2024/04/23 更新

写真a

ウエノ マサキ
上野 将紀
UENO Masaki
所属
脳研究所 教授
職名
教授
外部リンク

学位

  • 獣医学 ( 2006年3月   東京大学 )

研究キーワード

  • 神経発生

  • 神経再生

  • 神経可塑性

研究分野

  • ライフサイエンス / 神経形態学

経歴(researchmap)

  • 新潟大学脳研究所   教授

    2021年6月 - 現在

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  • 新潟大学脳研究所   テニュアトラック教授

    2018年10月 - 2021年5月

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  • 新潟大学脳研究所   特任教授

    2016年9月 - 2018年9月

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  • 科学技術振興機構   さきがけ研究者

    2013年9月 - 2017年3月

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  • 日本学術振興会   海外特別研究員

    2012年8月 - 2013年9月

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  • シンシナティ小児病院医療センター   発生生物学部門   客員研究員

    2012年4月 - 2017年1月

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  • 大阪大学   Graduate School of Medicine   助教

    2008年4月 - 2012年3月

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  • 大阪大学   Graduate School of Medicine   特任研究員

    2007年12月 - 2008年3月

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  • 千葉大学大学院医学系研究院   産学官連携研究員

    2007年8月 - 2007年11月

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  • 理化学研究所脳科学総合研究センター   研究員

    2006年4月 - 2007年7月

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  • 東京大学   Graduate School of Agricultural and Life Sciences   博士課程

    2002年4月 - 2006年3月

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  • 東京大学   農学部獣医学課程

    2002年3月

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▶ 全件表示

経歴

  • 新潟大学   脳研究所 基礎神経科学部門   教授

    2020年4月 - 現在

  • 新潟大学   脳研究所 生命科学リソース研究センター   教授

    2018年10月 - 2020年3月

  • 新潟大学   脳研究所   特任教授

    2016年9月 - 2018年9月

所属学協会

留学歴

  • シンシナティ小児病院   客員研究員

    2012年4月 - 2017年1月

取得資格

  • 獣医師

 

論文

  • TDP-43 differentially propagates to induce antero- and retrograde degeneration in the corticospinal circuits in mouse focal ALS models. 査読 国際誌

    Shintaro Tsuboguchi, Yuka Nakamura, Tomohiko Ishihara, Taisuke Kato, Tokiharu Sato, Akihide Koyama, Hideki Mori, Yuka Koike, Osamu Onodera, Masaki Ueno

    Acta neuropathologica   2023年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by TDP-43 inclusions in the cortical and spinal motor neurons. It remains unknown whether and how pathogenic TDP-43 spreads across neural connections to progress degenerative processes in the cortico-spinal motor circuitry. Here we established novel mouse ALS models that initially induced mutant TDP-43 inclusions in specific neuronal or cell types in the motor circuits, and investigated whether TDP-43 and relevant pathological processes spread across neuronal or cellular connections. We first developed ALS models that primarily induced TDP-43 inclusions in the corticospinal neurons, spinal motor neurons, or forelimb skeletal muscle, by using adeno-associated virus (AAV) expressing mutant TDP-43. We found that TDP-43 induced in the corticospinal neurons was transported along the axons anterogradely and transferred to the oligodendrocytes along the corticospinal tract (CST), coinciding with mild axon degeneration. In contrast, TDP-43 introduced in the spinal motor neurons did not spread retrogradely to the cortical or spinal neurons; however, it induced an extreme loss of spinal motor neurons and subsequent degeneration of neighboring spinal neurons, suggesting a degenerative propagation in a retrograde manner in the spinal cord. The intraspinal degeneration further led to severe muscle atrophy. Finally, TDP-43 induced in the skeletal muscle did not propagate pathological events to spinal neurons retrogradely. Our data revealed that mutant TDP-43 spread across neuro-glial connections anterogradely in the corticospinal pathway, whereas it exhibited different retrograde degenerative properties in the spinal circuits. This suggests that pathogenic TDP-43 may induce distinct antero- and retrograde mechanisms of degeneration in the motor system in ALS.

    DOI: 10.1007/s00401-023-02615-8

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  • Cerebrospinal fluid-contacting neuron tracing reveals structural and functional connectivity for locomotion in the mouse spinal cord. 査読 国際誌

    Yuka Nakamura, Miyuki Kurabe, Mami Matsumoto, Tokiharu Sato, Satoshi Miytashita, Kana Hoshina, Yoshinori Kamiya, Kazuki Tainaka, Hitoshi Matsuzawa, Nobuhiko Ohno, Masaki Ueno

    eLife   12   2023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)  

    Cerebrospinal fluid-contacting neurons (CSF-cNs) are enigmatic mechano- or chemosensory cells lying along the central canal of the spinal cord. Recent studies in zebrafish larvae and lampreys have shown that CSF-cNs control postures and movements via spinal connections. However, the structures, connectivity, and functions in mammals remain largely unknown. Here we developed a method to genetically target mouse CSF-cNs that highlighted structural connections and functions. We first found that intracerebroventricular injection of adeno-associated virus with a neuron-specific promoter and Pkd2l1-Cre mice specifically labeled CSF-cNs. Single-cell labeling of 71 CSF-cNs revealed rostral axon extensions of over 1800 μm in unmyelinated bundles in the ventral funiculus and terminated on CSF-cNs to form a recurrent circuitry, which was further determined by serial electron microscopy and electrophysiology. CSF-cNs were also found to connect with axial motor neurons and premotor interneurons around the central canal and within the axon bundles. Chemogenetic CSF-cNs inactivation reduced speed and step frequency during treadmill locomotion. Our data revealed the basic structures and connections of mouse CSF-cNs to control spinal motor circuits for proper locomotion. The versatile methods developed in this study will contribute to further understanding of CSF-cN functions in mammals.

    DOI: 10.7554/eLife.83108

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  • Modulation of Both Intrinsic and Extrinsic Factors Additively Promotes Rewiring of Corticospinal Circuits after Spinal Cord Injury. 査読 国際誌

    Yuka Nakamura, Masaki Ueno, Jesse K Niehaus, Richard A Lang, Yi Zheng, Yutaka Yoshida

    The Journal of neuroscience : the official journal of the Society for Neuroscience   41 ( 50 )   10247 - 10260   2021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)  

    Axon regeneration after spinal cord injury (SCI) is limited by both a decreased intrinsic ability of neurons to grow axons and the growth-hindering effects of extrinsic inhibitory molecules expressed around the lesion. Deletion of phosphatase and tensin homolog (Pten) augments mechanistic target of rapamycin (mTOR) signaling and enhances the intrinsic regenerative response of injured corticospinal neurons after SCI. Because of the variety of growth-restrictive extrinsic molecules, it remains unclear how inhibition of conserved inhibitory signaling elements would affect axon regeneration and rewiring after SCI. Moreover, it remains unknown how a combinatorial approach to modulate both extrinsic and intrinsic mechanisms can enhance regeneration and rewiring after SCI. In the present study, we deleted RhoA and RhoC, which encode small GTPases that mediate growth inhibition signals of a variety of extrinsic molecules, to remove global extrinsic pathways. RhoA/RhoC double deletion in mice suppressed retraction or dieback of corticospinal axons after SCI. In contrast, Pten deletion increased regrowth of corticospinal axons into the lesion core. Although deletion of both RhoA and Pten did not promote axon regrowth across the lesion or motor recovery, it additively promoted rewiring of corticospinal circuits connecting the cerebral cortex, spinal cord, and hindlimb muscles. Our genetic findings, therefore, reveal that a combinatorial approach to modulate both intrinsic and extrinsic factors can additively promote neural circuit rewiring after SCI.SIGNIFICANCE STATEMENT SCI often causes severe motor deficits because of damage to the corticospinal tract (CST), the major neural pathway for voluntary movements. Regeneration of CST axons is required to reconstruct motor circuits and restore functions; however, a lower intrinsic ability to grow axons and extrinsic inhibitory molecules severely limit axon regeneration in the CNS. Here, we investigated whether suppression of extrinsic inhibitory cues by genetic deletion of Rho as well as enhancement of the intrinsic pathway by deletion of Pten could enable axon regrowth and rewiring of the CST after SCI. We show that simultaneous elimination of extrinsic and intrinsic signaling pathways can additively promote axon sprouting and rewiring of the corticospinal circuits. Our data demonstrate a potential molecular approach to reconstruct motor pathways after SCI.

    DOI: 10.1523/JNEUROSCI.2649-20.2021

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  • Restoring neuro-immune circuitry after brain and spinal cord injuries. 査読 国際誌

    Masaki Ueno

    International immunology   33 ( 6 )   311 - 325   2021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)  

    Neuro-immune interactions are essential for our body's defense and homeostasis. Anatomical and physiological analyses have shown that the nervous system comprises multiple pathways that regulate the dynamics and functions of immune cells, which are mainly mediated by the autonomic nervous system and adrenal signals. These are disturbed when the neurons and circuits are damaged by diseases of the central nervous system (CNS). Injuries caused by stroke or trauma often cause immune dysfunction by abrogation of the immune-regulating neural pathways, which leads to an increased risk of infections. Here, I review the structures and functions of the neural pathways connecting the brain and the immune system, and the neurogenic mechanisms of immune dysfunction that emerge after CNS injuries. Recent technological advances in manipulating specific neural circuits have added mechanistic aspects of neuro-immune interactions and their dysfunctions. Understanding the neural bases of immune control and their pathological processes will deepen our knowledge of homeostasis and lead to the development of strategies to cure immune deficiencies observed in various CNS disorders.

