論文 - 田中　謙二

Mutant glial fibrillary acidic protein reduces the capacity for glutamate uptake in hippocampal astrocytes.

Yamazaki Y, Fujiwara H, Goto JI, Tanaka KF

Neuroscience letters 874   138511 2026年03月

ISSN  0304-3940

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Descending locus coeruleus noradrenergic signaling to spinal astrocyte subset is required for stress-induced mechanical pain hypersensitivity.

Kawanabe-Kobayashi R, Uchiyama S, Yoshihara K, Koga K, Kojima D, McHugh TJ, Hatada I, Matsui K, Tanaka KF, Tsuda M

eLife 14 2026年03月

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船員健診における腸内菌叢の研究(第1報)　船員のエンテロタイプと疾患

吉開 泰信, 田中 謙二, 桑原 康雄, 一矢 有一, 舛本 博史, 水島 明, 吉澤 滋, 高木 重人, 齊藤 忠範, 田内 潤, 櫻井 裕

海上医学研究 （(一財)船員保険会）   （ 53 ） 26 - 49 2026年01月

ISSN  0453-1000

船員における飲酒状況と関連する健康問題の研究

齊藤 忠範, 高木 重人, 庄田 昌隆, 田内 潤, 笹子 佳門, 櫻井 裕, 上妻 達也, 吉澤 滋, 田中 謙二, 小山 仁

海上医学研究 （(一財)船員保険会）   （ 53 ） 1 - 25 2026年01月

ISSN  0453-1000

【精神展開剤とは何か?　社会に与えるインパクトとは?】精神展開剤の作用機序

田中 謙二

精神看護 （(株)医学書院）  29 （ 1 ） 020 - 023 2026年01月

ISSN  1343-2761

　概要を見る

＜文献概要＞筆者に与えられたテーマは「精神展開剤の作用機序」です。まさに今、筆者を含めた世界中の研究者もその機序解明に全力を捧げています。研究しているということはつまりわかっていないということです。じゃあ、わかっていないのに何を教えてくれるんですか?というもっともな指摘があろうかと思います。ここでは、精神看護に関わる方々に知ってもらって損のない豆知識を筆者の独断で選別して、読者の方々と共有したいと思います。

【電子顕微鏡が照らす医学研究の最前線】マクロからミクロレベルに至る脳構造変化の階層的解析を用いたジスキネジアの病態メカニズム解明

阿部 欣史, 田中 謙二

医学のあゆみ （医歯薬出版(株)）  295 （ 7 ） 580 - 584 2025年11月

ISSN  0039-2359

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＜文献概要＞レボドパ誘発性ジスキネジア(LID)と遅発性ジスキネジア(TD)は,それぞれ異なる薬剤の長期使用によって引き起こされる副作用であり,原因や治療対象は異なるにもかかわらず,共通して不随意運動という症状を示す.本研究では,この類似した病態の背景にある神経構造変化を明らかにするため,MRIによる全脳マクロ解析と,超解像顕微鏡および電子顕微鏡によるミクロ解析を組み合わせた階層的手法を用いた.その結果,両モデルマウスにおいて,淡蒼球(GPe)の線条体中型有棘ニューロン(MSN)の神経終末で小胞GABAトランスポーター(VGAT)の過剰発現と,MSN神経終末・標的細胞の肥大化が共通して認められた.さらに,VGATの発現量を操作する実験により,この構造変化がジスキネジアの原因であることが実証された.加えて,病態形成の背景には,ドパミンD2受容体シグナルの低下(1st hit)に加え,ドパミン濃度の周期的変動(2nd hit)が構造可塑性を誘導する"Two-Hit仮説"が提唱された.この成果は,構造解析技術によって病態の因果構造を明らかにし,基礎と臨床をつなぐ新たな視点を提供するものである.

Validation of phiC31-mediated expression and functional knockout of Opn3 in the Opn3-phiC31o knock-in mouse.

Kwok RKY, Ikuta H, Iba C, Nakano Y, Ma Z, Chuai Y, Hiraoka Y, Sayanagi T, Kurihara T, Moritoh S, Tanaka KF

Eye and vision (London, England) 12 （ 1 ） 41 2025年10月

ISSN  2326-0254

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Combination method of macroscopic imaging with MRI and microscopic imaging with super resolution microscopy for brain microstructure analysis.

