2021/10/25 更新

写真a

キタウラ ヒロキ
北浦 弘樹
KITAURA Hiroki
所属
脳研究所 特任准教授
職名
特任准教授
外部リンク

学位

  • 博士(医学) ( 2005年3月   新潟大学 )

研究キーワード

  • 病態神経科学, てんかん, 光学的イメージング, てんかん病理,

研究分野

  • ライフサイエンス / 神経機能学

  • ライフサイエンス / 病態神経科学  / てんかん

  • ライフサイエンス / 神経形態学  / 神経病理学

  • ライフサイエンス / 生理学  / 光学的イメージング

経歴(researchmap)

  • 新潟大学脳研究所   病理学分野   特任准教授

    2019年9月 - 現在

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  • 新潟大学   脳研究所 病理学分野   助教

    2008年4月 - 2019年8月

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  • 新潟大学 脳研究所 システム脳生理学分野   Brain Research Institute   機関研究員

    2005年4月 - 2008年3月

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  • 公立八鹿病院 歯科口腔外科

    2000年6月 - 2001年3月

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  • 神戸市立中央市民病院 歯科口腔外科

    1998年5月 - 2000年5月

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経歴

  • 新潟大学   脳研究所   特任准教授

    2019年9月 - 現在

  • 新潟大学   脳研究所 統合脳機能研究センター   助教

    2008年4月 - 2019年8月

学歴

  • 新潟大学医歯学総合研究科博士課程(システム脳生理学分野)

    2001年4月 - 2005年3月

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  • 東北大学歯学部歯学科

    1992年4月 - 1998年3月

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所属学協会

委員歴

  • 日本てんかん学会   評議員  

    2021年 - 現在   

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    団体区分:学協会

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論文

  • Reactive astrocytes contribute to epileptogenesis in patients with cavernous angioma. 査読 国際誌

    Hiroki Kitaura, Tetsuya Hiraishi, Yosuke Itoh, Makoto Oishi, Yukihiko Fujii, Masafumi Fukuda, Akiyoshi Kakita

    Epilepsy research   176   106732 - 106732   2021年7月

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    担当区分:筆頭著者, 責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    OBJECTIVE: Patients with cavernous angioma (CA) often suffer from severe epilepsy, and surgical resection is often performed to attenuate these epileptic seizures. Several studies have suggested that surgical removal of the surrounding hemosiderin-pigmented tissues adjacent to CA achieves better seizure control than restricted lesionectomy. Pathological examination of the resected foci reveals not only hemosiderin pigmentation but also various degrees of inflammatory change, such as hemosiderin-laden macrophages, gliosis and fibrosis. However, there is some controversy regarding the epileptogenic potential of these regions due to the uncertain nature of the mechanisms contributing to these histopathological changes. METHODS: To investigate the correlations between neuron hyperexcitability and evident pathological changes, we performed ex vivo flavoprotein fluorescence imaging using surgically resected epileptogenic foci surrounding CA. The mirror surfaces of the tissues used for the physiological experiment were also subjected to morphological examination. RESULTS: Hemosiderin-laden macrophages and many gemistocytic astrocytes were observed in the area adjacent to CA, where horizontal spreading excitations were detected significantly more frequently. Outside these areas, we found fine granular iron deposits and only a few fibrillary astrocytes, and weakly propagating excitations were detected. Furthermore, areas of enhanced activation were more clearly correlated with the glial proliferation index than with iron deposition. CONCLUSION: These results suggest that the epileptogenesis in patients with CA may be based on a biological process, such as alteration of glial function, rather than direct chemical reactions involving iron deposition.

    DOI: 10.1016/j.eplepsyres.2021.106732

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  • Longitudinal GluCEST MRI Changes and Cerebral Blood Flow in 5xFAD Mice 査読

    Hironaka Igarashi, Satoshi Ueki, Hiroki Kitaura, Tae Kera, Ken Ohno, Masaki Ohkubo, Mika Terumitsu-Tsujita, Akiyoshi Kakita, Ingrid L Kwee

    Contrast Media & Molecular Imaging   2020   1 - 12   2020年11月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Hindawi Limited  

    Many of the focal neurological symptoms associated with Alzheimer’s disease (AD) are due to synaptic loss. Glutamate chemical exchange saturation transfer (GluCEST) magnetic resonance imaging (MRI) is a candidate method to assess synaptic dysfunction. We assessed chronological changes in GluCEST in a 5xFAD mouse model of AD, comparing Glucest effects and regional cerebral blood flow (CBF). GluCEST effects and CBF in 5xFAD mice aged 1–15 months and their littermates (WT) were measured. Neurite orientation dispersion and density imaging (NODDI) MRI reflecting dendritic/axonal density was also measured and compared with GluCEST in 7-month-old mice. While regional CBF’s decrease began at 7 months, GluCEST-reduction effects preceded hypoperfusion of the temporal cortex and hippocampus. While longitudinal 5xFAD mouse measurements revealed a correlation between the regional GluCEST effects and CBF, a generalized linear mixed model revealed statistically different correlations in cortical and basal brain regions. Further, NODDI-derived neurite density correlated with GluCEST effects in the parietal cortex, but not in the hippocampus, thereby revealing regional differences in pathophysiological mechanisms. Finally, GluCEST’s effects correlated with regional synaptophysin. These results demonstrate that GluCEST can reflect subtle synaptic changes and may be a potential imaging method for AD diagnosis as well as serve as a biomarker of AD progression.

    DOI: 10.1155/2020/8831936

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    その他リンク: http://downloads.hindawi.com/journals/cmmi/2020/8831936.xml

  • Proteomic profile differentiating between mesial temporal lobe epilepsy with and without hippocampal sclerosis. 査読 国際誌

    Ayako Furukawa, Akiyoshi Kakita, Yoichi Chiba, Hiroki Kitaura, Yukihiko Fujii, Masafumi Fukuda, Shigeki Kameyama, Atsuyoshi Shimada

    Epilepsy research   168   106502 - 106502   2020年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Hippocampal sclerosis (HS) is the most common neuropathological condition in adults with drug-resistant epilepsy and represents a critical feature in mesial temporal lobe epilepsy (MTLE) syndrome. Although epileptogenic brain tissue is associated with glutamate excitotoxicity leading to oxidative stress, the proteins that are targets of oxidative damage remain to be determined. In the present study we designed comprehensive analyses of changes in protein expression level and protein oxidation status in the hippocampus or neocortex to highlight proteins associated with excitotoxicity by comparing MTLE patients with relatively mild excitotoxicity (MTLE patients without HS, MTLE-non-HS) and those with severe excitotoxicity (MTLE patients with HS, MTLE-HS). We performed 2-dimensional fluorescence difference gel electrophoresis, 2D-oxyblot analysis, and mass spectrometric amino acid sequencing. We identified 16 proteins at 18 spots in which the protein expression levels differed between sclerotic and non-sclerotic hippocampi. In the sclerotic hippocampus, the expression levels of several synaptic proteins were decreased, and those of some glia-associated proteins increased. We confirmed histologically that all MTLE-HS cases examined exhibited severe neuronal cell loss and remarkable astrocytic gliosis in the hippocampi. In all MTLE-non-HS cases examined, neurons were spared and gliosis was unremarkable. Therefore, we consider that decreased synaptic proteins are a manifestation of loss of neuronal cell bodies and dendrites, whereas increased glia-associated proteins are a manifestation of proliferation and hypertrophy of astrocytes. These are considered to be the result of hippocampal sclerosis. In contrast, the expression level of d-3-phosphoglycerate dehydrogenase (PHGDH), an l-serine synthetic enzyme expressed exclusively by astrocytes, was decreased, and that of stathmin 1, a neurite extension-related protein expressed by neurons, was increased in the sclerotic hippocampus. These findings cannot be explained solely as the result of hippocampal sclerosis. Rather, these changes can be involved in the continuation of seizure disorders in MTLE-HS. In addition, the protein carbonylation detection, an indicator of protein oxidation caused by excitotoxicity of multiple seizures and/or status epilepticus, revealed that the carbonyl level of collapsin response mediator protein 2 (CRMP2) increased significantly in the sclerotic hippocampus. In conclusion, protein identification following profiling of protein expression levels and detection of oxidative proteins indicated potential pathognomonic protein changes. The decreased expression of PHGDH, increased expression of stathmin 1, and carbonylation of CRMP2 differentiate between MTLE with and without HS. Therefore, further investigations of PHGDH, stathmin 1 and CRMP2 are promising to study more detailed effects of excitotoxicity on epileptogenic hippocampal tissue.

    DOI: 10.1016/j.eplepsyres.2020.106502

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  • Glial pathology in a novel spontaneous mutant mouse of the Eif2b5 gene: a vanishing white matter disease model. 査読 国際誌

    Mika Terumitsu-Tsujita, Hiroki Kitaura, Ikuo Miura, Yuji Kiyama, Fumiko Goto, Yoshiko Muraki, Shiho Ominato, Norikazu Hara, Anna Simankova, Norihisa Bizen, Kazuhiro Kashiwagi, Takuhiro Ito, Yasuko Toyoshima, Akiyoshi Kakita, Toshiya Manabe, Shigeharu Wakana, Hirohide Takebayashi, Hironaka Igarashi

    Journal of neurochemistry   154 ( 1 )   25 - 40   2020年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Vanishing white matter disease (VWM) is an autosomal recessive neurological disorder caused by mutation(s) in any subunit of eukaryotic translation initiation factor 2B (eIF2B), an activator of translation initiation factor eIF2. VWM occurs with mutation of the genes encoding eIF2B subunits (EIF2B1, EIF2B2, EIF2B3, EIF2B4, and EIF2B5). However, little is known regarding the underlying pathogenetic mechanisms or how to treat patients with VWM. Here we describe the identification and detailed analysis of a new spontaneous mutant mouse harboring a point mutation in the Eif2b5 gene (p.Ile98Met). Homozygous Eif2b5I98M mutant mice exhibited a small body, abnormal gait, male and female infertility, epileptic seizures, and a shortened lifespan. Biochemical analyses indicated that the mutant eIF2B protein with the Eif2b5I98M mutation decreased guanine nucleotide exchange activity on eIF2, and the level of the endoplasmic reticulum stress marker activating transcription factor 4 was elevated in the 1-month-old Eif2b5I98M brain. Histological analyses indicated up-regulated glial fibrillary acidic protein immunoreactivity in the astrocytes of the Eif2b5I98M forebrain and translocation of Bergmann glia in the Eif2b5I98M cerebellum, as well as increased mRNA expression of an endoplasmic reticulum stress marker, C/EBP homologous protein. Disruption of myelin and clustering of oligodendrocyte progenitor cells were also indicated in the white matter of the Eif2b5I98M spinal cord at 8 months old. Our data show that Eif2b5I98M mutants are a good model for understanding VWM pathogenesis and therapy development. Cover Image for this issue: doi: 10.1111/jnc.14751.