    DOI: 10.1093/intimm/dxab017

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  • Lesion Area in the Cerebral Cortex Determines the Patterns of Axon Rewiring of Motor and Sensory Corticospinal Tracts After Stroke. 査読 国際誌

    Tokiharu Sato, Yuka Nakamura, Akinori Takeda, Masaki Ueno

    Frontiers in neuroscience   15   737034 - 737034   2021年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The corticospinal tract (CST) is an essential neural pathway for reorganization that recovers motor functions after brain injuries such as stroke. CST comprises multiple pathways derived from different sensorimotor areas of the cerebral cortex; however, the patterns of reorganization in such complex pathways postinjury are largely unknown. Here we comprehensively examined the rewiring patterns of the CST pathways of multiple cerebral origins in a mouse stroke model that varied in size and location in the sensorimotor cortex. We found that spared contralesional motor and sensory CST axons crossed the midline and sprouted into the denervated side of the cervical spinal cord after stroke in a large cortical area. In contrast, the contralesional CST fibers did not sprout in a small stroke, whereas the ipsilesional axons from the spared motor area grew on the denervated side. We further showed that motor and sensory CST axons did not innervate the projecting areas mutually when either one was injured. The present results reveal the basic principles that generate the patterns of CST rewiring, which depend on stroke location and CST subtype. Our data indicate the importance of targeting different neural substrates to restore function among the types of injury.

    DOI: 10.3389/fnins.2021.737034

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  • Inhibition of HDAC increases BDNF expression and promotes neuronal rewiring and functional recovery after brain injury. 査読 国際誌

    Naoki Sada, Yuki Fujita, Nanano Mizuta, Masaki Ueno, Takahisa Furukawa, Toshihide Yamashita

    Cell death & disease   11 ( 8 )   655 - 655   2020年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Brain injury causes serious motor, sensory, and cognitive disabilities. Accumulating evidence has demonstrated that histone deacetylase (HDAC) inhibitors exert neuroprotective effects against various insults to the central nervous system (CNS). In this study, we investigated the effects of the HDAC inhibition on the expression of brain-derived neurotrophic factor (BDNF) and functional recovery after traumatic brain injury (TBI) in mice. Administration of class I HDAC inhibitor increased the number of synaptic boutons in rewiring corticospinal fibers and improved the recovery of motor functions after TBI. Immunohistochemistry results showed that HDAC2 is mainly expressed in the neurons of the mouse spinal cord under normal conditions. After TBI, HDAC2 expression was increased in the spinal cord after 35 days, whereas BDNF expression was decreased after 42 days. Administration of CI-994 increased BDNF expression after TBI. Knockdown of HDAC2 elevated H4K5ac enrichment at the BDNF promoter, which was decreased following TBI. Together, our findings suggest that HDAC inhibition increases expression of neurotrophic factors, and promote neuronal rewiring and functional recovery following TBI.

    DOI: 10.1038/s41419-020-02897-w

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  • Olig2-Induced Semaphorin Expression Drives Corticospinal Axon Retraction After Spinal Cord Injury. 査読 国際誌

    Masaki Ueno, Yuka Nakamura, Hiroshi Nakagawa, Jesse K Niehaus, Mari Maezawa, Zirong Gu, Atsushi Kumanogoh, Hirohide Takebayashi, Qing Richard Lu, Masahiko Takada, Yutaka Yoshida

    Cerebral cortex (New York, N.Y. : 1991)   30 ( 11 )   5702 - 5716   2020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)  

    Axon regeneration is limited in the central nervous system, which hinders the reconstruction of functional circuits following spinal cord injury (SCI). Although various extrinsic molecules to repel axons following SCI have been identified, the role of semaphorins, a major class of axon guidance molecules, has not been thoroughly explored. Here we show that expression of semaphorins, including Sema5a and Sema6d, is elevated after SCI, and genetic deletion of either molecule or their receptors (neuropilin1 and plexinA1, respectively) suppresses axon retraction or dieback in injured corticospinal neurons. We further show that Olig2+ cells are essential for SCI-induced semaphorin expression, and that Olig2 binds to putative enhancer regions of the semaphorin genes. Finally, conditional deletion of Olig2 in the spinal cord reduces the expression of semaphorins, alleviating the axon retraction. These results demonstrate that semaphorins function as axon repellents following SCI, and reveal a novel transcriptional mechanism for controlling semaphorin levels around injured neurons to create zones hostile to axon regrowth.

    DOI: 10.1093/cercor/bhaa142

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  • Combinational Approach of Genetic SHP-1 Suppression and Voluntary Exercise Promotes Corticospinal Tract Sprouting and Motor Recovery Following Brain Injury. 査読 国際誌

    Takashi Tanaka, Tetsufumi Ito, Megumi Sumizono, Munenori Ono, Nobuo Kato, Satoru Honma, Masaki Ueno

    Neurorehabilitation and neural repair   34 ( 6 )   558 - 570   2020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. Brain injury often causes severe motor dysfunction, leading to difficulties with living a self-reliant social life. Injured neural circuits must be reconstructed to restore functions, but the adult brain is limited in its ability to restore neuronal connections. The combination of molecular targeting, which enhances neural plasticity, and rehabilitative motor exercise is an important therapeutic approach to promote neuronal rewiring in the spared circuits and motor recovery. Objective. We tested whether genetic reduction of Src homology 2-containing phosphatase-1 (SHP-1), an inhibitor of brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) signaling, has synergistic effects with rehabilitative training to promote reorganization of motor circuits and functional recovery in a mouse model of brain injury. Methods. Rewiring of the corticospinal circuit was examined using neuronal tracers following unilateral cortical injury in control mice and in Shp-1 mutant mice subjected to voluntary exercise. Recovery of motor functions was assessed using motor behavior tests. Results. We found that rehabilitative exercise decreased SHP-1 and increased BDNF and TrkB expression in the contralesional motor cortex after the injury. Genetic reduction of SHP-1 and voluntary exercise significantly increased sprouting of corticospinal tract axons and enhanced motor recovery in the impaired forelimb. Conclusions. Our data demonstrate that combining voluntary exercise and SHP-1 suppression promotes motor recovery and neural circuit reorganization after brain injury.

    DOI: 10.1177/1545968320921827

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  • Ghrelin-insulin-like growth factor-1 axis is activated via autonomic neural circuits in the non-alcoholic fatty liver disease. 査読 国際誌

    Takuro Nagoya, Kenya Kamimura, Ryosuke Inoue, Masayoshi Ko, Takashi Owaki, Yusuke Niwa, Norihiro Sakai, Toru Setsu, Akira Sakamaki, Takeshi Yokoo, Hiroteru Kamimura, Yuka Nakamura, Masaki Ueno, Shuji Terai

    Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society   32 ( 5 )   e13799   2020年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: The correlation of the growth hormone (GH) and insulin-like growth factor-1 (IGF-1) with non-alcoholic fatty liver disease (NAFLD) has been reported in epidemiological studies. However, the mechanisms of molecular and inter-organ systems that render these factors to influence on NAFLD have not been elucidated. In this study, we examined the induction of ghrelin which is the GH-releasing hormone and IGF-1, and involvement of autonomic neural circuits, in the pathogenesis of NAFLD. METHODS: The expression of gastric and hypothalamic ghrelin, neural activation in the brain, and serum IGF-1 were examined in NAFLD models of choline-deficient defined l-amino-acid diet-fed, melanocortin 4 receptor knockout mice, and partial hepatectomy mice with or without the blockades of autonomic nerves to test the contribution of neural circuits connecting the brain, liver, and stomach. KEY RESULTS: The fatty changes in the liver increased the expression of gastric ghrelin through the autonomic pathways which sends the neural signals to the arcuate nucleus in the hypothalamus through the afferent vagal nerve which reached the pituitary gland to release GH and then stimulate the IGF-1 release from the liver. In addition, high levels of ghrelin expression in the arcuate nucleus were correlated with NAFLD progression regardless of the circuits. CONCLUSIONS: Our study demonstrated that the fatty liver stimulates the autonomic nervous signal circuits which suppress the progression of the disease by activating the gastric ghrelin expression, the neural signal transduction in the brain, and the release of IGF-1 from the liver.

    DOI: 10.1111/nmo.13799

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  • Netrin-G1 Regulates Microglial Accumulation along Axons and Supports the Survival of Layer V Neurons in the Postnatal Mouse Brain. 査読 国際誌

    Yuki Fujita, Toru Nakanishi, Masaki Ueno, Shigeyoshi Itohara, Toshihide Yamashita

    Cell reports   31 ( 4 )   107580 - 107580   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)  

    Microglia, the resident immune cells of the central nervous system, accumulate along subcerebral projection axons and support neuronal survival during the early postnatal period. It remains unknown how microglia follow an axon-specific distribution pattern to maintain neural circuits. Here, we investigated the mechanisms of microglial accumulation along subcerebral projection axons that were necessary for microglial accumulation in the internal capsule. Screening of molecules involved in this accumulation of microglia to axons of layer V cortical neurons identified netrin-G1, a member of the netrin family of axon guidance molecules with a glycosyl-phosphatidylinositol anchor. Deletion or knockdown of the netrin-G1 gene Ntng1 reduced microglial accumulation and caused loss of cortical neurons. Netrin-G1 ligand-Ngl1 knockout-mice-derived microglia showed reduced accumulation along the axons compared with wild-type microglia. Thus, microglia accumulate around the subcerebral projection axons via NGL1-netrin-G1 signaling and support neuronal survival. Our observations unveil bidirectional neurotrophic interactions between neurons and microglia.

    DOI: 10.1016/j.celrep.2020.107580

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  • Dual functions of microglia in the formation and refinement of neural circuits during development. 査読 国際誌

    Konishi H, Kiyama H, Ueno M

    International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience   77   18 - 25   2019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)  

    DOI: 10.1016/j.ijdevneu.2018.09.009

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  • Skilled Movements in Mice Require Inhibition of Corticospinal Axon Collateral Formation in the Spinal Cord by Semaphorin Signaling. 査読

    Zirong Gu, Masaki Ueno, Kelsey Klinefelter, Madhulika Mamidi, Takeshi Yagi, Yutaka Yoshida

    The Journal of neuroscience : the official journal of the Society for Neuroscience   39 ( 45 )   8885 - 8899   2019年9月

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    掲載種別:研究論文(学術雑誌)  

    DOI: 10.1523/jneurosci.2832-18.2019

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  • Corticospinal Circuits from the Sensory and Motor Cortices Differentially Regulate Skilled Movements through Distinct Spinal Interneurons 査読

    Masaki Ueno, Yuka Nakamura, Jie Li, Zirong Gu, Jesse Niehaus, Mari Maezawa, Steven A. Crone, Martyn Goulding, Mark L. Baccei, Yutaka Yoshida

    Cell Reports   23 ( 5 )   1286 - 1300.e7   2018年5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 B.V.  