Nakano Y, Tanaka KF, Abe Y

Anatomical science international 100 （ 4 ） 465 - 479 2025年09月

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【脳と体をつなぐ要　グリア細胞と疾患　可視化と脳情報デコーディングでその多様性と病態変化を理解し、治療をめざす】(第3章)グリア細胞と神経系疾患　アストロサイトを標的とした皮質下嚢胞をもつ大頭型白質脳症に対するAAV遺伝子治療開発

生田 光, 田中 謙二

実験医学 （(株)羊土社）  43 （ 10 ） 1612 - 1617 2025年06月

ISSN  0288-5514

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遺伝性小児神経疾患について,その原因遺伝子の同定が急速に進みつつある一方で,未だ根本的な治療法のない疾患も多い.皮質下嚢胞をもつ大頭型白質脳症(MLC)もまた,根治療法のない遺伝性小児神経疾患の1つである.MLC症例の大部分がアストロサイト特異的に発現するMLC1遺伝子の機能喪失変異によって引き起こされることから,われわれはアデノ随伴ウイルス(AAV)ベクターを用いてMLC患者に対しMLC1遺伝子補充療法を行うことを目指している.ここでは,病態モデルマウスを用いた前臨床遺伝子治療研究について報告する.(著者抄録)

Duplication of the autism-related gene Chd8 leads to behavioral hyperactivity and neurodevelopmental defects in mice.

Kawamura A, Fujii K, Tamada K, Abe Y, Nitahara K, Iwasaki T, Yagishita S, Tanaka KF, Takumi T, Takao K, Nishiyama M

Nature communications 16 （ 1 ） 4641 2025年05月

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Autism spectrum disorder-like behaviors induced by hyper-glutamatergic NMDA receptor signaling through hypo-serotonergic 5-HT1A receptor signaling in the prefrontal cortex in mice exposed to prenatal valproic acid

Kurahashi H., Kunisawa K., Tanaka K.F., Kubota H., Hasegawa M., Miyachi M., Moriya Y., Hasegawa Y., Nagai T., Saito K., Nabeshima T., Mouri A.

Neuropsychopharmacology 50 （ 5 ） 739 - 750 2025年04月

ISSN  0893133X

　概要を見る

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by repetitive behaviors, social deficits, and cognitive impairments. Maternal use of valproic acid (VPA) during pregnancy is associated with an increased risk of ASD in offspring. The prevailing pathophysiological hypothesis for ASD involves excitation/inhibition (E/I) imbalances and serotonergic dysfunction. Here, we investigated the association between glutamatergic-serotonergic neuronal interactions and ASD-like behaviors in mice exposed to prenatal VPA. Prenatal VPA exposure induced excessive repetitive self-grooming behavior and impaired social behavior and object recognition memory in young adult period. Prenatal VPA mice showed hyper-glutamatergic function (increase in basal extracellular glutamate levels and CaMKII phosphorylation) and hypo-serotonergic function (decrease in 5-hydroxyindoleacetic acid and stimulation-induced serotonin [5-HT] release, but an increase in 5-HT transporter expression) in the prefrontal cortex. Treatment with a low-affinity NMDA receptor antagonist (memantine), a selective 5-HT reuptake inhibitor (fluoxetine), and a 5-HT<inf>1A</inf> receptor agonist (tandospirone) attenuated both the increase in CaMKII phosphorylation and ASD-like behavior of prenatal VPA mice. Opto-genetic activation of the serotonergic neuronal system attenuated impairments in social behavior and object recognition memory in prenatal VPA mice. WAY-100635—a 5-HT<inf>1A</inf> receptor antagonist—antagonized the effect of fluoxetine on impaired social behavior and object recognition memory. These results suggest that E/I imbalance and ASD-like behavior are associated with hypo-serotonergic receptor signaling through 5-HT<inf>1A</inf> receptors in prenatal VPA mice.

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Schizophrenia-related Xpo7 haploinsufficiency leads to behavioral and nuclear transport pathologies.

