本精神科救急学会  

医中誌

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記述言語：日本語   出版者・発行元：(一社)日本自殺予防学会  

医中誌

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記述言語：日本語   出版者・発行元：(公社)日本精神神経学会  

医中誌

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記述言語：日本語   出版者・発行元：(公社)日本精神神経学会  

医中誌

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記述言語：日本語   出版者・発行元：(公社)日本精神神経学会  

医中誌

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記述言語：日本語   出版者・発行元：(公社)日本精神神経学会  

医中誌

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記述言語：日本語   出版者・発行元：(公社)日本精神神経学会  

医中誌

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記述言語：日本語   出版者・発行元：(株)医学書院  

医中誌

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記述言語：日本語   出版者・発行元：(公社)日本精神神経学会  

医中誌

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記述言語：日本語   出版者・発行元：(公社)日本精神神経学会  

医中誌

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記述言語：日本語   出版者・発行元：(株)ワールドプランニング  

医中誌

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記述言語：日本語   出版者・発行元：(一社)日本総合病院精神医学会  

医中誌

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記述言語：日本語   出版者・発行元：(一社)日本総合病院精神医学会  

医中誌

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記述言語：日本語   出版者・発行元：(一社)日本総合病院精神医学会  

医中誌

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担当区分：筆頭著者   記述言語：日本語   出版者・発行元：(株)星和書店  

医中誌

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記述言語：日本語   出版者・発行元：(公社)日本精神神経学会  

医中誌

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記述言語：日本語   出版者・発行元：(一社)日本総合病院精神医学会  

医中誌

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記述言語：日本語   出版者・発行元：(公社)日本精神神経学会  

医中誌

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記述言語：日本語   出版者・発行元：札幌医科大学医療人育成センター  

医中誌

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）  

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記述言語：日本語   出版者・発行元：(公社)日本精神神経学会  

医中誌

J-GLOBAL

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記述言語：日本語   掲載種別：研究発表ペーパー・要旨（全国大会，その他学術会議）   出版者・発行元：(一社)日本神経精神薬理学会  

医中誌

J-GLOBAL

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記述言語：日本語   出版者・発行元：(公社)日本精神神経学会  

医中誌

J-GLOBAL

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記述言語：日本語   出版者・発行元：(公社)日本精神神経学会  

その他リンク:： http://search.jamas.or.jp/link/ui/2016150873

医中誌

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記述言語：日本語   出版者・発行元：(株)響文社  

医中誌

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記述言語：日本語   出版者・発行元：(公社)日本精神神経学会  

医中誌

J-GLOBAL

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記述言語：日本語   出版者・発行元：(公社)日本精神神経学会  

医中誌

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）  

Web of Science

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）  

Web of Science

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記述言語：日本語   出版者・発行元：(公財)先進医薬研究振興財団  

医中誌

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記述言語：日本語   出版者・発行元：(株)響文社  

医中誌

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記述言語：日本語   出版者・発行元：日本臨床精神神経薬理学会・日本神経精神薬理学会  

医中誌

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）  

Web of Science

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）  

Web of Science

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記述言語：日本語   出版者・発行元：(公社)日本精神神経学会  

医中誌

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記述言語：日本語   出版者・発行元：(株)響文社  

医中誌

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）  

Web of Science

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）  

Web of Science

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）  

Web of Science

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）  

Web of Science

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記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）   出版者・発行元：日本生物学的精神医学会  

その他リンク:： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2012&ichushi_jid=J05574&link_issn=&doc_id=20120725390004&doc_link_id=%2Fcy8jbiop%2F2012%2F002302%2F005%2F0109-0114%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcy8jbiop%2F2012%2F002302%2F005%2F0109-0114%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

医中誌

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記述言語：英語   出版者・発行元：日本神経化学会  

医中誌

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）  

Web of Science

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）  

Web of Science

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）  

Web of Science

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記述言語：日本語   出版者・発行元：日本ストレス学会  

その他リンク:： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2010&ichushi_jid=J02753&link_issn=&doc_id=20110524180001&doc_link_id=%2Ffd6stres%2F2010%2F002503%2F002%2F0167-0177%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Ffd6stres%2F2010%2F002503%2F002%2F0167-0177%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

医中誌

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）  

Web of Science

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）  

Web of Science

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）  

Web of Science

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）  

Web of Science

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記述言語：日本語   出版者・発行元：(公財)先進医薬研究振興財団  

その他リンク:： https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-22791132/

CiNii Research

医中誌

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）  

Web of Science

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）  

Web of Science

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）  

Web of Science

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）  

Web of Science

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）  

Web of Science

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記述言語：日本語   出版者・発行元：日本アルコール・薬物医学会  

医中誌

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記述言語：日本語   出版者・発行元：日本アルコール・薬物医学会  

医中誌

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記述言語：日本語   出版者・発行元：日本アルコール・薬物医学会  

医中誌

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記述言語：日本語   出版者・発行元：日本アルコール・薬物医学会  

医中誌

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記述言語：日本語   出版者・発行元：(株)アークメディア  

医中誌

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記述言語：日本語   出版者・発行元：(公財)先進医薬研究振興財団  

医中誌

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）  

DOI： 10.1016/j.neures.2009.09.868

Web of Science

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記述言語：日本語   出版者・発行元：日本アルコール・薬物医学会  

医中誌

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記述言語：日本語   出版者・発行元：日本アルコール・薬物医学会  

医中誌

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記述言語：日本語   出版者・発行元：日本アルコール・薬物医学会  

医中誌

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）  

Web of Science

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）  

Web of Science

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）  

Web of Science

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）  

Web of Science

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）  

Web of Science

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記述言語：日本語   出版者・発行元：(一社)日本神経精神薬理学会  

医中誌

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）  

Web of Science

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記述言語：日本語   出版者・発行元：(株)響文社  

医中誌

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記述言語：日本語   出版者・発行元：日本アルコール・薬物医学会  

医中誌

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記述言語：日本語   出版者・発行元：日本アルコール・薬物医学会  

医中誌

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記述言語：日本語   出版者・発行元：(公社)日本精神神経学会  

その他リンク:： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2006&ichushi_jid=J00755&link_issn=&doc_id=20061115310010&doc_link_id=1522825130354856960&url=https%3A%2F%2Fcir.nii.ac.jp%2Fcrid%2F1522825130354856960&type=CiNii&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00003_1.gif

医中誌

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）  

Web of Science

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記述言語：日本語   出版者・発行元：(株)星和書店  

医中誌

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）  

Web of Science

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記述言語：日本語   出版者・発行元：(株)響文社  

医中誌

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記述言語：日本語   出版者・発行元：日本アルコール・薬物医学会  

医中誌

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記述言語：日本語   出版者・発行元：日本アルコール・薬物医学会  

医中誌

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記述言語：日本語   出版者・発行元：日本アルコール・薬物医学会  

医中誌

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