    Little is known about the organizational and functional connectivity of the corticospinal (CS) circuits that are essential for voluntary movement. Here, we map the connectivity between CS neurons in the forelimb motor and sensory cortices and various spinal interneurons, demonstrating that distinct CS-interneuron circuits control specific aspects of skilled movements. CS fibers originating in the mouse motor cortex directly synapse onto premotor interneurons, including those expressing Chx10. Lesions of the motor cortex or silencing of spinal Chx10+ interneurons produces deficits in skilled reaching. In contrast, CS neurons in the sensory cortex do not synapse directly onto premotor interneurons, and they preferentially connect to Vglut3+ spinal interneurons. Lesions to the sensory cortex or inhibition of Vglut3+ interneurons cause deficits in food pellet release movements in goal-oriented tasks. These findings reveal that CS neurons in the motor and sensory cortices differentially control skilled movements through distinct CS-spinal interneuron circuits. Ueno et al. generate a detailed connectivity map between corticospinal (CS) neurons in the motor and sensory cortices and spinal interneurons. The CS circuits originating from the motor and sensory cortices connect to distinct subpopulations of spinal interneurons to control discrete aspects of skilled movements.

    DOI: 10.1016/j.celrep.2018.03.137

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  • MARCKSL1 Regulates Spine Formation in the Amygdala and Controls the Hypothalamic-Pituitary-Adrenal Axis and Anxiety-Like Behaviors 査読

    Takashi Tanaka, Shoko Shimizu, Masaki Ueno, Yoshitaka Fujihara, Masahito Ikawa, Shingo Miyata

    EBioMedicine   30   62 - 73   2018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:Elsevier B.V.  

    Abnormalities in limbic neural circuits have been implicated in the onset of anxiety disorders. However, the molecular pathogenesis underlying anxiety disorders remains poorly elucidated. Here, we demonstrate that myristoylated alanine-rich C-kinase substrate like 1 (MARCKSL1) regulates amygdala circuitry to control the activity of the hypothalamic-pituitary-adrenal (HPA) axis, as well as induces anxiety-like behaviors in mice. MARCKSL1 expression was predominantly localized in the prefrontal cortex (PFC), hypothalamus, hippocampus, and amygdala of the adult mouse brain. MARCKSL1 transgenic (Tg) mice exhibited anxiety-like behaviors dependent on corticotropin-releasing hormone. MARCKSL1 increased spine formation in the central amygdala, and downregulation of MARCKSL1 in the amygdala normalized both increased HPA axis activity and elevated anxiety-like behaviors in Tg mice. Furthermore, MARCKSL1 expression was increased in the PFC and amygdala in a brain injury model associated with anxiety-like behaviors. Our findings suggest that MARCKSL1 expression in the amygdala plays an important role in anxiety-like behaviors.

    DOI: 10.1016/j.ebiom.2018.03.018

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  • Control of species-dependent cortico-motoneuronal connections underlying manual dexterity 査読

    Zirong Gu, John Kalamboglas, Shin Yoshioka, Wenqi Han, Zhuo Li, Yuka Imamura Kawasawa, Sirisha Pochareddy, Zhen Li, Fuchen Liu, Xuming Xu, Sagara Wijeratne, Masaki Ueno, Emily Blatz, Joseph Salomone, Atsushi Kumanogoh, Mladen-Roko Rasin, Brian Gebelein, Matthew T. Weirauch, Nenad Sestan, John H. Martin, Yutaka Yoshida

    SCIENCE   357 ( 6349 )   400 - 404   2017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)   出版者・発行元:AMER ASSOC ADVANCEMENT SCIENCE  

    Superior manual dexterity in higher primates emerged together with the appearance of cortico-motoneuronal (CM) connections during the evolution of the mammalian corticospinal (CS) system. Previously thought to be specific to higher primates, we identified transient CM connections in early postnatal mice, which are eventually eliminated by Sema6D-PlexA1 signaling. PlexA1 mutant mice maintain CM connections into adulthood and exhibit superior manual dexterity as compared with that of controls. Last, differing PlexA1 expression in layer 5 of the motor cortex, which is strong in wild-type mice but weak in humans, may be explained by FEZF2-mediated cis-regulatory elements that are found only in higher primates. Thus, species-dependent regulation of PlexA1 expression may have been crucial in the evolution of mammalian CS systems that improved fine motor control in higher primates.

    DOI: 10.1126/science.aan3721

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  • Skilled Movements Require Non-apoptotic Bax/Bak Pathway-Mediated Corticospinal Circuit Reorganization 査読

    Zirong Gu, Najet Serradj, Masaki Ueno, Mishi Liang, Jie Li, Mark L. Baccei, John H. Martin, Yutaka Yoshida

    NEURON   94 ( 3 )   626 - +   2017年5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:CELL PRESS  

    Early postnatal mammals, including human babies, can perform only basic motor tasks. The acquisition of skilled behaviors occurs later, requiring anatomical changes in neural circuitry to support the development of coordinated activation or suppression of functionally related muscle groups. How this circuit reorganization occurs during postnatal development remains poorly understood. Here we explore the connectivity between corticospinal (CS) neurons in the motor cortex and muscles in mice. Using trans-synaptic viral and electrophysiological assays, we identify the early postnatal reorganization of CS circuitry for antagonistic muscle pairs. We further show that this synaptic rearrangement requires the activity-dependent, non-apoptotic Bax/Bak-caspase signaling cascade. Adult Bax/Bak mutant mice exhibit aberrant co-activation of antagonistic muscle pairs and skilled grasping deficits but normal reaching and retrieval behaviors. Our findings reveal key cellular and molecular mechanisms driving postnatal motor circuit reorganization and the resulting impacts on muscle activation patterns and the execution of skilled movements.

    DOI: 10.1016/j.neuron.2017.04.019

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  • Silencing spinal interneurons inhibits immune suppressive autonomic reflexes caused by spinal cord injury 査読

    Masaki Ueno, Yuka Ueno-Nakamura, Jesse Niehaus, Phillip G. Popovich, Yutaka Yoshida

    NATURE NEUROSCIENCE   19 ( 6 )   784 - +   2016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:NATURE PUBLISHING GROUP  

    Spinal cord injury (SCI) at high spinal levels (e.g., above thoracic level 5) causes systemic immune suppression; however, the underlying mechanisms are unknown. Here we show that profound plasticity develops within spinal autonomic circuitry below the injury, creating a sympathetic anti-inflammatory reflex, and that chemogenetic silencing of this reflex circuitry blocks post-SCI immune suppression. These data provide new insights and potential therapeutic options for limiting the devastating consequences of post-traumatic autonomic hyperreflexia and post-injury immune suppression.

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  • A selector orchestrates cortical function 招待

    Masaki Ueno, Ryosuke Fujiki, Toshihide Yamashita

    NATURE NEUROSCIENCE   17 ( 8 )   1016 - 1017   2014年8月

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    記述言語:英語   出版者・発行元:NATURE PUBLISHING GROUP  

    Molecular orchestration mediated by Fezf2, a master transcriptional regulator of a particular type of cortical neurons, directly determines both their identity and axonal routing, and thus their connectivity.

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  • Bidirectional tuning of microglia in the developing brain: from neurogenesis to neural circuit formation 査読

    Masaki Ueno, Toshihide Yamashita

    CURRENT OPINION IN NEUROBIOLOGY   27   8 - 15   2014年8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:CURRENT BIOLOGY LTD  

    The developing brain employs multi-step processes to construct neural circuitry. Recent studies have highlighted that microglia, traditionally known to be the resident immune cells in the brain, have essential roles in these processes, which range from neurogenesis to establishing synaptic connections. Microglia play bidirectional roles for maintaining proper circuitry: eliminating unnecessary cells, axons, and synapses, while supporting the neighboring ones. Although these processes are performed in different parts of the neuron, similar molecular mechanisms are possibly involved. This paper reviews recent progress on the knowledge of the roles of microglia in brain development, and further discusses the application of this knowledge in therapies for brain disorders and injuries.

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  • ifn-γ-dependent secretion of IL-10 from Th1 cells and microglia/macrophages contributes to functional recovery after spinal cord injury. 査読

    Ishii H, Tanabe S, Ueno M, Kubo T, Kayama H, Serada S, Fujimoto M, Takeda K, Naka T, Yamashita T

    Cell death & disease   4   e710   2013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)  

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  • Layer v cortical neurons require microglial support for survival during postnatal development 査読

    Masaki Ueno, Yuki Fujita, Tatsuhide Tanaka, Yuka Nakamura, Junichi Kikuta, Masaru Ishii, Toshihide Yamashita

    Nature Neuroscience   16 ( 5 )   543 - 551   2013年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Neurons require trophic support during neural circuit formation
    however, how the cellular milieu contributes to neuronal survival remains unclear. We found that layer V cortical neurons require support from microglia for survival during postnatal development. Specifically, we found that microglia accumulated close to the subcerebral and callosal projection axons in the postnatal brain. Inactivation of microglia by minocycline treatment or transient ablation of microglia in CD11b-DTR transgenic mice led to increased apoptosis, specifically in layer V subcerebral and callosal projection neurons. CX3CR1 in microglia was required for the survival of layer V neurons. Microglia consistently promoted the survival of cortical neurons in vitro. In addition, we identified microglia-derived IGF1 as a trophic factor that maintained neuronal survival. Our results highlight a neuron-glia interaction that is indispensable for network formation during a specific period in the developing brain. © 2013 Nature America, Inc. All rights reserved.