Toyoda S, Kikuchi M, Abe Y, Tashiro K, Handa T, Katayama S, Motokawa Y, Tanaka KF, Takahashi H, Shiwaku H

EMBO reports 26 （ 4 ） 948 - 981 2025年02月

ISSN  1469-221X

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Social Bonds Retain Oxytocin-Mediated Brain-Liver Axis to Retard Atherosclerosis

Ko S., Anzai A., Liu X., Kinouchi K., Yamanoi K., Torimitsu T., Ichihara G., Kitakata H., Shirakawa K., Katsumata Y., Endo J., Hayashi K., Yoshida M., Nishimori K., Tanaka K.F., Onaka T., Sano M., Ieda M.

Circulation Research 136 （ 1 ） 78 - 90 2025年01月

ISSN  00097330

　概要を見る

BACKGROUNDS: Social interaction with others is essential to life. Although social isolation and loneliness have been implicated as increased risks of cardiometabolic and cardiovascular diseases and all-cause mortality, the cellular and molecular mechanisms by which social connection maintains cardiometabolic and cardiovascular health remain largely unresolved. METHODS: To investigate how social connection protects against cardiometabolic and cardiovascular diseases, atherosclerosis-prone, high-fat diet-fed Apoe^−/− mouse siblings were randomly assigned to either individual or grouped housing for 12 weeks. Histological, flow cytometric, biochemical, gene, and protein analyses were performed to assess atherosclerotic lesions, systemic metabolism, inflammation, and stress response. The effects of oxytocin on hepatocytes and subsequent cardiometabolic and cardiovascular function were investigated by in vivo and in vitro approaches. RESULTS: Apoe^−/− mice housed individually developed larger vulnerable atherosclerotic lesions by disrupted lipid metabolism compared with those of mice in regular group housing, irrespective of body weight, eating behavior, feeding conditions, sympathetic nervous activity, glucocorticoid response, or systemic inflammation. Mechanistically, the chronic isolation reduced the hypothalamic production of oxytocin, which controls bile acid production and LPL (lipoprotein lipase) activity through the peripheral OXTR (oxytocin receptor) in hepatocytes, whose downstream targets include Cyp7a1, Angptl4, and Angptl8. While hepatocyte-specific OXTR-null mice and mice receiving adeno-associated virus targeting OXTR on hepatocytes led to severe dyslipidemia and aggravated atherosclerosis, oral oxytocin supplementation to socially isolated mice, but not to hepatocyte-specific OXTR conditional knockout mice, improved lipid profiles and retarded atherosclerosis development. CONCLUSIONS: These results identify a novel brain-liver axis that links sociality to hepatic lipid metabolism, thus proposing a potential therapeutic strategy for loneliness-associated atherosclerosis progression.

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Editor spotlight: Interview with Kenji F. Tanaka, Senior Editor for the “Neurotools, Methods, and Neurochemistry Resources” category

Gospodinov D., Tanaka K.F.

Journal of Neurochemistry 169 （ 1 ） e16277 2025年01月

ISSN  00223042

　概要を見る

Kenji F. Tanaka is a Professor in Brain Sciences at the Institute for Advanced Medical Research, Keio University School of Medicine in Japan. He has been conducting research on glial cells for more than 20 years and is an expert in cell-type-specific and time-controllable gene expression techniques. Kenji F. Tanaka has been a member of the JNC Editorial Board since 2019 and recently transitioned to the role of Senior Editor for the new JNC manuscript category: “Neurotools, Methods, and Neurochemistry Resources”. We interviewed him to learn about his goals as Senior Editor for this category, as well as key moments in his career and advice for young scientists. (Figure presented.)

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Visualization of myelin-forming oligodendrocytes in the adult mouse brain

Yokoyama K., Hiraoka Y., Abe Y., Tanaka K.F.