    DOI: 10.1111/jnc.14887

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  • Versatile whole-organ/body staining and imaging based on electrolyte-gel properties of biological tissues. 査読 国際誌

    Etsuo A Susaki, Chika Shimizu, Akihiro Kuno, Kazuki Tainaka, Xiang Li, Kengo Nishi, Ken Morishima, Hiroaki Ono, Koji L Ode, Yuki Saeki, Kazunari Miyamichi, Kaoru Isa, Chihiro Yokoyama, Hiroki Kitaura, Masako Ikemura, Tetsuo Ushiku, Yoshihiro Shimizu, Takashi Saito, Takaomi C Saido, Masashi Fukayama, Hirotaka Onoe, Kazushige Touhara, Tadashi Isa, Akiyoshi Kakita, Mitsuhiro Shibayama, Hiroki R Ueda

    Nature communications   11 ( 1 )   1982 - 1982   2020年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Whole-organ/body three-dimensional (3D) staining and imaging have been enduring challenges in histology. By dissecting the complex physicochemical environment of the staining system, we developed a highly optimized 3D staining imaging pipeline based on CUBIC. Based on our precise characterization of biological tissues as an electrolyte gel, we experimentally evaluated broad 3D staining conditions by using an artificial tissue-mimicking material. The combination of optimized conditions allows a bottom-up design of a superior 3D staining protocol that can uniformly label whole adult mouse brains, an adult marmoset brain hemisphere, an ~1 cm3 tissue block of a postmortem adult human cerebellum, and an entire infant marmoset body with dozens of antibodies and cell-impermeant nuclear stains. The whole-organ 3D images collected by light-sheet microscopy are used for computational analyses and whole-organ comparison analysis between species. This pipeline, named CUBIC-HistoVIsion, thus offers advanced opportunities for organ- and organism-scale histological analysis of multicellular systems.

    DOI: 10.1038/s41467-020-15906-5

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  • Skull diploë is rich in aquaporin-4. 査読 国際誌

    Yuji Suzuki, Hiroki Kitaura, Yukimi Nakamura, Akiyoshi Kakita, Vincent J Huber, Nicholas Capozzoli, Ingrid L Kwee, Tsutomu Nakada

    Heliyon   6 ( 1 )   e03259 - e03259   2020年1月

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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:Elsevier BV  

    Aquaporin-4 (AQP4) is a water conducting membrane integral protein channel which is widely expressed in the astrocyte system of the brain. During the development of the AQP4 positron emission tomography (PET) imaging agent [11C]TGN-020 (N-(1,3,4-thiadiazol-2-yl)pyridine-3-[11C]-carboxamide), significant radioligand uptake was observed in the skull, where there was no known distribution of any aquaporin family proteins. Herein we confirmed via a newly developed method for bone-tissue immunohistology, a hitherto unrecognized distribution of AQP4, and not AQP1, in the skull. Other bony structures, by contrast, showed virtually no uptake of [11C]TGN-020, and likewise, do not express either AQP4 or AQP1. Immunohistological analysis demonstrated that the AQP4 expression in the skull is restricted to the diploë. Consequently, we suspect AQP4 plays a pivotal role in the formation and maintenance of yellow marrow and the diploë. However, elucidating the exact nature of that role will require further studies.

    DOI: 10.1016/j.heliyon.2020.e03259

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  • Reciprocal connectivity between secondary auditory cortical field and amygdala in mice. 査読 国際誌

    Hiroaki Tsukano, Xubin Hou, Masao Horie, Hiroki Kitaura, Nana Nishio, Ryuichi Hishida, Kuniyuki Takahashi, Akiyoshi Kakita, Hirohide Takebayashi, Sayaka Sugiyama, Katsuei Shibuki

    Scientific reports   9 ( 1 )   19610 - 19610   2019年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Recent studies have examined the feedback pathway from the amygdala to the auditory cortex in conjunction with the feedforward pathway from the auditory cortex to the amygdala. However, these connections have not been fully characterized. Here, to visualize the comprehensive connectivity between the auditory cortex and amygdala, we injected cholera toxin subunit b (CTB), a bidirectional tracer, into multiple subfields in the mouse auditory cortex after identifying the location of these subfields using flavoprotein fluorescence imaging. After injecting CTB into the secondary auditory field (A2), we found densely innervated CTB-positive axon terminals that were mainly located in the lateral amygdala (La), and slight innervations in other divisions such as the basal amygdala. Moreover, we found a large number of retrogradely-stained CTB-positive neurons in La after injecting CTB into A2. When injecting CTB into the primary auditory cortex (A1), a small number of CTB-positive neurons and axons were visualized in the amygdala. Finally, we found a near complete absence of connections between the other auditory cortical fields and the amygdala. These data suggest that reciprocal connections between A2 and La are main conduits for communication between the auditory cortex and amygdala in mice.

    DOI: 10.1038/s41598-019-56092-9

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  • G3BP1 inhibits ubiquitinated protein aggregations induced by p62 and USP10. 査読 国際誌

    Sergei Anisimov, Masahiko Takahashi, Taichi Kakihana, Yoshinori Katsuragi, Hiroki Kitaura, Lu Zhang, Akiyoshi Kakita, Masahiro Fujii

    Scientific reports   9 ( 1 )   12896 - 12896   2019年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The aberrant accumulation of ubiquitinated protein aggregates in cells plays a critical role in the pathogenesis of several degenerative diseases, including Parkinson disease (PD) and cystic fibrosis (CF). In this study, we found that Ras GTPase-activating protein-binding protein 1 (G3BP1) inhibits ubiquitinated protein aggregations induced by p62 and USP10 in cultured cells. p62 is a ubiquitin receptor, and p62 and its binding partner USP10 have been shown to augment ubiquitinated protein aggregation. G3BP1 interacted with p62 and USP10 and inhibited p62/USP10-induced protein aggregation. The G3BP1 inhibition of protein aggregations targeted two aggregation-prone proteins, α-synuclein and CFTR-ΔF508, which are causative factors of PD and CF, respectively. G3BP1 depletion increased the amounts of ubiquitinated α-synuclein and CFTR-ΔF508 protein. A proteasome reporter indicated that G3BP1 depletion inhibits the proteasome activity. We herein present evidence that G3BP1, p62 and USP10 together control ubiquitinated protein toxicity by controlling both ubiquitination and aggregation. Taken together, these results suggest that G3BP1, p62 and USP10 could be therapeutic targets for ubiquitinated protein aggregation disorders, including PD and CF.

    DOI: 10.1038/s41598-019-46237-1

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  • USP10 is a critical factor for Tau-positive stress granule formation in neuronal cells. 査読 国際誌

    Svetlana Piatnitskaia, Masahiko Takahashi, Hiroki Kitaura, Yoshinori Katsuragi, Taichi Kakihana, Lu Zhang, Akiyoshi Kakita, Yuriko Iwakura, Hiroyuki Nawa, Takeshi Miura, Takeshi Ikeuchi, Toshifumi Hara, Masahiro Fujii

    Scientific reports   9 ( 1 )   10591 - 10591   2019年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Tau aggregates in neurons of brain lesions is a hallmark pathology of tauopathies, including Alzheimer's disease (AD). Recent studies suggest that the RNA-binding protein TIA1 initiates Tau aggregation by inducing the formation of stress granules (SGs) containing Tau. SGs are stress-inducible cytoplasmic protein aggregates containing many RNA-binding proteins that has been implicated as an initial site of multiple pathogenic protein aggregates in several neurodegenerative diseases. In this study, we found that ubiquitin-specific protease 10 (USP10) is a critical factor for the formation of Tau/TIA1/USP10-positive SGs. Proteasome inhibition or TIA1-overexpression in HT22 neuronal cells induced the formation of TIA1/Tau-positive SGs, and the formations were severely attenuated by depletion of USP10. In addition, the overexpression of USP10 without stress stimuli in HT22 cells induced TIA1/Tau/USP10-positive SGs in a deubiquitinase-independent manner. In AD brain lesions, USP10 was colocalized with Tau aggregates in the cell body of neurons. The present findings suggest that USP10 plays a key role in the initiation of pathogenic Tau aggregation in AD through SG formation.

    DOI: 10.1038/s41598-019-47033-7

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  • Surgical strategy for focal cortical dysplasia based on the analysis of the spike onset and peak zones on magnetoencephalography. 査読

    Sergei A, Takahashi M, Katsuragi Y, Kakihana T, Kitaura H, Zhang L, Kakita A, Fujii M

    J Neurosurg   2019年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  • G3BP1 inhibits ubiquitinated protein aggregations by interacting with p62 and USP10. 査読

    Sergei A, Takahashi M, Katsuragi Y, Kakihana T, Kitaura H, Zhang L, Kakita A, Fujii M

    Sci Rep   2019年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  • USP10 Is a Driver of Ubiquitinated Protein Aggregation and Aggresome Formation to Inhibit Apoptosis. 査読 国際誌

    Masahiko Takahashi, Hiroki Kitaura, Akiyoshi Kakita, Taichi Kakihana, Yoshinori Katsuragi, Masaaki Nameta, Lu Zhang, Yuriko Iwakura, Hiroyuki Nawa, Masaya Higuchi, Masaaki Komatsu, Masahiro Fujii

    iScience   9   433 - 450   2018年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Accumulation of ubiquitinated proteins is cytotoxic, but cells inactivate these cytotoxicities by inducing aggresome formation. We found that ubiquitin-specific protease 10 (USP10) inhibits ubiquitinated protein-induced apoptosis by inducing aggresome formation. USP10 interacted with the ubiquitin receptor p62 and the interaction augmented p62-dependent ubiquitinated protein aggregation and aggresome formation, thereby cooperatively inhibiting apoptosis. We provide evidence that USP10/p62-induced protein aggregates inhibit proteasome activity, which increases the amount of ubiquitinated proteins and promotes aggresome formation. USP10 induced aggresomes containing α-synuclein, a pathogenic protein in Parkinson disease, in cultured cells. In Parkinson disease brains, USP10 was colocalized with α-synuclein in the disease-linked aggresome-like inclusion Lewy bodies, suggesting that USP10 inhibits α-synuclein-induced neurotoxicity by promoting Lewy body formation. Collectively, these findings suggest that USP10 is a critical factor to control protein aggregation, aggresome formation, and cytotoxicity in protein-aggregation-related diseases.