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  • Suppression of SHP-1 promotes corticospinal tract sprouting and functional recovery after brain injury 査読

    T. Tanaka, Y. Fujita, M. Ueno, L. D. Shultz, T. Yamashita

    Cell Death and Disease   4 ( 4 )   e567   2013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)  

    Reorganization of spared neural network connections is one of the most important processes for restoring impaired function after brain injury. However, plasticity is quite limited in the adult brain due to the presence of inhibitory molecules and a lack of intrinsic neuronal signals for axonal growth. Src homology 2-containing phosphatase (SHP)-1 has been shown to have a role in axon growth inhibition. Here, we tested the hypothesis that SHP-1 negatively affects axonal reorganization. We observed that unilateral motor cortex injury led to increased expression and activity of SHP-1 in the contralesional cortex. In this model, corticospinal axons originating from the contralesional cortex sprouted into the denervated side of the cervical spinal cord after injury. We observed that the number of sprouting fibers was increased in SHP-1-deficient heterozygous viable motheaten (+/mev) mice, which show reduced SHP-1 activity, and in wild-type mice treated with an SHP inhibitor. Motor function recovery of impaired forelimb was enhanced in +/mev mice. Collectively, our results indicate that downregulation of SHP-1 activity promotes corticospinal tract sprouting and functional recovery after brain injury. © 2013 Macmillan Publishers Limited All rights reserved.

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  • Bilateral movement training promotes axonal remodeling of the corticospinal tract and recovery of motor function following traumatic brain injury in mice 査読

    H. Nakagawa, M. Ueno, T. Itokazu, T. Yamashita

    CELL DEATH & DISEASE   4   e534   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)   出版者・発行元:NATURE PUBLISHING GROUP  

    Traumatic brain injury (TBI) results in severe motor function impairment, and subsequent recovery is often incomplete. Rehabilitative training is considered to promote restoration of the injured neural network, thus facilitating functional recovery. However, no studies have assessed the effect of such trainings in the context of neural rewiring. Here, we investigated the effects of two types of rehabilitative training on corticospinal tract (CST) plasticity and motor recovery in mice. We injured the unilateral motor cortex with contusion, which induced hemiparesis on the contralesional side. After the injury, mice performed either a single pellet-reaching task (simple repetitive training) or a rotarod task (bilateral movement training). Multiple behavioral tests were then used to assess forelimb motor function recovery: staircase, ladder walk, capellini handling, single pellet, and rotarod tests. The TBI+rotarod group performed most forelimb motor tasks (staircase, ladder walk, and capellini handling tests) better than the TBI-only group did. In contrast, the TBI+reaching group did not perform better except in the single pellet test. After the injury, the contralateral CST, labeled by biotinylated dextran amine, formed sprouting fibers into the denervated side of the cervical spinal cord. The number of these fibers was significantly higher in the TBI+rotarod group, whereas it did not increase in the TBI+reaching group. These results indicate that bilateral movement training effectively promotes axonal rewiring and motor function recovery, whereas the effect of simple repetitive training is limited. Cell Death and Disease (2013) 4, e534; doi:10.1038/cddis.2013.62; published online 7 March 2013

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  • Soluble β-amyloid Precursor Protein Alpha Binds to p75 Neurotrophin Receptor to Promote Neurite Outgrowth. 査読 国際誌

    Hasebe N, Fujita Y, Ueno M, Yoshimura K, Fujino Y, Yamashita T

    PloS one   8 ( 12 )   e82321   2013年

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    記述言語:英語   出版者・発行元:12  

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  • Adoptive transfer of Th1-conditioned lymphocytes promotes axonal remodeling and functional recovery after spinal cord injury 査読

    H. Ishii, X. Jin, M. Ueno, S. Tanabe, T. Kubo, S. Serada, T. Naka, T. Yamashita

    CELL DEATH & DISEASE   3   e363   2012年8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:NATURE PUBLISHING GROUP  

    The role of T lymphocytes in central nervous system (CNS) injuries is controversial, with inconsistent results reported concerning the effects of T-lymphocyte transfer on spinal cord injury (SCI). Here, we demonstrate that a specific T-lymphocyte subset enhances functional recovery after contusion SCI in mice. Intraperitoneal adoptive transfer of type 1 helper T (Th1)-conditioned cells 4 days after SCI promoted recovery of locomotor activity and tactile sensation and concomitantly induced regrowth of corticospinal tract and serotonergic fibers. However, neither type 2 helper T (Th2)- nor IL-17-producing helper T (Th17)-conditioned cells had such effects. Activation of microglia and macrophages were observed in the spinal cords of Th1-transfered mice after SCI. Specifically, M2 subtype of microglia/macrophages was upregulated after Th1 cell transfer. Neutralization of interleukin 10 secreted by Th1-conditioned cells significantly attenuated the beneficial effects by Th1-conditioned lymphocytes after SCI. We also found that Th1-conditioned lymphocytes secreted significantly higher levels of neurotrophic factor, neurotrophin 3 (NT-3), than Th2- or Th17-conditioned cells. Thus, adoptive transfer of pro-inflammatory Th1-conditioned cells has neuroprotective effects after SCI, with prospective implications in immunomodulatory treatment of CNS injury. Cell Death and Disease (2012) 3, e363; doi:10.1038/cddis.2012.106; published online 9 August 2012

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  • Intraspinal rewiring of the corticospinal tract requires target-derived brain-derived neurotrophic factor and compensates lost function after brain injury 査読

    Masaki Ueno, Yasufumi Hayano, Hiroshi Nakagawa, Toshihide Yamashita

    BRAIN   135 ( 4 )   1253 - 1267   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:OXFORD UNIV PRESS  

    Brain injury that results in an initial behavioural deficit is frequently followed by spontaneous recovery. The intrinsic mechanism of this functional recovery has never been fully understood. Here, we show that reorganization of the corticospinal tract induced by target-derived brain-derived neurotrophic factor is crucial for spontaneous recovery of motor function following brain injury. After destruction of unilateral sensorimotor cortex, intact-side corticospinal tract formed sprouting fibres into the specific lamina of the denervated side of the cervical spinal cord, and made new contact with two types of spinal interneurons-segmental and propriospinal neurons. Anatomical and electrophysiological analyses revealed that this rewired corticospinal tract functionally linked to motor neurons and forelimb muscles. This newly formed corticospinal circuit was necessary for motor recovery, because transection of the circuit led to impairment of recovering forelimb function. Knockdown of brain-derived neurotrophic factor in the spinal neurons or its receptor in the intact corticospinal neurons diminished fibre sprouting of the corticospinal tract. Our findings establish the anatomical, functional and molecular basis for the intrinsic capacity of neurons to form compensatory neural network following injury.

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  • 脳損傷後の皮質脊髄路再編成におけるSHP-1シグナル抑制の効果

    田中 貴士, 藤田 幸, 上野 将紀, 山下 俊英

    理学療法学Supplement   2011   Ab0460 - Ab0460   2012年

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    記述言語:日本語   出版者・発行元:公益社団法人 日本理学療法士協会  

    【目的】 脳損傷後の機能回復は、中枢神経の軸索再生能力が低いため非常に限定的である。しかし、損傷を免れた皮質脊髄路軸索からの側枝形成(Sprouting)により代償的な神経回路の再構築が一部おこり、運動機能の回復がもたらされることがある。この代償性回路形成の促進が中枢神経再生への有効な手段になると期待されるが、効率的な神経回路の再構築には、神経細胞自体の軸索伸長能力を増強することが重要である。本研究では、軸索再生の阻害作用をもつチロシン脱リン酸化酵素SHP-1に着目し、SHP-1の抑制が皮質脊髄路の再編成を促すか否か検証した。【方法】 生後40日齢の野生型およびSHP-1ヘテロ欠損マウスに対し、左大脳皮質運動野の切除術を施した。切除前後の非損傷側大脳皮質において、SHP-1および軸索伸長因子として知られるSTAT3の発現量とリン酸化(活性化)の程度を、Real-Time PCR、Western blottingおよび免疫組織化学染色法を用いて解析した。また、脳損傷後の皮質脊髄路の再形成の程度を検証するため、非損傷側の右大脳皮質運動野に順行性トレーサーであるBiotinylated dextran amine (BDA)を注入し、非損傷側皮質脊髄路の損傷側へのSprouting数を頚髄において解析した。さらに、脳損傷後の運動機能の回復過程を、前肢の運動機能評価法であるCylinder testとGrid-walking testを用いて評価した。【倫理的配慮】 全ての動物実験は大阪大学大学院医学系研究科動物実験規定を遵守し、動物の個体数や苦痛は最小限にとどめて行なった。また遺伝子組換え動物に対しては、大阪大学遺伝子組換え実験実施規則に基づき実験を実施した。【結果】 健常な野生型マウス大脳皮質の免疫組織化学染色により、皮質脊髄路を構成する第V層ニューロンにSHP-1が局在することが確認された。Real-Time PCRを用いて野生型マウスにおけるSHP-1の発現量を調べた結果、脳損傷後にSHP-1の発現量増加が認められた。次に、SHP-1およびSTAT3の活性化について調べるため、Western blottingによりSHP-1およびSTAT3のリン酸化を解析した。その結果、野生型マウスでは、脳損傷後にSHP-1のリン酸化は有意な増加を示したが、STAT3のリン酸化に変化はみられなかった。一方、SHP-1ヘテロ欠損マウスでは、脳損傷後にSHP-1の増加はみられず、STAT3のリン酸化が有意に増加した。さらに、SHP-1ヘテロ欠損マウスでは野生型マウスと比較して、皮質脊髄路の頚髄におけるSprouting数の増加および前肢の運動機能回復が有意に認められた。【考察】 本研究により、大脳皮質損傷後、SHP-1が軸索伸長因子として重要なSTAT3を脱リン酸化(不活性化)することが示唆された。また、SHP-1ヘテロ欠損マウスにおいて、大脳皮質損傷後のSprouting数の増加および前肢の運動機能回復が有意に認められた。以上のことから、SHP-1の抑制がSTAT3の活性化を促すことで、非損傷側皮質脊髄路のSprouting数を増加し、これに伴う神経回路再編成の促進が運動機能回復に寄与することが示唆された。【理学療法学研究としての意義】 脳損傷後、傷害から免れた皮質脊髄路のSproutingにより代償的な神経回路の再形成がおこり、運動機能の回復が得られることがあるが、この現象は非常に限定的である。代償性回路形成を促進するメカニズムを解明することにより、効果的な神経回路の再編成を促すという新たな観点からリハビリテーション治療の可能性を開くことが期待できる。