Journal of Neurochemistry 169 （ 1 ） e16218 2025年01月

ISSN  00223042

　概要を見る

Oligodendrocyte (OL) differentiation from oligodendrocyte precursor cells (OPCs) is considered to result in two populations: premyelinating and myelinating OLs. Recent single-cell RNA sequence data subdivided these populations into newly formed (NFOLs), myelin-forming (MFOLs), and mature (MOLs) oligodendrocytes. However, which newly proposed population corresponds to premyelinating or myelinating OLs is unknown. We focused on the NFOL-specific long non-coding oligodendrocyte 1 gene (LncOL1) and sought to label NFOLs under the control of the LncOL1 promoter using a tetracycline-controllable gene induction system. We demonstrated that LncOL1 was expressed by premyelinating OLs and that the MFOL-specific gene, Ctps, was not, indicating that NFOLs correspond to premyelinating OLs and that MFOLs and MOLs correspond to myelinating OLs. We then generated a LncOL1-tTA mouse in which a tetracycline transactivator (tTA) cassette was inserted downstream from the LncOL1 transcription initiation site. By crossing the LncOL1-tTA mice with tetO reporter mice, we generated LncOL1-tTA::tetO-yellow fluorescent protein (YFP) double-transgenic (LncOL1-YFP) mice. Although LncOL1 is non-coding, YFP was detected in LncOL1-YFP mice, indicating successful tTA translation. Unexpectedly, we found that the morphology of LncOL1-tTA-driven YFP⁺ cells was distinct from that of LncOL1⁺ premyelinating OLs and that the labeled cells instead appeared as myelinating OLs. We demonstrated from their RNA expression that YFP-labeled OLs were MFOLs, but not MOLs. Using the unique property of delayed YFP induction, we sought to determine whether MFOLs are constantly supplied from OPCs and differentiate into MOLs, or whether MFOLs pause their differentiation and sustain this stage in the adult brain. To achieve this objective, we irradiated adult LncOL1-YFP brains with X-rays to deplete dividing OPCs and their progeny. The irradiation extinguished YFP-labeled OLs, indicating that adult OPCs differentiated into MOLs during a single period. We established a new transgenic mouse line that genetically labels MFOLs, providing a reliable tool for investigating the dynamics of adult oligodendrogenesis. (Figure presented.).

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Systemic nicotinamide mononucleotide administration to mitigate post-cardiac arrest brain injury in mice.

Kaito D, Tamura T, Suzuki S, Onishi R, Tanaka KF, Yoshino J, Matsuoka T, Maeshima K, Sasaki J, Homma K

PloS one 20 （ 10 ） e0334608 2025年

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Correlations of brain structure with the social behavior of 15q11-13 duplication mice, an animal model of autism

Zhao Z., Okada N., Yagishita S., Yahata N., Nitta N., Shibata S., Abe Y., Morita S., Kumagai E., Tanaka K.F., Suhara T., Takumi T., Kasai K., Jinde S.

Neuroscience Research 209   42 - 49 2024年12月

ISSN  01680102

　概要を見る

Duplication of chromosome 15q11–13 has been reported to be one of the most frequent cytogenetic copy number variations in autism spectrum disorder (ASD), and a mouse model of paternal 15q11–13 duplication was generated, termed 15q dup mice. While previous studies have replicated some of the behavioral and brain structural phenotypes of ASD separately, the relationship between brain structure and behavior has rarely been examined. In this study, we performed behavioral experiments related to anxiety and social behaviors and magnetic resonance imaging (MRI) using the same set of 15q dup and wild-type mice. 15q dup mice showed increased anxiety and a tendency toward alterations in social behaviors, as reported previously, as well as variability in terms of sociability. MRI analysis revealed that a lower sociability index was correlated with a smaller gray matter volume in the right medial entorhinal cortex. These results may help to understand how variability in behavioral phenotypes of ASD arises even in individuals with the same genetic background and to determine the individual differences in neurodevelopmental trajectory correlated with specific brain structures that underlie these phenotypes.

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Optogenetic activation of serotonergic neurons changes masticatory movement in freely moving mice

Dantsuji M., Mochizuki A., Nakayama K., Kanamaru M., Izumizaki M., Tanaka K.F., Inoue T., Nakamura S.