    DOI: 10.1016/j.isci.2018.11.006

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  • てんかんにて発症した海綿状血管腫の周囲脳組織のイメージング解析

    福多 真史, 北浦 弘樹, 増田 浩, 白水 洋史, 伊藤 陽祐, 東島 威史, 大石 誠, 平石 哲也, 藤井 幸彦, 柿田 明美

    てんかん研究   36 ( 2 )   433 - 433   2018年9月

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    記述言語:日本語   出版者・発行元:(一社)日本てんかん学会  

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  • フラビン蛍光イメージングによるてんかん原性の解析 招待 査読

    北浦弘樹, 柿田明美

    Clin Neurosci   36 ( 8 )   970 - 972   2018年8月

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    担当区分:筆頭著者, 責任著者   記述言語:日本語   掲載種別:研究論文(学術雑誌)  

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  • Aquaporin Positron Emission Tomography Differentiates Between Grade III and IV Human Astrocytoma. 査読 国際誌

    Yuji Suzuki, Yukihiro Nakamura, Kenichi Yamada, Satoshi Kurabe, Kouichirou Okamoto, Hiroshi Aoki, Hiroki Kitaura, Akiyoshi Kakita, Yukihiko Fujii, Vincent J Huber, Hironaka Igarashi, Ingrid L Kwee, Tsutomu Nakada

    Neurosurgery   82 ( 6 )   842 - 846   2018年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Aquaporin (AQP) water channels play a significant role in mesenchymal microvascular proliferation and infiltrative growth. AQPs are highly expressed in malignant astrocytomas, and a positive correlation is observed between their expression levels and histological tumor grade. OBJECTIVE: To examine the utility of aquaporin positron emission tomography (PET) for differentiating between astrocytoma grade III and grade IV using the AQP radioligand [11C]TGN-020. METHODS: Fifteen astrocytoma patients, grade III (n = 7) and grade IV (n = 8), and 10 healthy volunteers underwent [11C]TGN-020 aquaporin PET imaging. Surgical tissues of astrocytoma patients were examined for histopathological grading using the WHO classification standard and expression of AQP1 and AQP4 immunohistochemically. RESULTS: Mean standardized uptake values of astrocytoma grade III and IV (0.51 ± 0.11 vs 1.50 ± 0.44, respectively) were higher than normal white matter (0.17 ± 0.02, P < .001) for both tumor grades. Importantly, mean standardized uptake values of astrocytoma grade IV were significantly higher than grade III (P < .01). CONCLUSION: Our study demonstrated that [11C]TGN-020 aquaporin PET imaging differentiated between astrocytoma grades III and IV. We suggest its clinical application as a noninvasive diagnostic tool would lead to advancements in the management of these malignant brain tumors.

    DOI: 10.1093/neuros/nyx314

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  • Pathophysiological Characteristics Associated With Epileptogenesis in Human Hippocampal Sclerosis. 査読 国際誌

    Hiroki Kitaura, Hiroshi Shirozu, Hiroshi Masuda, Masafumi Fukuda, Yukihiko Fujii, Akiyoshi Kakita

    EBioMedicine   29   38 - 46   2018年3月

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    担当区分:筆頭著者, 責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Elsevier B.V.  

    Mesial temporal lobe epilepsy (MTLE) is the most frequent focal epileptic syndrome in adults, and the majority of seizures originate primarily from the hippocampus. The resected hippocampal tissue often shows severe neuronal loss, a condition referred to as hippocampal sclerosis (HS). In order to understand hippocampal epileptogenesis in MTLE, it seems important to clarify any discrepancies between the clinical and pathological features of affected patients. Here we investigated epileptiform activities ex vivo using living hippocampal tissue taken from patients with MTLE. Flavoprotein fluorescence imaging and local field potential recordings revealed that epileptiform activities developed from the subiculum. Moreover, physiological and morphological experiments revealed possible impairment of K+ clearance in the subiculum affected by HS. Stimulation of mossy fibers induced recurrent trans-synaptic activity in the granule cell layer of the dentate gyrus, suggesting that mossy fiber sprouting in HS also contributes to the epileptogenic mechanism. These results indicate that pathophysiological alterations involving the subiculum and dentate gyrus could be responsible for epileptogenesis in patients with MTLE.

    DOI: 10.1016/j.ebiom.2018.02.013

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  • Biallelic Variants in CNPY3, Encoding an Endoplasmic Reticulum Chaperone, Cause Early-Onset Epileptic Encephalopathy. 査読 国際誌

    Hiroki Mutoh, Mitsuhiro Kato, Tenpei Akita, Takuma Shibata, Hiroyuki Wakamoto, Hiroko Ikeda, Hiroki Kitaura, Kazushi Aoto, Mitsuko Nakashima, Tianying Wang, Chihiro Ohba, Satoko Miyatake, Noriko Miyake, Akiyoshi Kakita, Kensuke Miyake, Atsuo Fukuda, Naomichi Matsumoto, Hirotomo Saitsu

    American journal of human genetics   102 ( 2 )   321 - 329   2018年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Early-onset epileptic encephalopathies, including West syndrome (WS), are a group of neurological disorders characterized by developmental impairments and intractable seizures from early infancy. We have now identified biallelic CNPY3 variants in three individuals with WS; these include compound-heterozygous missense and frameshift variants in a family with two affected siblings (individuals 1 and 2) and a homozygous splicing variant in a consanguineous family (individual 3). All three individuals showed hippocampal malrotation. In individuals 1 and 2, electroencephalography (EEG) revealed characteristic fast waves and diffuse sharp- and slow-wave complexes. The fast waves were clinically associated with seizures. CNPY3 encodes a co-chaperone in the endoplasmic reticulum and regulates the subcellular distribution and responses of multiple Toll-like receptors. The amount of CNPY3 in lymphoblastoid cells derived from individuals 1 and 2 was severely lower than that in control cells. Cnpy3-knockout mice exhibited spastic or dystonic features under resting conditions and hyperactivity and anxiolytic behavior during the open field test. Also, their resting EEG showed enhanced activity in the fast beta frequency band (20-35 Hz), which could mimic the fast waves in individuals 1 and 2. These data suggest that CNPY3 and Cnpy3 perform essential roles in brain function in addition to known Toll-like receptor-dependent immune responses.

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  • Features of amygdala in patients with mesial temporal lobe epilepsy and hippocampal sclerosis: An MRI volumetric and histopathological study. 査読 国際誌

    Yoko Nakayama, Hiroshi Masuda, Hiroshi Shirozu, Yosuke Ito, Takefumi Higashijima, Hiroki Kitaura, Yukihiko Fujii, Akiyoshi Kakita, Masafumi Fukuda

    Epilepsy research   135   50 - 55   2017年9月

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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:ELSEVIER SCIENCE BV  

    OBJECTIVE: It is well-known that there is a correlation between the neuropathological grade of hippocampal sclerosis (HS) and neuroradiological atrophy of the hippocampus in mesial temporal lobe epilepsy (mTLE) patients. However, there is no strict definition or criterion regarding neuron loss and atrophy of the amygdala neighboring the hippocampus. We examined the relationship between HS and neuronal loss in the amygdala. MATERIALS AND METHODS: Nineteen mTLE patients with neuropathological proof of HS were assigned to Group A, while seven mTLE patients without HS were assigned to Group B. We used FreeSurfer software to measure amygdala volume automatically based on pre-operation magnetic resonance images. Neurons observed using Klüver-Barrera (KB) staining in resected amygdala tissue were counted. and the extent of immunostaining with stress marker antibodies was semiquantitatively evaluated. RESULTS: There was no significant difference in amygdala volume between the two groups (Group A: 1.41±0.24; Group B: 1.41±0.29cm3; p=0.98), nor in the neuron cellularity of resected amygdala specimens (Group A: 3.98±0.97; Group B: 3.67±0.67 10×-4 number of neurons/μm2; p=0.40). However, the HSP70 level, representing acute stress against epilepsy, in Group A patients was significantly larger than that in Group B. There was no significant difference in the level of Bcl-2, which is known as a protein that inhibits cell death, between the two groups. CONCLUSIONS: Neuronal loss and volume loss in the amygdala may not necessarily follow hippocampal sclerosis. From the analysis of stress proteins, epileptic attacks are as likely to damage the amygdala as the hippocampus but do not lead to neuronal death in the amygdala.

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  • Ca2+ -permeable AMPA receptors associated with epileptogenesis of hypothalamic hamartoma. 査読 国際誌

    Hiroki Kitaura, Masaki Sonoda, Sayaka Teramoto, Hiroshi Shirozu, Hiroshi Shimizu, Tadashi Kimura, Hiroshi Masuda, Yosuke Ito, Hitoshi Takahashi, Shin Kwak, Shigeki Kameyama, Akiyoshi Kakita

    Epilepsia   58 ( 4 )   e59-e63 - E63   2017年4月

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    担当区分:筆頭著者, 責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY  

    Hypothalamic hamartoma (HH), composed of neurons and glia without apparent cytologic abnormalities, is a rare developmental malformation in humans. Patients with HH often have characteristic medically refractory gelastic seizures, and intrinsic epileptogenesis within the lesions has been speculated. Herein we provide evidence to suggest that in HH neurons, Ca2+ permeability through α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors is aberrantly elevated. In needle biopsy specimens of HH tissue, field potential recordings demonstrated spontaneous epileptiform activities similar to those observed in other etiologically distinct epileptogenic tissues. In HH, however, these activities were clearly abolished by application of Joro Spider Toxin (JSTX), a specific inhibitor of the Ca2+ -permeable AMPA receptor. Consistent with these physiologic findings, the neuronal nuclei showed disappearance of adenosine deaminase acting on RNA 2 (ADAR2) immunoreactivity. Furthermore, examination of glutamate receptor 2 (GluA2) messenger RNA (mRNA) revealed that editing efficiency at the glutamine/arginine site was significantly low. These results suggest that neurons in HH may bear Ca2+ -permeable AMPA receptors due to dislocation of ADAR2.

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  • mTORとてんかん 招待 査読

    北浦弘樹, 武井延之, 中島光子, 松本直通, 柿田明美

    Epilepsy   10 ( 2 )   97 - 102   2016年11月

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    担当区分:筆頭著者, 責任著者   記述言語:日本語   掲載種別:研究論文(学術雑誌)  

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  • フラビン蛍光イメージングによるてんかん原性の解析 招待 査読

    北浦弘樹, 柿田明美

    Epilepsy   9 ( 2 )   82 - 84   2015年11月

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    担当区分:筆頭著者, 責任著者   記述言語:日本語   掲載種別:研究論文(学術雑誌)  

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  • Characteristic expression of p57/Kip2 in balloon cells in focal cortical dysplasia. 査読 国際誌

    Tadashi Kimura, Hiroki Kitaura, Hiroshi Masuda, Shigeki Kameyama, Yuko Saito, Kenji Sugai, Taisuke Otsuki, Atsuko Nakazawa, Nobuhito Morota, Takamichi Yamamoto, Kouji Iida, Masanori Nakagawa, Toshiki Mizuno, Hitoshi Takahashi, Akiyoshi Kakita

    Neuropathology : official journal of the Japanese Society of Neuropathology   35 ( 5 )   401 - 9   2015年10月

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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:WILEY-BLACKWELL  

    Balloon cells are a pathognomonic cellular feature of various cortical malformations, including focal cortical dysplasia type IIb (FCD IIb), cortical tubers of tuberous sclerosis (TSC) and hemimegalencephaly (HME). In the present study, we investigated the immunohistochemical expression of p57/Kip2, a member of the Cip/Kip family of cyclin-dependent kinase inhibitory proteins, in balloon cells in surgical specimens taken from 26, 17 and six patients with FCD IIb, TSC and HME, respectively. Characteristic dot-like reactivity with a faint, intense, reticular and process-like pattern was confined to the proximal portion of the cytoplasmic processes of the cells. Immunoelectron microscopy revealed the p57/Kip2 reactivity on intermediate filaments in the proximal portion of the processes. The immunohistochemical profile appeared similar to that of CD34; however, a double immunofluorescence study demonstrated that no cells showed reactivity for both p57/Kip2 and CD34. The frequencies of the p57/Kip2-positive cells in FCD IIb and HME were significantly higher than those in TSC, suggesting that the balloon cells may be heterogeneous. These findings suggest some functional significance of the protein on the cytoplasmic processes of balloon cells and appear consistent with the notion that the cells are abnormally differentiated progenitor cells.