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  • c-Jun N-terminal kinase induces axonal degeneration and limits motor recovery after spinal cord injury in mice. 査読 国際誌

    Kazuhiro Yoshimura, Masaki Ueno, Sachiko Lee, Yuka Nakamura, Akinobu Sato, Koichi Yoshimura, Haruhiko Kishima, Toshiki Yoshimine, Toshihide Yamashita

    Neuroscience research   71 ( 3 )   266 - 77   2011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:3  

    c-Jun N-terminal kinase (JNK) mediates neuronal death in response to stress and injury in the CNS and peripheral nervous system. Here, we show that JNK also regulates retrograde axonal degeneration (axonal dieback) after spinal cord injury (SCI) in mice. Activated phospho-JNK was highly expressed in damaged corticospinal tract (CST) axons after thoracic SCI by hemisection. Local administration of SP600125, a JNK inhibitor, prevented accumulation of amyloid-β precursor protein and retraction of the severed CST axons as well as preserved the axonal arbors rostral to the injury site. The treatment with SP600125 also improved functional recovery of the hindlimbs, assessed by Basso mouse scale open-field scores and the grid-walking test. In Jnk1(-/-) and Jnk3(-/-) mice, we observed prevention of axonal degeneration and enhancement of motor recovery after SCI. These results indicate that both JNK1 and JNK3 induce axonal degeneration and limit motor recovery after SCI. Thus, a JNK inhibitor may be a suitable therapeutic agent for SCI.

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  • RhoA Activation and Effect of Rho-kinase Inhibitor in the Development of Retinal Neovascularization in a Mouse Model of Oxygen-induced Retinopathy 査読

    Xiaoyun Fang, Masaki Ueno, Toshihide Yamashita, Yasushi Ikuno

    CURRENT EYE RESEARCH   36 ( 11 )   1028 - 1036   2011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:INFORMA HEALTHCARE  

    Purpose: To study RhoA activation and the effect of the Rho-kinase inhibitor in the development of retinal neovascularization in a mouse model of oxygen-induced retinopathy (OIR).
    Methods: C57BL/6 mice at postnatal day (P7) were exposed to hyper-oxygen for 5 days and returned to room air for 5 days to induce OIR. RhoA-GTP, an active form of RhoA, in retinas at P12, P13 and P17 was detected. Mice received a single intravitreal injection of Y27632 (5 mu M or 50 mu M), a Rho-kinase inhibitor, in one eye during the transition from oxygen to room air at P12. Contralateral eyes were used as the control. Fluorescein-conjugated dextran angiography of retinal whole mount was prepared to score features of neovascular retinopathy at P17. The preretinal neovascular nuclei quantification was performed in frozen sections as well to evaluate the neovascularization.
    Results: The retinal RhoA-GTP in OIR mice significantly increased from 0.24 +/- 0.06 at P12 to 0.38 +/- 0.12 at P13 (p < 0.05). The median total retinopathy score of 5.7 was significantly lower in eyes treated with Y27632 than controls (p < 0.001). Significant improvement was found in the specific categories of vascular tufts (p < 0.01) and extraretinal neovascularization (p < 0.05) in treated eyes. Those treated eyes also had a significantly decreased number of neovascular nuclei (p < 0.01).
    Conclusions: These results suggest that Rho/Rho-kinase signaling pathways are involved in the early process of hypoxia-induced retinal neovascularization and Y27632 might have therapeutic potential for the treatment of retinal neovascularization.

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  • Activated Microglia Inhibit Axonal Growth through RGMa 査読

    Mari Kitayama, Masaki Ueno, Toru Itakura, Toshihide Yamashita

    PLOS ONE   6 ( 9 )   e25234   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:PUBLIC LIBRARY SCIENCE  

    By causing damage to neural networks, spinal cord injuries (SCI) often result in severe motor and sensory dysfunction. Functional recovery requires axonal regrowth and regeneration of neural network, processes that are quite limited in the adult central nervous system (CNS). Previous work has shown that SCI lesions contain an accumulation of activated microglia, which can have multiple pathophysiological influences. Here, we show that activated microglia inhibit axonal growth via repulsive guidance molecule a (RGMa). We found that microglia activated by lipopolysaccharide (LPS) inhibited neurite outgrowth and induced growth cone collapse of cortical neurons in vitro-a pattern that was only observed when there was direct contact between microglia and neurons. After microglia were activated by LPS, they increased expression of RGMa; however, treatment with RGMa-neutralizing antibodies or transfection of RGMa siRNA attenuated the inhibitory effects of microglia on axonal outgrowth. Furthermore, minocycline, an inhibitor of microglial activation, attenuated the effects of microglia and RGMa expression. Finally, we examined whether these in vitro patterns could also be observed in vivo. Indeed, in a mouse SCI model, minocycline treatment reduced the accumulation of microglia and decreased RGMa expression after SCI, leading to reduced dieback in injured corticospinal tracts. These results suggest that activated microglia play a major role in inhibiting axon regeneration via RGMa in the injured CNS.

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  • Kinematic analyses reveal impaired locomotion following injury of the motor cortex in mice 査読

    Masaki Ueno, Toshihide Yamashita

    EXPERIMENTAL NEUROLOGY   230 ( 2 )   280 - 290   2011年8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  

    Brain injury in the motor cortex can result in deleterious functional deficits of skilled and fine motor functions. However, in contrast to humans, the destruction of cortex and its descending fibers has been thought not to cause remarkable deficits in simple locomotion in quadropedal animals. In the present study, we aimed to investigate in detail how lesion of the sensorimotor cortex affected locomotion ability in mice using the KinemaTracer system, a novel video-based kinematic analyzer. We found that traumatic injury to the left sensorimotor cortex induced several apparent deficits in the movement of contralesional right limbs during treadmill locomotion. The step length of right limbs decreased, and the speed in the forward direction was abrogated in the swing phase. The coordinates and angle of each joint were also changed after the injury. Some of the abnormal values in these parameters gradually recovered near the control level. The number of cFos-expressing neurons following locomotion significantly decreased in the right side of the spinal cord in injured mice, suggesting a role for cortex and descending fibers in locomotion. In contrast, interlimb coordination did not change remarkably even after the injury, supporting the notion that the basic locomotor pattern was determined by intraspinal neural circuits. These results indicate that the motor cortex and its descending fibers regulate several aspects of fine limb movement during locomotion. Our findings provide practical parameters to assess motor deficits and recovery following cortical injury in mice. (C) 2011 Elsevier Inc. All rights reserved.

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  • Corticospinal tract fibers cross the ephrin-B3-negative part of the midline of the spinal cord after brain injury 査読

    Shusaku Omoto, Masaki Ueno, Soichiro Mochio, Toshihide Yamashita

    NEUROSCIENCE RESEARCH   69 ( 3 )   187 - 195   2011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 IRELAND LTD  

    The fibers of corticospinal tract (CST), which control fine motor function, predominantly project to the contralateral spinal cord, not recross to the ipsilateral side. Ephrin-B3, which is expressed in the midline of the spinal cord, and its receptor, EphA4, are crucial for preventing CST fibers from recrossing the midline in the developing spinal cord. However, these fibers can cross the midline to the denervated side after a unilateral CST or cortical injury. We determined the reason CST fibers can cross the midline after a cortical injury and the changes in ephrin-B3-EphA4 signaling associated with such a crossing. We first examined axonal sprouting from CST fibers after unilateral ablation of the motor cortex in postnatal and adult mice. CST fibers crossed the midline of the spinal cord after cortical ablation, especially when conducted during the early postnatal period. These fibers were well associated with functional recovery after the injury. We next assessed the mRNA expression of ephrin-B3 and EphA4 before and after the ablation. Surprisingly, no changes were detected in the expression patterns. We found, however, that ephrin-B3 expression in the ventral part of the midline disappeared after postnatal day 9 (P9), but was pronounced along the entire midline before P6. Most of the CST fibers crossed the midline through the ventral region, where ephrin-B3 expression was absent. Our results suggest that ephrin-B3 is not expressed along the entire midline of the spinal cord, and sprouting axons can cross the midline at ephrin-B3-negative areas. (C) 2010 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

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  • Axonal remodeling for motor recovery after traumatic brain injury requires downregulation of γ-aminobutyric acid signaling. 査読

    Lee S, Ueno M, Yamashita T

    Cell death & disease   2   e133   2011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)  

    DOI: 10.1038/cddis.2011.16

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  • Dynamic Spatiotemporal Gene Expression in Embryonic Mouse Thalamus 査読

    Asuka Suzuki-Hirano, Masaharu Ogawa, Ayane Kataoka, Aya C. Yoshida, Daisuke Itoh, Masaki Ueno, Seth Blackshaw, Tomomi Shimogori

    JOURNAL OF COMPARATIVE NEUROLOGY   519 ( 3 )   528 - 543   2011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)   出版者・発行元:WILEY-LISS  

    The anatomy of the mammalian thalamus is characterized by nuclei, which can be readily identified in postnatal animals. However, the molecular mechanisms that guide specification and differentiation of neurons in specific thalamic nuclei are still largely unknown, and few molecular markers are available for most of these thalamic subregions at early stages of development. We therefore searched for patterned gene expression restricted to specific mouse thalamic regions by in situ hybridization during the onset of thalamic neurogenesis (embryonic [E] days E10.5-E12.5). To obtain correct regional information, we used Shh as a landmark and compared spatial relationships with the zona limitans intrathalamica (Zli), the border of the p2 and p3 compartments of the diencephalon. We identified genes that are expressed specifically in the ventricular zone of the thalamic neuroepithelium and also identified a number of genes that already exhibited regional identity at E12.5. Although many genes expressed in the mantle regions of the thalamus at E12.5 showed regionally restricted patterns, none of these clearly corresponded to individual thalamic nuclei. We next examined gene expression at E15.5, when thalamocortical axons (TCAs) project from distinct regions of the thalamus and reach their targets in the cerebral cortex. Regionally restricted patterns of gene expression were again seen for many genes, but some regionally bounded expression patterns in the early postnatal thalamus had shifted substantially by E15.5. These findings reveal that nucleogenesis in the developing thalamus is associated with selective and complex changes in gene expression and provide a list of genes that may actively regulate the development of thalamic nuclei. J. Comp. Neurol. 519:528-543, 2011. (C) 2010 Wiley-Liss, Inc.