Scientific Reports 14 （ 1 ） 27703 2024年12月

　概要を見る

The serotonergic system modulates the neural circuits involved in jaw movement; however, the role of serotonin (5-HT) neurons in masticatory movement remains unclear. Here, we investigated the effect of selective activation of 5-HT neurons in the dorsal raphe nucleus (DRN), or the raphe obscurus nucleus (ROb), on voluntary masticatory movement using transgenic mice expressing the channelrhodopsin-2 (ChR2) mutant (C128S) in central 5-HT neurons. During voluntary mastication, DRN blue light illumination increased masticatory frequency and decreased the root mean square peak amplitude of electromyography (EMG) in the masseter muscles. DRN blue light illumination also decreased EMG burst duration in the masseter and digastric muscles. These changes were blocked by a 5-HT<inf>2A</inf> receptor antagonist. Conversely, ROb blue light illumination during voluntary mastication did not affect masticatory frequency and EMG bursts in the masseter and digastric muscles. DRN or ROb blue light illumination during the resting state did not induce rhythmic jaw movement such as mastication but induced an increase in EMG activity in masseter and digastric muscles. These results suggest that both DRN and ROb 5-HT neurons may facilitate jaw movement. Furthermore, DRN 5-HT neuron may contribute to changes in masticatory patterns during the masticatory sequence.

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Disease-relevant upregulation of P2Y1 receptor in astrocytes enhances neuronal excitability via IGFBP2

Shigetomi E., Suzuki H., Hirayama Y.J., Sano F., Nagai Y., Yoshihara K., Koga K., Tateoka T., Yoshioka H., Shinozaki Y., Kinouchi H., Tanaka K.F., Bito H., Tsuda M., Koizumi S.

Nature Communications 15 （ 1 ） 6525 2024年12月

　概要を見る

Reactive astrocytes play a pivotal role in the pathogenesis of neurological diseases; however, their functional phenotype and the downstream molecules by which they modify disease pathogenesis remain unclear. Here, we genetically increase P2Y<inf>1</inf> receptor (P2Y1R) expression, which is upregulated in reactive astrocytes in several neurological diseases, in astrocytes of male mice to explore its function and the downstream molecule. This astrocyte-specific P2Y1R overexpression causes neuronal hyperexcitability by increasing both astrocytic and neuronal Ca²⁺ signals. We identify insulin-like growth factor-binding protein 2 (IGFBP2) as a downstream molecule of P2Y1R in astrocytes; IGFBP2 acts as an excitatory signal to cause neuronal excitation. In neurological disease models of epilepsy and stroke, reactive astrocytes upregulate P2Y1R and increase IGFBP2. The present findings identify a mechanism underlying astrocyte-driven neuronal hyperexcitability, which is likely to be shared by several neurological disorders, providing insights that might be relevant for intervention in diverse neurological disorders.

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Establishment and Use of Primary Cultured Astrocytes from Alexander Disease Model Mice

Kubota Y., Shigetomi E., Saito K., Shinozaki Y., Kobayashi K., Tanaka M., Parajuli B., Tanaka K.F., Koizumi S.

International Journal of Molecular Sciences 25 （ 22 ）  2024年11月

ISSN  16616596

　概要を見る

Alexander disease (AxD) is an intractable neurodegenerative disease caused by mutations in glial fibrillary acidic protein (GFAP), which is predominantly expressed in astrocytes. Thus, AxD is a primary astrocyte disease. However, it remains unclear how GFAP mutations affect astrocytes and cause AxD pathology. Three features are characteristic of AxD astrocytes in vivo: (1) Rosenthal fibers (RFs), the hallmark of AxD; (2) aberrant Ca²⁺ signals (AxCa); and (3) upregulation of disease-associated genes (AxGen). We established a primary culture system for astrocytes from an AxD transgenic mouse model, and used it to analyze the above features of AxD pathogenesis in astrocytes in vitro. We observed the formation of RFs in AxD primary cultures. The abundance of RFs was greater in AxD-transgene-homozygous compared with -hemizygous astrocytes, indicating a gene dosage effect, and this abundance increased with time in culture, indicating a developmental process effect. However, cultured AxD astrocytes did not exhibit changes in either AxCa or AxGen. We therefore conclude that RFs in astrocytes form via a cell-autonomous mechanism, whereas AxCa and AxGen are likely to occur via a non-cell-autonomous mechanism through interactions with other cells, such as neurons, microglia, and vascular cells. Although primary cultured AxD astrocytes are suitable for elucidating the mechanisms of RFs formation and for intervention studies, it should be noted that they cannot reflect the pathophysiology of non-cell-autonomous events in astrocytes.

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