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  • Somatic Mutations in MTOR Cause Focal cortical dysplasia Type IIb 査読

    Nakashima M, Saitsu H, Takei N, Tohyama J, Kato M, Kitaura H, Shiina M, Shirouzu H, Masuda H, Watanabe K, Ohba C, Tsurusaki Y, Miyake N, Zheng YJ, Sato T, Takebayashi H, Ogata K, Kameyama S, Kakita A, Matsumoto N

    Ann. Neurol   78 ( 3 )   375 - 386   2015年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1002/ana.24444

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  • Ligand-Based Molecular MRI: O-17 JJVCPE Amyloid Imaging in Transgenic Mice 査読

    Kiyotaka Suzuki, Hironaka Igarashi, Vincent J. Huber, Hiroki Kitaura, Ingrid L. Kwee, Tsutomu Nakada

    JOURNAL OF NEUROIMAGING   24 ( 6 )   595 - 598   2014年11月

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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:WILEY-BLACKWELL  

    BACKGROUND
    Development of molecular MR imaging (MRI) similar to PET imaging using contrast agents such as gadolinium as probe have been inherently hampered by incompatibility between potential probe (charged molecules) and membrane permeability. Nevertheless, considering the inherent spatial resolution limit for PET of 700 mu, the superior microscopic resolution of MRI of 4 mu presents a strong incentive for research into ligand-based molecular MRI.
    METHODS
    O-17 exhibits JJ vicinal coupling with a covalently bound proton in a hydroxyl group. This O-17 coupled proton can be ionized in water solution and interexchange with other water protons. This property can be utilized as "probe" in T2-weighted imaging and developed into ligand-based molecular MRI. We examined beta-amyloid distribution in human APP overexpressed transgenic mice in vivo following injection of O-17 labeled Pittsburg compound B (O-17-PiB).
    RESULTS
    JJVCPE imaging successfully imaged O-17-PiB, unequivocally establishing that O-17 JJVCPE imaging can be developed into PET-like molecular MRI in clinical medicine.
    CONCLUSIONS
    The study represents the first successful ligand-based molecular MRI in vivo. This is also the first in vivo amyloid imaging using MRI. High-resolution molecular MRI with high specificity under clinical settings, such as in vivo microscopic imaging of senile plaque, is a foreseeable aim.

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  • 結節性硬化症 招待 査読

    北浦弘樹, 柿田明美

    Epilepsy   8 ( 2 )   74 - 76   2014年11月

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    担当区分:筆頭著者, 責任著者   記述言語:日本語   掲載種別:研究論文(学術雑誌)  

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  • The kick-in system: a novel rapid knock-in strategy. 査読 国際誌

    Yuko Tomonoh, Masanobu Deshimaru, Kimi Araki, Yasuhiro Miyazaki, Tomoko Arasaki, Yasuyoshi Tanaka, Haruna Kitamura, Fumiaki Mori, Koichi Wakabayashi, Sayaka Yamashita, Ryo Saito, Masayuki Itoh, Taku Uchida, Junko Yamada, Keisuke Migita, Shinya Ueno, Hiroki Kitaura, Akiyoshi Kakita, Christoph Lossin, Yukio Takano, Shinichi Hirose

    PloS one   9 ( 2 )   e88549   2014年

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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:PUBLIC LIBRARY SCIENCE  

    Knock-in mouse models have contributed tremendously to our understanding of human disorders. However, generation of knock-in animals requires a significant investment of time and effort. We addressed this problem by developing a novel knock-in system that circumvents several traditional challenges by establishing stem cells with acceptor elements enveloping a particular genomic target. Once established, these acceptor embryonic stem (ES) cells are efficient at directionally incorporating mutated target DNA using modified Cre/lox technology. This is advantageous, because knock-ins are not restricted to one a priori selected variation. Rather, it is possible to generate several mutant animal lines harboring desired alterations in the targeted area. Acceptor ES cell generation is the rate-limiting step, lasting approximately 2 months. Subsequent manipulations toward animal production require an additional 8 weeks, but this delimits the full period from conception of the genetic alteration to its animal incorporation. We call this system a "kick-in" to emphasize its unique characteristics of speed and convenience. To demonstrate the functionality of the kick-in methodology, we generated two mouse lines with separate mutant versions of the voltage-dependent potassium channel Kv7.2 (Kcnq2): p.Tyr284Cys (Y284C) and p.Ala306Thr (A306T); both variations have been associated with benign familial neonatal epilepsy. Adult mice homozygous for Y284C, heretofore unexamined in animals, presented with spontaneous seizures, whereas A306T homozygotes died early. Heterozygous mice of both lines showed increased sensitivity to pentylenetetrazole, possibly due to a reduction in M-current in CA1 hippocampal pyramidal neurons. Our observations for the A306T animals match those obtained with traditional knock-in technology, demonstrating that the kick-in system can readily generate mice bearing various mutations, making it a suitable feeder technology toward streamlined phenotyping.

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  • Glioneuonal tumorの周囲脳組織のイメージング解析と病理組織学的所見の検討

    福多 真史, 北浦 弘樹, 大石 誠, 高尾 哲郎, 平石 哲也, 澁木 克栄, 柿田 明美, 藤井 幸彦

    てんかん研究   31 ( 2 )   405 - 405   2013年9月

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    記述言語:日本語   出版者・発行元:(一社)日本てんかん学会  

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  • Optical imaging of human epileptogenic tissues in vitro. 招待 査読 国際誌

    Hiroki Kitaura, Akiyoshi Kakita

    Neuropathology : official journal of the Japanese Society of Neuropathology   33 ( 4 )   469 - 74   2013年8月

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    担当区分:筆頭著者, 責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY  

    Epilepsy is a chronic disorder characterized by abnormal spatiotemporal neural activities. To clarify its physiological mechanisms and associated morphological features, we investigated neuronal activities using the flavoprotein fluorescence imaging technique and histopathological changes in epileptogenic tissue resected from patients with epilepsy. We applied an imaging technique suitable for examining human brain slices, and as a consequence achieved sufficient responses with high reproducibility. Moreover, we detected significant alterations in neuronal morphology associated with the acquired responses. Therefore, this strategy is useful for gaining a better understanding of the pathomechanisms underlying intractable epilepsy.

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  • Significance of horizontal propagation of synchronized activities in human epileptic neocortex investigated by optical imaging and immunohistological study. 査読 国際誌

    Tetsuya Hiraishi, Hiroki Kitaura, Makoto Oishi, Masafumi Fukuda, Shigeki Kameyama, Hitoshi Takahashi, Akiyoshi Kakita, Yukihiko Fujii

    Epilepsy research   104 ( 1-2 )   59 - 67   2013年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    To characterize the physiological condition of human epileptic neocortex, we employed flavoprotein fluorescence imaging (FFI), an optical imaging method which detects intrinsic signals accompanying neural activation, and immunohistologically studied human cortical specimens. The experimented materials were cortical tissues surrounding various intracerebral lesions obtained from 5 patients with epilepsy (epileptic patients: EPs) and 5 without epilepsy (non-epileptic patients: NEPs). These tissues were immersed in oxygenated artificial cerebrospinal fluid immediately after removal in the operating room. Signal changes of FFI in the cortical layers subjected to electrical stimulation were observed under bicuculline methiodide perfusion. Immunohistological staining for parvalbumin (PV), calbindin, and calretinin were performed on the same specimens to evaluate expressions of calcium-binding protein positive cells. The FFI study showed the characteristic cortical propagation pattern of elicited activities horizontally along the cortical layers in EPs but not in NEPs. The propagated area with more than 0.5% signal changes was significantly larger in EPs than in NEPs (p=0.008). Only the expression of PV positive neurons was significantly lower in EPs than in NEPs (p=0.006). The propagated area on FFI and the decrease in PV positive neurons correlated significantly (R=-0.78, p=0.04). The present study visualized the unique horizontal propagation of signal changes on FFI and demonstrated a correlation of this propagation with immunohistological decreases in PV positive neurons in human epileptic cortex. Further investigations may elucidate the mechanism of hyper-excitability and hyper-synchronization in epileptic cortical tissue itself.

    DOI: 10.1016/j.eplepsyres.2012.09.014

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  • てんかんにて発症した海綿状血管腫の周囲脳組織のイメージング解析と病理組織学的所見の検討

    福多 真史, 北浦 弘樹, 大石 誠, 平石 哲也, 澁木 克栄, 柿田 明美, 藤井 幸彦

    てんかん研究   30 ( 2 )   398 - 398   2012年9月

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    記述言語:日本語   出版者・発行元:(一社)日本てんかん学会  

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  • Periventricular nodular heterotopia functionally couples with the overlying hippocampus 査読

    Hiroki Kitaura, Makoto Oishi, Nobuyuki Takei, Yong-Juan Fu, Tetsuya Hiraishi, Masafumi Fukuda, Hitoshi Takahashi, Katsuei Shibuki, Yukihiko Fujii, Akiyoshi Kakita

    EPILEPSIA   53 ( 7 )   e127 - e131   2012年7月

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    担当区分:筆頭著者, 責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Patients with periventricular nodular heterotopia (PVNH) often have severe epilepsy. However, it is unclear how the heterotopia contributes to epileptogenesis. Recently, electrophysiologic studies using intraoperative depth electrodes have indicated that interaction between the heterotopia and overlying cortex is crucial for seizure onset. We performed an in vitro physiologic study using slices of resected brain from a 22-year-old man with PVNH, who manifested medically refractory mesial temporal lobe epilepsy. Preoperative evaluation indicated that the right mesial temporal structure and PVNH were the epileptogenic focus. The resected tissue was immediately immersed in cold artificial cerebrospinal fluid, and then slices of the brain tissue including the heterotopic nodules and overlying hippocampus were prepared. We electrically stimulated the incubated slices, and the elicited neural activities were analyzed as changes in the flavoprotein fluorescence signals. When we stimulated either the heterotopic nodule or the overlying hippocampus, clear functional coupling of neural activities between these structures was observed. The coupling response evoked by stimulation of the subiculum and developing within the heterotopic nodule was enhanced by application of bicuculline. Therefore, activities of the hippocampus and the nodule are closely correlated.