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  • Paired Immunoglobulin-like Receptor B Knockout Does Not Enhance Axonal Regeneration or Locomotor Recovery after Spinal Cord Injury 査読

    Yuka Nakamura, Yuki Fujita, Masaki Ueno, Toshiyuki Takai, Toshihide Yamashita

    JOURNAL OF BIOLOGICAL CHEMISTRY   286 ( 3 )   1876 - 1883   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:AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

    Myelin components that inhibit axonal regeneration are believed to contribute significantly to the lack of axonal regeneration noted in the adult central nervous system. Three proteins found in myelin, Nogo, myelin-associated glycoprotein, and oligodendrocyte-myelin glycoprotein, inhibit neurite outgrowth in vitro. All of these proteins interact with the same receptors, namely, the Nogo receptor (NgR) and paired immunoglobulin-like receptor B (PIR-B). As per previous reports, corticospinal tract (CST) regeneration is not enhanced in NgR-knock-out mice after spinal cord injury. Therefore, we assessed CST regeneration in PIR-B-knock-out mice. We found that hindlimb motor function, as assessed using the Basso mouse scale, footprint test, inclined plane test, and beam walking test, did not differ between the PIR-B-knock-out and wildtype mice after dorsal hemisection of the spinal cord. Further, tracing of the CST fibers after injury did not reveal enhanced axonal regeneration or sprouting in the CST of the PIR-B-knock-out mice. Systemic administration of NEP1-40, a NgR antagonist, to PIR-B knock-out mice did not enhance the regenerative response. These results indicate that PIR-B knockout is not sufficient to induce extensive axonal regeneration after spinal cord injury.

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  • Genetic Deletion of Paired Immunoglobulin-Like Receptor B Does Not Promote Axonal Plasticity or Functional Recovery after Traumatic Brain Injury 査読

    Shusaku Omoto, Masaki Ueno, Soichiro Mochio, Toshiyuki Takai, Toshihide Yamashita

    JOURNAL OF NEUROSCIENCE   30 ( 39 )   13045 - 13052   2010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:SOC NEUROSCIENCE  

    The rewiring of neural networks is a fundamental step in recovering behavioral functions after brain injury. However, there is limited potential for axonal plasticity in the adult CNS. The myelin-associated proteins Nogo, myelin-associated glycoprotein (MAG), and oligodendrocyte myelin glycoprotein (OMgp) are known to inhibit axonal plasticity, and thus targeting the inhibitory pathways they participate in is a potential means of promoting plasticity and functional recovery. Each of Nogo, MAG, and OMgp interacts with both the Nogo receptor (NgR) and paired immunoglobulin-like receptor B (PirB). Here, we determined whether blocking PirB activity enhances axonal reorganization and functional recovery after cortical injury. We found that axons of the contralesional corticospinal tract sprouted into the denervated side of the cervical spinal cord after unilateral injury of the motor cortex. The extent to which this axonal reorganization occurred was far greater in mice lesioned during early postnatal days than in mice lesioned at an age when myelin had begun to form. This suggests that myelin-associated proteins might limit axonal remodeling in vivo. However, the number of sprouting fibers within either the corticospinal or corticorubral tract was not enhanced in PirB(-/-) mice. Blocking PirB signaling also failed to enhance functional recovery with three motor tests. Our results suggest that blocking the function of PirB is not sufficient to promote axonal reorganization or functional recovery after cortical injury.

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  • Olfactory Mucosal Transplantation After Spinal Cord Injury Improves Voiding Efficiency by Suppressing Detrusor-Sphincter Dyssynergia in Rats 査読

    Jiro Nakayama, Tetsuya Takao, Hiroshi Kiuchi, Keisuke Yamamoto, Shinichiro Fukuhara, Yasushi Miyagawa, Masanori Aoki, Koichi Iwatsuki, Toshiki Yoshimine, Masaki Ueno, Toshihide Yamashita, Norio Nonomura, Akira Tsujimura, Akihiko Okuyama

    JOURNAL OF UROLOGY   184 ( 2 )   775 - 782   2010年8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 INC  

    Purpose: Several recent studies showed that olfactory mucosal transplantation after spinal cord injury promotes extensive regeneration of the injured spinal cord. We examined the efficacy of olfactory mucosal transplantation for bladder dysfunction after spinal cord injury in rats.
    Materials and Methods: In adult female rats the Th9-10 spinal cord was completely transected, followed by olfactory mucosal transplantation or gelatin sponge filling as the control. Each group was examined by cystometrogram and external urethral sphincter electromyogram. Calcitonin gene-related peptide and growth associated protein 43 double positive expression in the L6/S1 dorsal horn was evaluated by immunohistochemistry. Transplant sites were examined by immunohistochemistry with antibodies against neurofilament M and neuronal class III beta-tubulin.
    Results: On cystometrogram voiding efficiency was significantly higher in the transplantation group than in controls. On external urethral sphincter electromyogram with simultaneous cystometrogram the transplantation group showed a larger ratio of interburst silent periods to burst activity duration and a greater number of high frequency oscillations. In the transplantation group calcitonin gene-related peptide and growth associated protein 43 double positive expression in the L6/S1 dorsal horn was less dense than in controls. The transplantation group showed strong neurofilament M and neuronal class III beta-tubulin expression at the transplant site.
    Conclusions: Olfactory mucosal transplantation after spinal cord injury weakened external urethral sphincter excessive bursting and increased the urethral opening to improve voiding efficiency. Olfactory mucosal transplantation may modify emergence of the spinal micturition reflex after spinal cord injury. Transplantation resulted in new axons growing at the transplant site, implying the possible existence of interneuron bridging across the injured spinal cord.

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  • Expression of galectin-1 in immune cells and glial cells after spinal cord injury 査読

    Dai Kurihara, Masaki Ueno, Tatsuhide Tanaka, Toshihide Yamashita

    NEUROSCIENCE RESEARCH   66 ( 3 )   265 - 270   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 IRELAND LTD  

    Galectin-1, a member of a family of beta-galactoside-binding proteins, is differentially expressed by various tissues and performs a wide range of biological functions. Galectin-1 has been shown to mediate inflammation and to be involved in axonal regeneration in the oxidized form and in axonal degeneration in the reduced form, however. its involvement in injury and the repair processes after spinal cord Injury have not been studied Therefore, we studied galectin-1 expression in injured spinal cords Immunostaining analysis of galectin-1 in injured spinal cords revealed that galectin-l-expressing cells assembled around the lesion site Galectin-1 was intensively expressed by neutrophils 1 day. by microglia/macrophages 3 days. and by astrocytes 7 days after spinal cord injury These results Suggest that galectin-1 may be associated with the pathogenesis of spinal cord Injury (C) 2009 Elsevier Ireland Ltd and the Japan Neuroscience Society All rights reserved.

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  • Limited functional recovery in rats with complete spinal cord injury after transplantation of whole-layer olfactory mucosa: laboratory investigation. 査読 国際誌

    Masanori Aoki, Haruhiko Kishima, Kazuhiro Yoshimura, Masahiro Ishihara, Masaki Ueno, Katsuhiko Hata, Toshihide Yamashita, Koichi Iwatsuki, Toshiki Yoshimine

    Journal of neurosurgery. Spine   12 ( 2 )   122 - 30   2010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)   出版者・発行元:2  

    OBJECT: The olfactory mucosa (OM) consists of 2 layers, the epithelium and the lamina propria. Attempts have been made to restore motor function in rat models of spinal cord injury (SCI) by transplanting olfactory ensheathing cells from the lamina propria, but there has been no attempt to transplant the OM in animal models. To investigate the potential of the OM to restore motor function, the authors developed a rat model of SCI and delayed transplantation of syngenic OM. METHODS: Two weeks after complete transection of the spinal cord at the T-10 level in Wistar rats, pieces of syngenic whole-layer OM were transplanted into the lesion. Rats that underwent respiratory mucosa transplantation were used as controls. The authors evaluated the locomotor activity according to the Basso-Beattie-Bresnahan scale for 8 weeks after transplantation. Obtained spinal cords were analyzed histologically. Results The OM transplantation rats showed significantly greater hindlimb locomotor recovery than the respiratory mucosa-transplanted rats. However, the recovery was limited according to the Basso-Beattie-Bresnahan scale. In the histological examination, the serotonergic raphespinal tract was regenerated. The pseudocyst cavity volume in the vicinity of the SCI lesion correlated negatively with the functional recovery. CONCLUSIONS: Transplantation of whole-layer OM in rats contributes to functional recovery from SCI, but the effect is limited. In addition to OM transplantation, other means would be necessary for better outcomes in clinical situations.

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  • Engulfment of Axon Debris by Microglia Requires p38 MAPK Activity 査読

    Tatsuhide Tanaka, Masaki Ueno, Toshihide Yamashita

    JOURNAL OF BIOLOGICAL CHEMISTRY   284 ( 32 )   21626 - 21636   2009年8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:AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

    The clearance of debris after injuries to the nervous system is a critical step for restoration of the injured neural network. Microglia are thought to be involved in elimination of degenerating neurons and axons in the central nervous system (CNS), presumably restoring a favorable environment after CNS injuries. However, the mechanism underlying debris clearance remains elusive. Here, we establish an in vitro assay system to estimate phagocytosis of axon debris. We employed a Wallerian degeneration model by cutting axons of the cortical explants. The cortical explants were co-cultured with primary microglia or the MG5 microglial cell line. The cortical neurites were then transected. MG5 cells efficiently phagocytosed the debris, whereas primary microglia showed phagocytic activity only when they were activated by lipopolysaccharide or interferon-beta. When MG5 cells or primary microglia were co-cultured with degenerated axons, p38 mitogen-activated protein kinase (MAPK) was activated in these cells. Engulfment of axon debris was blocked by the p38 MAPK inhibitor SB203580, indicating that p38 MAPK is required for phagocytic activity. Receptors that recognize dying cells appeared not to be involved in the process of phagocytosis of the axon debris. In addition, the axons undergoing Wallerian degeneration did not release lactate dehydrogenase, suggesting that degeneration of the severed axons and apoptosis may represent two distinct self-destruction programs. We observed regrowth of the severed neurites after axon debris was removed. This finding suggests that axon debris, in addition to myelin debris, is an inhibitory factor for axon regeneration.