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  • Epidermoid cyst involving the medial temporal lobe: Surgical pathologic features of the epileptogenic lesion 査読

    Tetsuya Hiraishi, Makoto Oishi, Hiroki Kitaura, Masae Ryufuku, Yong-Juan Fu, Masafumi Fukuda, Hitoshi Takahashi, Yukihiko Fujii, Akiyoshi Kakita

    NEUROPATHOLOGY   32 ( 2 )   196 - 201   2012年4月

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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:WILEY-BLACKWELL  

    Epidermoid cysts in the middle fossa are rare and may involve the temporal lobe and lateral ventricle. Affected patients often suffer from seizures, but the pathomechanisms underlying the epileptogenic lesions have remained unclear. Here we report the surgical pathological features of the hippocampus in a 31-year-old woman with mesial temporal lobe epilepsy (mTLE), in whom an epidermoid cyst involving the right basal cistern and inferior horn of the lateral ventricle was evident. The ictal electrocorticogram indicated seizure onset at the parahippocampal gyrus. An anterior temporal lobectomy and amygdalohippocampectomy were performed. Histologically, the hippocampus showed marked atrophy with severe loss of pyramidal neurons in the cornu Ammonis subfields and granule cell loss in the dentate gyrus. At the ventricular surface of the hippocampus, there were small granulomatous lesions with spicularly anchored keratin substance. These features indicated multiple and chronic stab wounds by the cyst contents and consequent local inflammatory responses within the parenchyma. The predisposition to adhesion between the tumor and hippocampus may have caused neurons to develop abnormal irritability to certain chemical mediators present in the cyst. Epileptogenicity involving the atrophic hippocampus and medial temporal lobes nearby may have developed in association with these processes. This case appears to provide information that is useful for surgical planning in patients with mTLE and epidermoid cysts involving the medial temporal lobe.

    DOI: 10.1111/j.1440-1789.2011.01243.x

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  • Hypertrophy of hippocampal end folium neurons in patients with mesial temporal lobe epilepsy 査読

    Masae Ryufuku, Yasuko Toyoshima, Hiroki Kitaura, Yingjun Zheng, Yong-Juan Fu, Hiroaki Miyahara, Hiroatsu Murakami, Hiroshi Masuda, Shigeki Kameyama, Hitoshi Takahashi, Akiyoshi Kakita

    NEUROPATHOLOGY   31 ( 5 )   476 - 485   2011年10月

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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:WILEY-BLACKWELL  

    Hypertrophic and dysmorphic neurons have been identified in the hippocampal end folium of patients with mesial temporal lobe epilepsy (mTLE). No data are available regarding the correlation between these cellular alterations and the severity of hippocampal sclerosis (HS), and the significance of this phenomenon has been unclear. We evaluated both the perikaryon and nuclear areas of residual neurons in the hippocampal end folium of 47 patients with mTLE, seven with lesional neocortical temporal lobe epilepsy (LTLE), and 10 controls without seizure episodes. According to the severity of neuron loss in the end folium, we defined mTLE cases showing slight (&lt;10%) or no, moderate (10-50%) and severe (&gt;50%) loss as groups A, B and C, respectively. We also performed immunohistochemistry with antibodies against heat shock protein 70 and the phosphorylated epitope of neurofilament. In both mTLE and LTLE cases, the perikaryon and nuclear areas of the end folium neurons were significantly greater than those in the controls (P&lt;0.0001), and those in mTLE were significantly greater than those in LTLE. There were no differences in areas between groups A and B, but the areas in group C were significantly greater than those of both groups A and B. Neurons with large, bizarre morphology were labeled with both antibodies. Neuronal hypertrophy is evident in patients with epilepsy, and appears to advance gradually as the hippocampal sclerosis becomes more severe. This alteration may be a consequence of cellular stress incurred by neurons.

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  • フラビン蛋白蛍光イメージング解析により脳室周囲異所性灰白質と側頭葉内側構造の生理学的関連を捉えた側頭葉てんかん手術例

    大石 誠, 北浦 弘樹, 福多 真史, 平石 哲也, 藤井 幸彦, 柿田 明美

    臨床神経生理学   39 ( 5 )   420 - 420   2011年10月

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    記述言語:日本語   出版者・発行元:(一社)日本臨床神経生理学会  

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  • Spatiotemporal dynamics of epileptiform propagations: imaging of human brain slices.

    Kitaura Hiroki, Hiraishi Tetsuya, Murakami Hiroatsu, Masuda Hiroshi, Fukuda Masafumi, Oishi Makoto, Ryufuku Masae, Fu Yong-Juan, Takahashi Hitoshi, Kameyama Shigeki, Fujii Yukihiko, Shibuki Katsuei, Kakita Akiyoshi

    Neuroimage   58 ( 1 )   50 - 59   2011年9月

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    担当区分:筆頭著者, 責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Seizure activities often originate from a localized region of the cerebral cortex and spread across large areas of the brain. The properties of these spreading abnormal discharges may account for clinical phenotypes in epilepsy patients, although the manner of their propagation and the underlying mechanisms are not well understood. In the present study we performed flavoprotein fluorescence imaging of cortical brain slices surgically resected from patients with partial epilepsy caused by various symptomatic lesions. Elicited neural activities in the epileptogenic tissue spread horizontally over the cortex momentarily, but those in control tissue taken from patients with brain tumors who had no history of epilepsy demonstrated only localized responses. Characteristically, the epileptiform propagation comprised early and late phases. When the stimulus intensity was changed gradually, the early phase showed an all-or-none behavior, whereas the late phase showed a gradual increase in the response. Moreover, the two phases were propagated through different cortical layers, suggesting that they are derived from distinct neural circuits. Morphological investigation revealed the presence

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  • Spatiotemporal dynamics of epileptiform propagations: Imaging of human brain slices 査読

    Hiroki Kitaura, Tetsuya Hiraishi, Hiroatsu Murakami, Hiroshi Masuda, Masafumi Fukuda, Makoto Oishi, Masae Ryufuku, Yong-Juan Fu, Hitoshi Takahashi, Shigeki Kameyama, Yukihiko Fujii, Katsuei Shibuki, Akiyoshi Kakita

    NEUROIMAGE   58 ( 1 )   50 - 59   2011年9月

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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:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    Seizure activities often originate from a localized region of the cerebral cortex and spread across large areas of the brain. The properties of these spreading abnormal discharges may account for clinical phenotypes in epilepsy patients, although the manner of their propagation and the underlying mechanisms are not well understood. In the present study we performed flavoprotein fluorescence imaging of cortical brain slices surgically resected from patients with partial epilepsy caused by various symptomatic lesions. Elicited neural activities in the epileptogenic tissue spread horizontally over the cortex momentarily, but those in control tissue taken from patients with brain tumors who had no history of epilepsy demonstrated only localized responses. Characteristically, the epileptiform propagation comprised early and late phases. When the stimulus intensity was changed gradually, the early phase showed an all-or-none behavior, whereas the late phase showed a gradual increase in the response. Moreover, the two phases were propagated through different cortical layers, suggesting that they are derived from distinct neural circuits. Morphological investigation revealed the presence of hypertrophic neurons and loss of dendritic spines, which might participate in the aberrant activities observed by flavoprotein fluorescence imaging. These findings indicate that synchronized activities of the early phase may play a key role in spreading abnormal discharges in human cortical epilepsies. (C) 2011 Elsevier Inc. All rights reserved.

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  • Balloon cells in the dentate gyrus in hippocampal sclerosis associated with non-herpetic acute limbic encephalitis 査読

    Hiroaki Miyahara, Masae Ryufuku, Yong-Juan Fu, Hiroki Kitaura, Hiroatsu Murakami, Hiroshi Masuda, Shigeki Kameyama, Hitoshi Takahashi, Akiyoshi Kakita

    SEIZURE-EUROPEAN JOURNAL OF EPILEPSY   20 ( 1 )   87 - 89   2011年1月

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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:W B SAUNDERS CO LTD  

    The presence of balloon cells, a pathognomonic cellular feature of focal cortical dysplasia type BB, in a background of hippocampal sclerosis is rare. Here we report the surgical pathologic features of the hippocampus resected from a 32-year-old woman with mesial temporal lobe epilepsy and a precipitating history of non-herpetic acute limbic encephalitis. Histologically, the resected specimen showed features of hippocampal sclerosis with granule cell dispersion. Characteristically, many balloon cells, immunoreactive for nestin, vimentin, glial fibrillary acidic protein (GFAP), GFAP-delta and CD34, were observed in the molecular and granule cell layers of the dentate gyrus. In the present case hippocampal sclerosis was an apparently acquired alteration, rather than a result of maldevelopment. The appearance of balloon cells raises questions regarding their origin and morphogenesis. (C) 2010 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

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  • てんかん原性病巣における細胞内情報伝達経路関連蛋白の発現解析 査読

    柿田明美, 鄭 英君, 龍福雅恵, 北浦弘樹, 村上博淳, 増田 浩, 亀山茂樹, 高橋 均, 武井延之

    てんかん治療研究振興財団研究年報 2011   22   31 - 38   2011年

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    記述言語:日本語   掲載種別:研究論文(大学,研究機関等紀要)  

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  • 新皮質てんかん病巣における興奮伝播様式の解析 ヒト脳スライス標本を用いた光学的イメージング

    北浦 弘樹, 平石 哲也, 村上 博淳, 増田 浩, 福多 真史, 大石 誠, 龍福 雅恵, 付 永娟, 高橋 均, 亀山 茂樹, 藤井 幸彦, 澁木 克栄, 柿田 明美

    てんかん研究   28 ( 2 )   232 - 233   2010年9月

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    記述言語:日本語   出版者・発行元:(一社)日本てんかん学会  

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  • Transcranial imaging of somatotopic map plasticity after tail cut in mice.

    Kitaura Hiroki, Hishida Ryuichi, Shibuki Katsuei

    Brain Res   1319   54 - 59   2010年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Peripheral afferent denervation induces reorganization of somatotopic maps in the primary somatosensory cortex (S1). In the present study, we investigated somatotopic map plasticity after tail cut. Neonatal mice at postnatal days (P) 2-3 and adult mice at eight weeks of age were anesthetized with ether, and approximately two thirds of the tail was cut from the tip. Both groups of mice were anesthetized with urethane (1.7g/kg, i.p.) at 10weeks of age, and transcranial flavoprotein fluorescence imaging was performed in the S1. Neural activities in the S1 were elicited by vibratory stimulation applied to the contralateral hindpaw or the tail in control mice. The cortical areas activated by hindpaw, tail base, and tail tip stimuli were placed in this order according to the medial and posterior direction. In mice with tail cut, the tail base area moved to the more medial and posterior area corresponding to the tail tip in control mice. The shift of the tail base area was observed in both neonatal and adult tail cut mice, indicating the absence of a critical period before eight weeks. Medial and posterior shift of the tail base area with regard to the bregma was confirmed in tail cut mi

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  • Transcranial imaging of somatotopic map plasticity after tail cut in mice 査読

    Hiroki Kitaura, Ryuichi Hishida, Katsuei Shibuki

    BRAIN RESEARCH   1319   54 - 59   2010年3月

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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:ELSEVIER SCIENCE BV  

    Peripheral afferent denervation induces reorganization of somatotopic maps in the primary somatosensory cortex (S1). In the present study, we investigated somatotopic map plasticity after tail cut. Neonatal mice at postnatal days (P) 2-3 and adult mice at eight weeks of age were anesthetized with ether, and approximately two thirds of the tail was cut from the tip. Both groups of mice were anesthetized with urethane (1.7 g/kg, i.p.) at 10 weeks of age, and transcranial flavoprotein fluorescence imaging was performed in the Si. Neural activities in the Si were elicited by vibratory stimulation applied to the contralateral hindpaw or the tail in control mice. The cortical areas activated by hindpaw, tail base, and tail tip stimuli were placed in this order according to the medial and posterior direction. In mice with tail cut, the tail base area moved to the more medial and posterior area corresponding to the tail tip in control mice. The shift of the tail base area was observed in both neonatal and adult tail cut mice, indicating the absence of a critical period before eight weeks. Medial and posterior shift of the tail base area with regard to the bregma was confirmed in tail cut mice. These data suggest that transcranial flavoprotein fluorescence imaging is a useful technique for investigating somatosensory map plasticity in mice. (C) 2010 Elsevier B.V. All rights reserved.

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  • Activity-dependent glial swelling is impaired in aquaporin-4 knockout mice 査読

    Hiroki Kitaura, Mika Tsujita, Vincent J. Huber, Akiyoshi Kakita, Katsuei Shibuki, Kenji Sakimura, Ingrid L. Kwee, Tsutomu Nakada

    NEUROSCIENCE RESEARCH   64 ( 2 )   208 - 212   2009年6月

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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:ELSEVIER IRELAND LTD  

    We investigated the role of aquaporin-4 (AQP4), a water channel expressed in glial cells, in neural activity mediated morphological changes observed in brain slice preparation. Changes in flavoprotein fluorescence (FF) and infrared light scattering (LS) signals were measured before and after repetitive stimulation of layer VI in rostral somatosensory cortical slices taken from AQP4 knockout(KO)and wildtype (WT) mice. Changes in FF, which reflect neural aerobic activities, were comparable for the two groups in all cortical layers. However, changes in LS signals, which are indicative of cell swelling, were significantly decreased in layer 1 of AQP4 KO mice compared to that of WT mice. We conclude that AQP4 likely plays a significant role in neural activity-dependent glial swelling. (C) 2009 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

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  • Activity-dependent glial swelling is impaired in aquaporin-4 knockout mice.

    Kitaura Hiroki, Tsujita Mika, Huber Vincent J, Kakita Akiyoshi, Shibuki Katsuei, Sakimura Kenji, Kwee Ingrid L, Nakada Tsutomu

    Neurosci Res   64 ( 2 )   208 - 212   2009年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    We investigated the role of aquaporin-4 (AQP4), a water channel expressed in glial cells, in neural activity mediated morphological changes observed in brain slice preparation. Changes in flavoprotein fluorescence (FF) and infrared light scattering (LS) signals were measured before and after repetitive stimulation of layer VI in rostral somatosensory cortical slices taken from AQP4 knockout (KO) and wild-type (WT) mice. Changes in FF, which reflect neural aerobic activities, were comparable for the two groups in all cortical layers. However, changes in LS signals, which are indicative of cell swelling, were significantly decreased in layer I of AQP4 KO mice compared to that of WT mice. We conclude that AQP4 likely plays a significant role in neural activity-dependent glial swelling.

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  • Flavoprotein Fluorescence Imaging of Experience-Dependent Cortical Plasticity in Rodents 査読

    Katsuei Shibuki, Ryuichi Hishida, Manavu Tohmi, Kuniyuki Takahashi, Hiroki Kitaura, Yamato Kubota

    2009年

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    記述言語:英語   出版者・発行元:CRC Press/Taylor & Francis  

    In this chapter, flavoprotein fluorescence imaging is described, with a focus on transcranial imaging for investigating experience-dependent plasticity in mice. The molecular mechanisms underlying higher brain functions are important subjects of neuroscience research. The cerebral cortex, which is expected to have essential roles in higher functions, has mainly been investigated in primates. However, the analytical methods for elucidating molecular mechanisms in the primate brain are rather limited. An alternative approach is to investigate higher cortical functions in rodents. In particular, mice are very useful for investigating molecular mechanisms, because many genetically manipulated strains are available. However, the cortical functions of rodents can not be studied intensively, partly because the cortex is fragile, and electrophysiological analysis is sometimes difficult. In contrast, mice have thin skulls that are transparent enough to allow transcranial imaging of the cortical activities through the intact skull (Schuett et al. 2002, Shibuki et al. 2007). Auditory, visual, and somatosensory cortices are visible through the intact skull (Figure 7.1A). Transcranial analysis of cortical functions has a number of technical merits: the operation to remove the skull is omitted so that surgical damages on the cortex can be avoided, and the fragile cortex of mice is kept intact within the skull during the recording experiments. Optical imaging of cortical activities usually requires experimental skills, whereas the transcranial imaging of the mouse cortical activities may be performed even by beginner neuroscientists or students. In transcranial analysis of cortical functions, application of exogenous indicators, such as voltage-sensitive dyes or calcium indicators, is difficult. Transcranial imaging may be performed in mice that express with protein sensors derived from GFP (McGann et al. 2005, Diez-Garcia et al. 2007). Alternatively, it may be performed using some intrinsic signals reflecting cortical activities. Most of intrinsic signals reflecting brain activities are coupled with activity-dependent facilitation of aerobic energy metabolism (Fein and Tsacopoulos 1988, Shibuki 1989, 1990, Vanzetta and Grinvald 1999). One of the results of facilitated energy metabolism is that oxyhemoglobin in the capillary is converted to deoxyhemoglobin, and that the light absorption properties of hemoglobin are changed (Frostig et al. 1990). Endogenous fluorescence changes are also produced by facilitated energy metabolism in the brain (Chance et al. 1962), because fluorescence substances such as NADH or flavoproteins are involved in aerobic energy metabolism (Figure 7.1B). Activity-dependent changes in endogenous fluorescence derived from NADH have been used to monitor brain activities (Chance et al. 1962, Rosenthal and Jöbsis 1971, Lothman et al. 1975, Lewis and Schuette 1976). However, decreases in fluorescence signals derived from NADH might also be caused by activity-dependent increases in blood flow (Kitaura et al. 2007), because both excitation light and emitted fluorescence are easily absorbed by hemoglobin. Although activity-dependent increases in flavoprotein fluorescence signal are unlikely to be mimicked by hemodynamic responses, flavoprotein fluorescence changes had not been used to monitor brain activities in previous studies, as these signals were not clearly recorded (Aubin et al. 1979). Endogenous fluorescence derived from NADH or flavoprotein is weak compared with that derived from fluorescence dyes. Therefore, clear separation of the faint fluorescence from the strong excitation light is essential. The faint fluorescence must be detected by a sensitive camera with a low noise level. Therefore, application of endogenous fluorescence derived from flavoproteins to functional brain imaging requires recent development of advanced optical devices (Shibuki et al. 2003, Reinert et al. 2004, Coutinho et al. 2004, Weber et al. 2004, Husson et al. 2007).

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  • Coupling of brain function and metabolism: Endogenous flavoprotein fluorescence imaging of neural activities by local changes in energy metabolism. 招待 査読

    Shibuki K, Hishida R, Kitaura H, Takahashi K, Tohmi M

    In Handbook of Neurochemistry & Molecular Neurobiology. 3rd Edition, Vol. 5, Neural Energy Utilization (Gibson G and Dienel G, ed). Springer, New York   322 - 342   2007年12月

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    記述言語:英語   掲載種別:研究論文(その他学術会議資料等)  

    DOI: 10.1007/978-0-387-30411-3_13

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  • Roles of nitric oxide as a vasodilator in neurovascular coupling of mouse somatosensory cortex 査読

    Hiroki Kitaura, Naonori Uozumi, Manavu Tohmi, Maya Yamazaki, Kenji Sakimura, Masaharu Kudoh, Takao Shimizu, Katsuei Shibuki

    NEUROSCIENCE RESEARCH   59 ( 2 )   160 - 171   2007年10月

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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:ELSEVIER IRELAND LTD  

    Neural activities trigger regional vasodilation in the brain. Diffusible messengers such as nitric oxide (NO) and prostanoids are considered to work as vasodilators in neurovascular coupling. However, their roles are still controversial. In the present study, cortical images of neural activities and vasodilation were recorded through the intact skull of C57BL/6 mice anesthetized with urethane. Flavoprotein fluorescence responses elicited by vibratory hindpaw stimulation were followed by darkening of arteriole images reflecting vasodilation in the somatosensory cortex. Vasodilation was also observed in light reflection images at the wavelength of 570 nm in the same mice. We perfused the surface of the cortex under the skull with 100 mu M N-G -nitro-L-arginine (L-NA), an inhibitor of NO synthase (NOS), and 10 mu M indomethacin, an inhibitor of cyclooxygenase (COX). These drugs suppressed vasodilation without changing flavoprotein fluorescence responses. A mixture Of L-NA and indomethacin almost completely eliminated vasodilation. In mice lacking neuronal NOS (nNOS), activity-dependent vasodilation was significantly suppressed compared with that in littermate control mice, while that in mice lacking cytosolic phospholipase A2 alpha (cPLA2 alpha) was unchanged. These results indicate that NO works as a vasodilator in neurovascular coupling of the mouse somatosensory cortex. (C) 2007 Published by Elsevier Ireland Ltd and the Japan Neuroscience Society.

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  • Functional local connections with differential activity-dependence and critical periods surrounding the primary auditory cortex in rat cerebral slices 査読

    Ryuichi Hishida, Daiki Kamatani, Hiroki Kitaura, Masaharu Kudoh, Katsuei Shibuki

    NEUROIMAGE   34 ( 2 )   679 - 693   2007年1月

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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:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    Sensory information is processed in neural networks connecting the primary sensory cortices with surrounding higher areas. Here, we investigated the properties of local connections between the primary auditory cortex (area 41) and surrounding areas (areas 20, 36, 18a and 39) in rat cerebral slices. Neural activities elicited by repetitive electrical stimulation were visualized using the activity-dependent changes in endogenous fluorescence derived from mitochondrial flavoproteins, which mostly reflect activities produced by polysynaptic glutamatergic transmission. Polysynaptic feedforward propagation was dominant compared with the corresponding polysynaptic feedback propagation between the primary (area 41) and secondary (areas 20 and 36) auditory cortices, while such a tendency was less clear in other pathways. Long inter-areal (&gt; 1 mm) propagation with the same dominancy was observed after laver V stimulation between areas 41 and 20, and was not affected by cutting the underlying white matter. Activity-dependent changes in neural activities induced by low-frequency stimulation in the presence of I mu M bicuculline were investigated using Ca2+ imaging. Significant potentiation of the polysynaptic Ca2+ activities was only observed in polysynaptic feedforward pathways from the primary to secondary auditory cortices. Experience-dependence of the connections between areas 41 and 20 was investigated using flavoprotein fluorescence imaging. The activities from areas 41 to 20 were reduced by cochlear lesions produced at P12 but not at P28, while the activities from areas 20 to 41 were reduced by the lesions at P28, suggesting the critical period for the polysynaptic feedforward connection was before P28, while for the polysynaptic feedback connection was after P28. (c) 2006 Elsevier Inc. All rights reserved.