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  • Etoposide Induces TRP53-Dependent Apoptosis and TRP53-Independent Cell Cycle Arrest in Trophoblasts of the Developing Mouse Placenta 査読

    Hirofumi Yamauchi, Kei-ichi Katayama, Masaki Ueno, Hiroyuki Kanemitsu, Chunja Nam, Takashi Mikami, Aya Saito, Yuka Ishida, Koji Uetsuka, Kunio Doi, Yasushi Ohmach, Hiroyuki Nakayama

    BIOLOGY OF REPRODUCTION   80 ( 4 )   813 - 822   2009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:SOC STUDY REPRODUCTION  

    Abnormal regulation of placental apoptosis and proliferation has been implicated in placental disorders. Recently, several DNA-damaging agents were reported to induce excessive apoptosis and reduce cell proliferation in the placenta; however, the molecular pathways of these toxic effects on the placenta are unclear. The aim of the present study was to determine the involvement of TRP53, a tumor suppressor that mediates cellular responses to DNA damage, in the induction of apoptosis and cell cycle arrest in the developing placenta. For this purpose, we treated pregnant mice on Day 12 of gestation with 10 mg/kg of etoposide and 5-Gy gamma irradiation, potent inducers of DNA damage. We found an increase in the number of trophoblastic apoptoses 8 and 24 h after etoposide injection and 6 and 24 h after irradiation in the placental labyrinth zone. The number of mitoses and DNA syntheses in trophoblasts decreased after treatment. The accumulation and phosphorylation of TRP53 protein were detected 8 and 6 h after etoposide injection and irradiation, respectively. In Trp53-deficient placentas, the induction of etoposide-induced trophoblastic apoptosis is abrogated, while the reduction of proliferation occurred similarly as in wild-type placentas. CDC2A, a regulator of G2/M progression, was inactivated by phosphorylation after etoposide injection and irradiation, suggesting that the cell cycle was arrested at the G2/M border by treatment. Our study demonstrated that etoposide injection induced TRP53-dependent apoptosis and TRP53-independent cell cycle arrest in labyrinthine trophoblasts, providing insights into the molecular pathway of placental disorders.

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  • Intrinsic regenerative mechanisms of central nervous system neurons 査読

    Rieko Muramatsu, Masaki Ueno, Toshihide Yamashita

    BIOSCIENCE TRENDS   3 ( 5 )   179 - 183   2009年

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    記述言語:英語   出版者・発行元:IRCA-BSSA  

    Injuries to the adult central nervous system (CNS), such as spinal cord injury and brain contusion, can cause permanent functional deficits if axonal connections are broken. Spontaneous functional recovery rarely occurs. It has been widely accepted that the extracellular environment of the CNS inhibits neuronal regeneration. However, it should be noted that another reason for injured neurons failing to regenerate is their weak intrinsic ability to do so. The regeneration of injured neurons is a process involving many intracellular phenomena, including cytoskeletal changes, gene and protein expression, and changes in the responsiveness to extracellular cues. The capacity of injured neurons to regenerate is modulated to some extent by changes in the expression of intracellular signaling molecules such as glycogen synthase kinase-3 beta and cyclic adenosine 3',5'-monophosphate. Knowledge of these effects has guided the development of animal models for regenerative therapies of CNS injury. Enhancing the intrinsic regenerative machinery of injured axons in the adult CNS is a potentially powerful strategy for treating patients with a CNS injury.

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  • Regulation of axonal elongation and pathfinding from the entorhinal cortex to the dentate gyrus in the hippocampus by the chemokine stromal cell-derived factor 1 alpha 査読

    Yoichi Ohshima, Takekazu Kubo, Ryuta Koyama, Masaki Ueno, Masanori Nakagawa, Toshihide Yamashita

    JOURNAL OF NEUROSCIENCE   28 ( 33 )   8344 - 8353   2008年8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  

    During the early developmental stage, a neural circuit is established between the entorhinal cortex (EC) and the hippocampal dentate gyrus (DG) via the perforant pathway. However, the manner in which the perforant fibers are navigated has mostly remained a mystery. Here, we analyzed the functional role of a chemokine, namely, stromal cell-derived factor 1 alpha(SDF-1 alpha), in the navigation of the perforant fibers. SDF-1 alpha was observed to promote neurite growth, which is dependent on mDia1, in cultured entorhinal cortical neurons obtained from rats at postnatal day 0. We then used entorhino-hippocampal cocultures comprising green fluorescence-labeled EC and DG slices to assess the projection of the perforant fibers from the EC. Although the specific laminar termination of the entorhinal axons was observed with this system, the number of appropriately terminating entorhinal axons decreased significantly when the SDF-1 alpha signaling pathway was blocked by a neutralizing antibody against SDF-1 alpha or by the specific SDF-1 alpha receptor antagonist AMD3100 (1,1 alpha-[1,4-phenylenebis(methylene)] bis-1,4,8,11-tetra-azacyclotetradecane octahydrochloride). Furthermore, inhibition of the SDF-1 alpha signaling pathway resulted in a decrease in the immunoreactivity for PSD-95 (postsynaptic density protein-95) in the DG, possibly because of a reduction in the number of projecting perforant fibers. These results demonstrate that SDF-1 alpha plays a critical role in promoting the growth of perforant fibers from the EC to the DG.

    DOI: 10.1523/JNEUROSCI.1670-08.2008

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  • Strategies for regenerating injured axons after spinal cord injury - insights from brain development. 査読

    Masaki Ueno

    Biologics : targets & therapy   2   253 - 264   2008年6月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:2  

    Axonal regeneration does not occur easily after an adult central nervous system (CNS) injury. Various attempts have partially succeeded in promoting axonal regeneration after the spinal cord injury (SCI). Interestingly, several recent therapeutic concepts have emerged from or been tightly linked to the researches on brain development. In a developing brain, remarkable and dynamic axonal elongation and sprouting occur even after the injury; this finding is essential to the development of a therapy for SCI. In this review, we overview the revealed mechanism of axonal tract formation and plasticity in the developing brain and compare the differences between a developing brain and a lesion site in an adult brain. One of the differences is that mature glial cells participate in the repair process in the case of adult injuries. Interestingly, these cells express inhibitory molecules that impede axonal regeneration such as myelin-associated proteins and the repulsive guidance molecules found originally in the developing brain for navigating axons to specific routes. Some reports have clearly elucidated that any treatment designed to suppress these inhibitory cues is beneficial for promoting regeneration and plasticity after an injury. Thus, understanding the developmental process will provide us with an important clue for designing therapeutic strategies for recovery from SCI.

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  • Gene expression profiles of drug-metabolizing enzymes (DMEs) in rat liver during pregnancy and lactation 査読

    Xi Jun He, Hirofumi Yamauchi, Kazuhiko Suzuki, Masaki Ueno, Hiroyuki Nakayama, Kunio Doi

    EXPERIMENTAL AND MOLECULAR PATHOLOGY   83 ( 3 )   428 - 434   2007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)   出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    A cDNA microarray analysis was conducted to examine hepatic gene expression profiles in pregnant and lactating F344 rats compared to a virgin control group using an Affymetrix GeneChip system. Of the approximately 16000 gene transcripts interrogated, more than 1000 were significantly modified in their expression when detected either in late pregnancy (19 days of gestation, GD 19, 513 genes upregulated and 579 downregulated) or on the day of delivery (Postpartum 0 day, PPD 0, 497 upregulated and 733 downregulated). Particular interest was paid to the gene expression of drug-metabolizing enzymes (DMEs) and nuclear receptors (NRs). Though the expression of a few genes, those forCYP7A1, CYP51 and Sultx3, increased, the expression of a number of genes encoding DMEs (Phase I and Phase II) and NRs decreased during pregnancy and lactation. Changes in the expression of 9 genes encoding DMEs and NRs were confirmed by quantitative real-time PCR. For all 9 genes tested, overall, the results of the microarray and real-time PCR analyses were in agreement. This is the first application of a microarray analysis to the expression profiling of genes encoding DMEs and NRs in the liver of pregnant and lactating rats. When combined with other studies, the present study may provide a basis for investigating the mechanism of toxicity of environmental or other nonphysiologic chemicals to the fetus and mother and drug safety during pregnancy and lactation. (c) 2006 Elsevier Inc. All rights reserved.

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  • Essential role of p53 in trophoblastic apoptosis induced in the developing rodent placenta by treatment with a DNA-damaging agent 査読

    Hirofumi Yamauchi, Kei-ichi Katayama, Masaki Ueno, Xi Jun He, Takashi Mikami, Koji Uetsuka, Kunio Doi, Hiroyuki Nakayama

    APOPTOSIS   12 ( 10 )   1743 - 1754   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:SPRINGER  

    Placental apoptosis plays important roles in both normal morphogenesis and pathogenesis. We previously reported that administration of cytosine arabinoside (Ara-C), a DNA-damaging agent, to pregnant rats induced apoptosis of trophoblasts in the placental labyrinth zone. Our aim here was to clarify the molecular pathway of DNA damage induced-trophoblastic apoptosis. We found the accumulation and phosphorylation of p53 protein, a tumor suppressor that mediates apoptosis under various cellular stresses, in Ara-C-treated rat placentas. Expression of the mRNAs of downstream targets of p53 was upregulated, suggesting that p53 exerts its function as a transcription factor. We also observed release of mitochondrial cytochrome c and activation of caspase-9, hallmarks of the intrinsic apoptotic pathway. Phosphorylation of Chk1 and H2A.X, target substrates of DNA damage transducers, was detected immediately after Ara-C treatment, suggesting activation of DNA damage cascades to phosphorylate p53. Ara-C-induced trophoblastic apoptosis was almost completely abrogated in placentas of Trp53 (coding p53)deficient mice, whereas the levels of physiological apoptosis in trophoblasts were similar among wild-type and Trp53-deficient mice. These results indicate that p53 is essential for DNA damage-induced trophoblastic apoptosis and suggest that the mechanisms that regulate the damage-induced apoptosis differ from those that regulate physiological apoptosis.