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  • Enduring critical period plasticity visualized by transcranial flavoprotein imaging in mouse primary visual cortex 査読

    Manavu Tohmi, Hiroki Kitaura, Seiji Komagata, Masaharu Kudoh, Katsuei Shibuki

    JOURNAL OF NEUROSCIENCE   26 ( 45 )   11775 - 11785   2006年11月

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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:SOC NEUROSCIENCE  

    Experience-dependent plasticity in the visual cortex was investigated using transcranial flavoprotein fluorescence imaging in mice anesthetized with urethane. On- and off-responses in the primary visual cortex were elicited by visual stimuli. Fluorescence responses and field potentials elicited by grating patterns decreased similarly as contrasts of visual stimuli were reduced. Fluorescence responses also decreased as spatial frequency of grating stimuli increased. Compared with intrinsic signal imaging in the same mice, fluorescence imaging showed faster responses with similar to 10 times larger signal changes. Retinotopic maps in the primary visual cortex and area LM were constructed using fluorescence imaging. After monocular deprivation ( MD) of 4 d starting from postnatal day 28 ( P28), deprived eye responses were suppressed compared with nondeprived eye responses in the binocular zone but not in the monocular zone. Imaging faithfully recapitulated a critical period for plasticity with maximal effects of MD observed around P28 and not in adulthood even under urethane anesthesia. Visual responses were compared before and after MD in the same mice, in which the skull was covered with clear acrylic dental resin. Deprived eye responses decreased after MD, whereas nondeprived eye responses increased. Effects of MD during a critical period were tested 2 weeks after reopening of the deprived eye. Significant ocular dominance plasticity was observed in responses elicited by moving grating patterns, but no long-lasting effect was found in visual responses elicited by light-emitting diode light stimuli. The present results indicate that transcranial flavoprotein fluorescence imaging is a powerful tool for investigating experience-dependent plasticity in the mouse visual cortex.

    DOI: 10.1523/JNEUROSCI.1643-06.2006

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  • 経頭蓋的自家蛍光イメージングで捉えたマウス体性感覚野機能マップの可塑性.

    池田謙輔, 北浦弘樹, 高橋邦行, 任海学, 澁木克栄

    新潟医学会雑誌   119   303 - 311   2005年12月

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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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  • Activity-dependent persisting modification of polysynaptic neural circuits involving layer V pyramidal neurons in rat auditory cortex in vitro 査読

    H Kitaura, R Hishida, M Kudoh, K Shibuki

    EUROPEAN JOURNAL OF NEUROSCIENCE   19 ( 2 )   356 - 364   2004年1月

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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:BLACKWELL PUBLISHING LTD  

    Synaptic plasticity in polysynaptic neural circuits permits modulation of the dynamic properties of these circuits. We investigated the properties of polysynaptic potentiation in pyramidal neurons in layer V of rat auditory cortex (AC) slices using the perforated patch clamp technique. The GABA(A) receptor inhibitor bicuculline was used to facilitate polysynaptic activity. The amplitude and duration of the polysynaptic activity were both gradually potentiated with repetitive stimulation (RS) at 12 s intervals. Potentiation was saturated within 10 min of the onset of RS. After the cessation of RS, the polysynaptic responses returned to control levels within 30 min. RS-induced potentiation was confirmed by fluorescence imaging of slices loaded with the Ca2+ indicator rhod-2. Such potentiation was not induced by stimulation at 60 s intervals. The magnitude of the RS-induced potentiation in layer V pyramidal neurons in the AC was greater than that in either layer II/III pyramidal neurons in the AC or layer V pyramidal neurons in the visual cortex. The NMDA receptor antagonist APV (100 mum), inhibited RS-induced potentiation. When stimulated at 1 Hz, the potentiated response appeared rapidly. In the absence of bicuculline, RS consisting of five pulses at 30 ms intervals, repeated at 12 s intervals for 10 min, elicited potentiation of firing activity, suggesting that the potentiation is independent of bicuculline. The present study demonstrates the dynamic properties of polysynaptic circuits involving layer V pyramidal neurons in the AC are strongly affected by activity-dependent synaptic potentiation.

    DOI: 10.1111/j.1460-9568.2003.03136.x

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  • 目で見るてんかん:海馬硬化症のてんかん原性 招待 査読

    北浦弘樹, 柿田明美

    Epilepsy   32   1 - 2   2021年11月

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    担当区分:筆頭著者, 責任著者  

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  • オプトジェネティクスと光イメージング 招待 査読

    北浦 弘樹

    Clinical Neuroscience   36 ( 8 )   970 - 972   2018年8月

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    担当区分:筆頭著者, 責任著者  

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  • AMPA型グルタミン酸受容体の構造とシナプス伝達機構 招待 査読

    北浦 弘樹

    ペランパネルによるてんかん治療のストラテジー   2018年

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    担当区分:筆頭著者, 責任著者  

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  • 小胞体シャペロンをコードするCNPY3の劣性変異は早期発症てんかん性脳症を引き起こす

    才津浩智, 武藤弘樹, 加藤光広, 秋田天平, 柴田琢磨, 若本裕之, 池田浩子, 北浦弘樹, 青戸一司, 中島光子, 大場ちひろ, 宮武聡子, 三宅紀子, 柿田明美, 三宅健介, 福田敦夫, 松本直通

    日本遺伝子診療学会大会プログラム・抄録集   25th   2018年

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  • 小胞体シャペロンをコードするCNPY3の劣性変異は早期発症てんかん性脳症を引き起こす

    才津浩智, 武藤弘樹, 加藤光広, 秋田天平, 柴田琢磨, 若本裕之, 池田浩子, 北浦弘樹, 青戸一司, 中島光子, 大場ちひろ, 宮武聡子, 三宅紀子, 柿田明美, 三宅健介, 福田敦夫, 松本直通

    日本先天異常学会学術集会プログラム・抄録集   58th   2018年

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  • mTORとてんかん 招待 査読

    北浦 弘樹

    Epilepsy   10 ( 2 )   39 - 44   2016年11月

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    担当区分:筆頭著者, 責任著者  

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  • フラビン蛍光イメージングによるてんかん原性の解析 招待 査読

    北浦 弘樹

    Epilepsy   9 ( 2 )   4 - 5   2015年11月

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    担当区分:筆頭著者, 責任著者  

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  • 目で見るてんかん:結節性硬化症 招待 査読

    北浦 弘樹

    Epilepsy   8 ( 2 )   4 - 5   2014年11月

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    担当区分:筆頭著者, 責任著者  

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  • Human granule cell dispersion associated with hippocampal sclerosis: Identification of neural progenitors and neurogenesis

    Masae Ryufuku, Yasuko Toyoshima, Yingiun Zheng, Hiroki Kitaura, Shigeki Kameyama, Hitoshi Takahashi, Akiyoshi Kakita

    NEUROSCIENCE RESEARCH   61   S127 - S127   2008年

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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)   出版者・発行元:ELSEVIER IRELAND LTD  

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  • Rapid recovery of somatosensory responses after partial denervation in the mice somatosensory cortex

    Seiji Komagata, Shanlin Chen, Hiroki Kitaura, Masaharu Kudoh, Minoru Shibata, Katsuei Shibuki

    NEUROSCIENCE RESEARCH   55   S156 - S156   2006年

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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)   出版者・発行元:ELSEVIER IRELAND LTD  

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講演・口頭発表等

  • Pathophysiological characteristics associated with epileptogenesis 招待

    Hioroki KItaura

    Asia-Oceania Society of Neuropatholgy  2021年9月 

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    開催年月日: 2021年9月

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  • てんかん病態解明の学際的アプローチ:グリアとニューロンの理論と実データ 招待

    北浦弘樹

    第62回日本神経学会 シンポジウム  2021年5月 

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    開催年月日: 2021年5月

    会議種別:シンポジウム・ワークショップ パネル(指名)  

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  • ヒトてんかん原性機序の病態生理学的研究 招待

    北浦弘樹

    新潟医学会 基調講演  2021年11月 

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    会議種別:口頭発表(招待・特別)  

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  • 海馬硬化症のてんかん原性:外科病理標本を用いた機能異常と形態異常の接点 招待

    北浦弘樹

    第54回日本てんかん学会 シンポジウム  2021年9月 

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    会議種別:シンポジウム・ワークショップ パネル(指名)  

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  • てんかん焦点組織の生理学的多様性:外科手術標本を用いた光学的イメージング解析 招待

    北浦弘樹

    愛知医療療育総合センター発達障害研究所 公開セミナー  2020年1月 

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  • てんかんにおけるグリアの役割 招待

    第53回日本てんかん学会 シンポジウム  2019年10月 

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  • 基礎研究から探るてんかん病態 招待

    第53回日本てんかん学会 シンポジウム  2019年10月 

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  • てんかんの病理 招待

    北浦弘樹

    第60回日本神経病理学会 教育セミナー  2019年7月 

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    会議種別:口頭発表(招待・特別)  

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  • Visualization of epileptogenic activities in human brain lesions ex vivo 招待

    第8回生理学研究所-霊長類研究所-新潟脳研合同シンポジウム  2019年3月 

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    記述言語:英語  

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  • てんかん焦点局所回路の可視化 招待

    北浦 弘樹

    第42回日本てんかん外科学会 シンポジウム  2019年1月 

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  • グリアのてんかん原性 招待

    北浦 弘樹

    第51回日本てんかん学会 シンポジウム  2017年11月 

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  • ヒト脳スライス標本を用いたてんかん焦点組織の病態生理学的解析 招待

    北浦弘樹

    新潟脳研-生理学研究所合同シンポジウム  2014年2月 

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  • てんかんの病態病理 招待

    北浦 弘樹

    第53回日本神経病理学会 シンポジウム  2012年6月 

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  • ヒト脳スライス標本を用いた光学的イメージング技術 招待

    北浦弘樹

    第1回トランスレーショナルてんかん研究会  2010年10月 

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    会議種別:口頭発表(招待・特別)  

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  • 二次性新皮質てんかんの興奮動態 招待

    北浦 弘樹

    第44回日本てんかん学会 シンポジウム  2010年10月 

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受賞

  • Juhn & Mary Wada 奨励賞

    2019年8月   日本てんかん学会  

    北浦 弘樹

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  • 第55回日本神経病理学会総会 優秀賞

    2014年6月   日本神経病理学会  

    北浦 弘樹

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  • 第45回日本てんかん学会総会 優秀賞

    2011年10月   日本てんかん学会  

    北浦 弘樹

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共同研究・競争的資金等の研究

  • デジタル3D神経病理学の創成

    研究課題/領域番号:20K20468  2019年6月 - 2022年3月

    日本学術振興会  科学研究費助成事業 挑戦的研究(開拓)  挑戦的研究(開拓)

    柿田 明美, 北浦 弘樹, 田井中 一貴, 齋藤 理恵

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    担当区分:研究分担者 

    配分額:25870000円 ( 直接経費:19900000円 、 間接経費:5970000円 )

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  • ヒト手術標本を用いたてんかん原性ネットワークのイメージング解析と制御

    研究課題/領域番号:19H03542  2019年4月 - 2022年3月

    日本学術振興会  科学研究費助成事業 基盤研究(B)  基盤研究(B)

    北浦 弘樹, 才津 浩智, 清水 宏, 柿田 明美

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    担当区分:研究代表者 

    配分額:17160000円 ( 直接経費:13200000円 、 間接経費:3960000円 )

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  • てんかん原性病巣の病態機序と制御:外科標本のイメージングプラクティス

    研究課題/領域番号:19H01061  2019年4月 - 2022年3月

    日本学術振興会  科学研究費助成事業 基盤研究(A)  基盤研究(A)

    柿田 明美, 田井中 一貴, 北浦 弘樹, 藤井 幸彦, 前原 健寿, 池田 昭夫

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    配分額:45500000円 ( 直接経費:35000000円 、 間接経費:10500000円 )

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  • 3D神経病理学へのフィージビリティー研究:透明化試薬を用いたてんかん病巣の解析

    研究課題/領域番号:16K14571  2016年4月 - 2018年3月

    日本学術振興会  科学研究費助成事業 挑戦的萌芽研究  挑戦的萌芽研究

    柿田 明美, 北浦 弘樹, 清水 宏

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    担当区分:研究分担者 

    配分額:3770000円 ( 直接経費:2900000円 、 間接経費:870000円 )

    難治てんかん原性病巣の外科的切除組織における脳病変をより正しく評価する目的から、脳の透明化技術とシート照明顕微鏡を使い、神経細胞やグリア細胞の配列を3次元で鮮明に捉える新規標本観察法を開発した。数百種類のケミカルスクリーニングを行いヒト脳組織専用新規CUBIC試薬と、一般蛍光染色法を開発した。本研究により、神経病理学領域におけるイノベーティブな新規方法論を開発できる可能性が拓けた。

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  • 海馬硬化症のてんかん原性:神経活動異常と3次元的形態異常の関連

    研究課題/領域番号:15K06751  2015年4月 - 2018年3月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    北浦 弘樹, 柿田 明美

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    担当区分:研究代表者  資金種別:競争的資金

    配分額:5070000円 ( 直接経費:3900000円 、 間接経費:1170000円 )

    内側側頭葉てんかんでは、臨床的に海馬にてんかん原性があると考えられている。切除された海馬組織における病理組織像には幾つかのパターンがあることが知られているが、これまではこうした病理組織像に対応した異常神経活動を、神経回路レベルで詳細に解析する術がなかった。そのため、てんかん患者の脳手術標本から生体外で異常な神経活動を可視化する手法を確立し、内側側頭葉てんかんの発症メカニズムを検討した。その結果、切除された海馬の中でも、海馬支脚で異常な神経活動が生じていることを見出し、さらに、この異常神経活動にはグリア細胞の機能異常が大きく関わっていることを明らかにした。

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  • VWM型白質脳症の病態決定因子の探索

    研究課題/領域番号:15K06909  2015年4月 - 2018年3月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    辻田 実加, Huber Vincent, 小田 佳奈子, 北浦 弘樹

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    配分額:5070000円 ( 直接経費:3900000円 、 間接経費:1170000円 )

    Vanishing white matter(VWM)型白質脳症は発症時期や重症度に幅があることが知られているが、分子レベルでの病態決定因子は明らかにされていない。本研究では、VWM型白質脳症の原因遺伝子変異マウス(Toy)を用いて量的形質遺伝子座( Quantitative trait locus、QTL)解析と遺伝子発現解析を用いた影響因子探索を試みた。B6,C3H近交系統間の歩行異常の開始時期の差を指標としたQTL解析で相関の検出された領域ではイオントランスポーターやアポリポタンパク関連因子の発現差が顕著であった。本法はVWM型白質脳症の病態の分子レベル解明に有用だろう。

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  • 皮質形成異常症におけるてんかん原性の機能的・形態学的解析

    2014年4月 - 2016年3月

    てんかん治療研究振興財団  研究助成 

    北浦 弘樹

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    担当区分:研究代表者  資金種別:競争的資金

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  • 内側側頭葉てんかんの病態病理:パラドクスに挑む

    研究課題/領域番号:25250008  2013年4月 - 2017年3月

    日本学術振興会  科学研究費助成事業 基盤研究(A)  基盤研究(A)

    柿田 明美, 藤井 幸彦, 北浦 弘樹

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    配分額:47710000円 ( 直接経費:36700000円 、 間接経費:11010000円 )

    内側側頭葉てんかんの発作は海馬から起こる。しかしながら、外科治療として摘出された海馬組織においては、海馬における神経細胞脱落が観察され、海馬硬化症と呼ばれている。我々は、内側側頭葉てんかん患者から切除された海馬組織を培養し、このてんかん原性を解析した。フラビン蛍光イメージング法と局所電場電位測定により、海馬支脚から発作が起始することを見出した。更に、海馬支脚においては、内向き整流性K+チャネル(Kir4.1)の発現が低下したアストロサイトが認められた。このことから、内側側頭葉てんかんのてんかん原性の獲得には海馬支脚の細胞外腔におけるK+恒常性の破綻が関与している可能性が示唆された。

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  • 内側側頭葉てんかんにおける海馬硬化症の病態生理学的意義

    研究課題/領域番号:25870252  2013年4月 - 2015年3月

    日本学術振興会  科学研究費助成事業 若手研究(B)  若手研究(B)

    北浦 弘樹

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    担当区分:研究代表者  資金種別:競争的資金

    配分額:4290000円 ( 直接経費:3300000円 、 間接経費:990000円 )

    内側側頭葉てんかんの主な病態である海馬硬化症について、形態と機能の両面から病態形成機序の解明に迫ることを目的として遂行した。そのために、まず、手術で摘出されたヒトの脳組織から生鮮脳スライス標本を作製して、フラビン蛍光イメージング法により神経活動の解析を行った。その後、同一標本を固定・染色して苔状線維の走行や病理組織学的変化などと対比して検討した。その結果、病理組織学的な海馬硬化の進展にあわせて、異なったてんかん原性機序が存在している可能性が示唆された。本研究で得られた成果は、将来内側側頭葉てんかんの新たな治療法の開発につながりうるものであると考えられた。

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  • ヒト脳組織スライスの検討によるてんかん原性の発現・獲得過程の解明

    研究課題/領域番号:24592116  2012年4月 - 2015年3月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    大石 誠, 平石 哲也, 北浦 弘樹

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    配分額:5460000円 ( 直接経費:4200000円 、 間接経費:1260000円 )

    脳組織において「てんかん原性」がいかに発現し獲得されるかは,いまなお解明されていない.本研究では,脳神経外科手術摘出直後の生きた大脳組織標本を実験に活用し,当施設で開発された蛍光イメージング(フラビン傾向反応)による組織の生理学的反応,特に刺激の易伝播性と,免疫組織学的所見・病理組織検索による抑制ニューロンの脱失所見が相関すること,しかもてんかん発症初期にすでにこの所見が見られていることを明らかにすることに成功し,てんかん原性の発現と獲得の過程の一部を視覚化し得ることができた.

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  • ヒト脳スライス標本を用いたてんかん病態形成機序の生理学的解明

    研究課題/領域番号:22700376  2010年 - 2011年

    日本学術振興会  科学研究費助成事業 若手研究(B)  若手研究(B)

    北浦 弘樹, 柿田 明美, 福多 真史, 亀山 茂樹

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    配分額:4030000円 ( 直接経費:3100000円 、 間接経費:930000円 )

    てんかんは人口の約1%をも侵す主要な脳神経疾患のひとつである。その主な病態形成機序は大脳皮質の神経細胞の過剰興奮であるとされているが、その詳細は明らかではない。そこで、我々は手術で摘出された実際のヒトのてんかん焦点組織からスライス標本を作製し、人工脳脊髄液中で維持することで、生きたままのてんかん焦点組織における興奮動態を観察することを試み、てんかん焦点組織に特有の興奮伝播様式があることを見出した。

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  • てんかん病巣における神経活動の伝播特性:外科病理標本の解析

    研究課題/領域番号:21300134  2009年 - 2011年

    日本学術振興会  科学研究費助成事業 基盤研究(B)  基盤研究(B)

    柿田 明美, 北浦 弘樹, 福多 真史

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    配分額:19370000円 ( 直接経費:14900000円 、 間接経費:4470000円 )

    難治てんかん原性病巣の病態形成機序を知る目的から,外科的切除脳組織を用いた病態病理学的解析を行った.すなわち, 2次性の新皮質てんかん焦点を対象に急性脳スライスを用い,焦点組織内におけるネットワーク異常について,フラビン蛍光イメージング法を用いた解析を進めた.対照群には,てんかん歴のない脳腫瘍患者において摘出された正常脳皮質を用いた.摘出された脳組織は直ちに手術室にて氷冷人工脳脊髄液に入れられ, bubbling視ながら実験室へ輸送した.実験室でスライス標本を作製し, Incubateを行った.電気刺激により惹起した興奮動態をフラビン蛍光イメージング法で画像化して解析した. 1次病変はDNT, angioma, Glioma, Glioblastoma, Pilocytic astrocytoma, Gliosis, Glial scar各一例であった.その結果,てんかん原性大脳皮質には特徴的な"てんかん様興奮伝播"が全例で認められた.この興奮伝播は2つの構成成分からなること,それぞれは異なる神経回路から生じていることを明らかにした.この特徴的な変化は1次病変に関わらず一定であった.これら生理学的に異常を示した部位においては,組織学的には,神経細胞の肥大と樹状突起の異常な結節様変化が生じていることを見出した.樹状突起のspineの喪失や細胞体の肥大化については過去にも多くの報告がある.その細胞形態の劇的な変化から,樹状突起への投射線維が細胞体へ直接投射しているとのモデルが提唱されている.このモデルは,今回の研究結果,即ち高度に同期した神経活動が細胞形態異常を示す広い範囲に認められたこととよく合致する。即ち, 2次性の新皮質てんかん病巣においては,特異的な"Epileptic Neuron"が存在するのではなく,むしろ神経回路網の改変によりてんかん原性を獲得したものと考えられた.

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  • 難治てんかん原性病巣の病態基盤:分子細胞生物学的解析

    研究課題/領域番号:19300124  2007年 - 2008年

    日本学術振興会  科学研究費助成事業 基盤研究(B)  基盤研究(B)

    柿田 明美, 北浦 弘樹

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    配分額:8970000円 ( 直接経費:6900000円 、 間接経費:2070000円 )

    難治てんかん原性病巣における病態形成機序を知る目的から, てんかん焦点として外科的に切除されたFCDとTSCの脳組織を対象に, 細胞内情報伝達経路関連蛋白の発現と翻訳後修飾を解析した. その結果, FCDではp-S6を介した蛋白合成系が活性化しており, TSCとは異なった病態形成機序があると考えられた. FCDとTSCの脳組織を対象に, 急性脳スライス標本を作製し病態生理学的解析を試みた。FCDおよびTSCの結節周囲では, 電気刺激により惹起された興奮が刺激中断後も持続し, 対象に比し遷延する傾向が認められた. 一方TSCの結飾部では同興奮は刺激中断後には速やかに減衰し, ベースラインに回帰した. 両者のepileptogenicityは異なるものと考えられた.

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メディア報道

  • 内側側頭葉てんかん発症メカニズム解明 新聞・雑誌

    新潟日報  社会面  2018年6月

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    執筆者:本人以外 

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