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  • Repair process of fetal brain after 5-azacytidine-induced damage 査読

    Masaki Ueno, Kei-ichi Katayama, Hirofumi Yamauchi, Akira Yasoshima, Hiroyuki Nakayama, Kunio Doi

    EUROPEAN JOURNAL OF NEUROSCIENCE   24 ( 10 )   2758 - 2768   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:BLACKWELL PUBLISHING  

    The fetal brain is susceptible to many extrinsic stresses. Some of these stresses induce excessive cell death in the prenatal stage, leading to anomalies in the neonatal brain. However, it is unclear how the developing brain responds to and repairs the prenatal tissue damage. We treated pregnant rats on day 13 of gestation with 5-azacytidine, one of the compounds that induces excessive cell death and inhibits proliferation in neural progenitor cells, to damage the fetal brain, and investigated the repair process up to 60 h after treatment. Histological analysis showed that 5-azacytidine induced strong apoptosis of neural cells. By 60 h, apoptotic cells disappeared and the tissue was repaired, although the telencephalic wall remained thinner than in controls. Flow cytometry analysis showed that the cell cycle distribution also returned to control levels at 60 h, suggesting that the repair process was completed around 60 h. During the repair period, amoeboid microglia infiltrated the brain and ingested the apoptotic cells. These microglial cells were positive for the multiple microglial markers, and mRNAs for the microglia-related cytokines tumor necrosis factor alpha, interleukin 1 beta and macrophage colony stimulating factor (M-CSF) were up-regulated. DNA microarray analysis showed the up-regulation of genes relevant to glial cells, inflammation, the extracellular matrix, glycolysis, proliferation and neural development. We show here that the developing brain has the capacity to respond to the damage induced by extrinsic chemical stresses, including changing the expression of numerous genes and the induction of microglia to aid the repair process.

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  • Evidence of apoptosis in the subventricular zone and rostral migratory stream in the MPTP mouse model of Parkinson disease 査読

    Xi Jun He, Hiroyuki Nakayama, Mei Dong, Hirofumi Yamauchi, Masaki Ueno, Koji Uetsuka, Kunio Doi

    JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY   65 ( 9 )   873 - 882   2006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:LIPPINCOTT WILLIAMS & WILKINS  

    1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is commonly used to create animal models of Parkinson disease. There is conflicting evidence on the occurrence of apoptosis induced by MPTP in the mouse substantia nigra pars compacta. We demonstrated that a single acute injection of MPTP induced apoptosis in the subventricular zone (SVZ) and rostral migratory stream (RMS) in the adult C57BL/6 mouse brain. The number of TUNEL-positive cells peaked at 24 hours after injection and decreased thereafter, paralleling the change in the number of cleaved caspase-3-positive cells after MPTP injection. Results of immunohistochemistry and ultrastructural analyses indicated that the majority of apoptotic cells in the SVZ and RMS were migrating neuroblasts (type A cells), whereas a few were astrocytes (type B cells). No apoptosis occurred in transit-amplifying progenitors (type C cells). The decrease in A cell numbers was most marked on day 2 and lasted to day 8 after the administration. A rapid and transient phagocytosis of apoptotic cells by microglial cells was demonstrated to parallel the MPTP-induced apoptosis. The present findings provide new insight into the extensive neurotoxicity of MPTP and may be valuable in reevaluating the MPTP mouse model of Parkinson disease.

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  • Cell cycle progression is required for nuclear migration of neural progenitor cells 査読

    M Ueno, K Katayama, H Yamauchi, H Nakayama, K Doi

    BRAIN RESEARCH   1088   57 - 67   2006年5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  

    In the developing brain, neural progenitor cells in the ventricular zone (VZ) show a typical migration pattern-interkinetic nuclear migration, in which nuclear position within the VZ is correlated with the cell cycle. However, the mechanisms underlying this regulation remain unclear. To clarify whether the cell cycle progression controls nuclear migration of neural progenitor cells, we determined whether chemically induced cell cycle arrest affected nuclear migration patterns in the VZ. Administration of 5-azacytidine (5AzC) or cyclophosphamide (CP) to pregnant mice induced cell cycle arrest in the fetal neural progenitor cells of the telencephalon: 5AzC induced G2/M-phase arrest, and CP induced S-phase arrest. We used 5-bromo-2'-deoxyuridine (BrdU) labeling to determine the position of the cell in the cell cycle and the nuclei within the VZ at the same time. Cells arrested in G2/ M-phase stopped migrating in the inner area of the VZ. Cells arrested in S-phase stopped migrating in the outer area. These results indicate that nuclear position within the VZ was correlated with cell cycle phase, even when the cell cycle was disrupted, and that the nuclei of neural progenitor cells can migrate only when their cell cycle is going. Our results suggest that cell cycle regulators might control the machinery of migration through a common regulatory mechanism. (c) 2006 Elsevier B.V. All rights reserved.

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  • Cell cycle and cell death regulation of neural progenitor cells in the 5-azacytidine (5AzC)-treated developing fetal brain 査読

    M Ueno, K Katayama, H Yamauchi, H Nakayama, K Doi

    EXPERIMENTAL NEUROLOGY   198 ( 1 )   154 - 166   2006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:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    In the developing brain, neural progenitor cells are susceptible to many extrinsic stresses, including DNA damage. We treated pregnant rats with 5-azacytidine (5AzC), a DNA demethylating and damaging agent, to investigate the cellular responses of the fetal brain, focusing on the regulation of proliferation and cell death. 5AzC first induced the accumulation of cells in abnormal mitosis, G2-phase accumulation, and then apoptosis of the neural progenitor cells. Most of the apoptotic cells were in G1 phase. Cell cycle transition studies suggested that G2/M progression was blocked, after which the cells moved to G I phase or underwent apoptosis. p53, a key factor for response to DNA damage, and some of its target genes showed increased expression in Western blot and DNA microarray analyses. In 5AzC-treated fetal brains of p53-deficient mice, apoptosis did not occur, although G2/M accumulation was induced. These results suggest that, in the developing brain, apoptosis is p53-dependent but that another mechanism governs the G2/M checkpoint. The G2/M regulator, Cdc:2, was activated by dephosphorylation through G2/M accumulation, suggesting accelerated entry into mitosis leading to accumulation of cells showing abnormal mitosis. Furthermore, some cells may have died due to mitotic catastrophe. Throughout brain development, various cell cycle and cell death regulation mechanisms provide neural progenitor cells with options for defense from DNA damage. (c) 2005 Elsevier Inc. All rights reserved.

    DOI: 10.1016/j.expneurol.2005.11.024

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  • Microarray analysis of genes in fetal central nervous system after ethylnitrosourea administration 査読

    K Katayama, M Ueno, H Yamauchi, H Nakayama, K Doi

    BIRTH DEFECTS RESEARCH PART B-DEVELOPMENTAL AND REPRODUCTIVE TOXICOLOGY   74 ( 3 )   255 - 260   2005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:WILEY-LISS  

    BACKGROUND: Ethylnitrosourea (ENU), a monofunctional alkylating agent, induces apoptosis and cell cycle arrest in neuroepithelial cells, neural stem cells in the fetal central nervous system (CNS). These effects occur immediately after the administration of ENU to pregnant animals resulting in fetal brain anomalies and long-term effects include brain tumors in the offspring. METHODS: Changes in gene expression were investigated in the fetal CNS after ENU administration to pregnant rats using microarray to identify the genes involved in the injury and recovery of the fetal CNS. RESULTS: The up-regulation of 21 genes in injury and 15 genes in recovery phases and down-regulation of 5 genes in injury and 3 genes in recovery phases were identified. The genes up-regulated in the injury phase contained p53-target genes that mediate apoptosis and cell cycle arrest, and those in the recovery phase contained cell proliferation-promoting genes. The genes down-regulated in the injury phase contained cholesterol biosynthesis-related genes. In addition, there were some genes that have not been identified to be involved in the CNS injury and recovery. CONCLUSIONS: The present study will provide a better understanding of the mechanisms of development, regeneration and carcinogenesis of the CNS as well as the mechanisms of ENU-induced fetal CNS injury and recovery. (c) 2005 Wiley-Liss, Inc.

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  • Ethylnitrosourea induces neural progenitor cell apoptosis after S-phase accumulation in a p53-dependent manner 査読

    K Katayama, M Ueno, H Yamauchi, T Nagata, H Nakayama, K Doi

    NEUROBIOLOGY OF DISEASE   18 ( 1 )   218 - 225   2005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)   出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    Neural progenitor cells populate the ventricular zone of the fetal central nervous system. In this study, immediately after the administration of ethylnitrosourea (ENU), an alkylating agent, an accumulation of neural progenitor cells in the S phase was observed. This event was caused by the inhibition or arrest of DNA replication rather than acceleration of the G1/S transition. Soon after this accumulation reached its peak, the number of cells in the G2/M phase decreased and the apoptotic cell count increased. In p53-deficient mice, both ENU-induced apoptosis and S-phase accumulation were almost completely abrogated. These findings indicate that ENU inhibits or arrests DNA replication in neural progenitor cells during the S phase and then evokes apoptosis before the cells enter the G2 phase. Furthermore, these data also demonstrate that both ENU-induced apoptosis and cell cycle perturbation in the S phase require p53. (C) 2004 Elsevier Inc. All rights reserved.

    DOI: 10.1016/j.nbd.2004.09.015

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  • Effects of prenatal hydroxyurea-treatment on mouse offspring 査読

    GH Woo, K Katayama, EJ Bak, M Ueno, H Yamauchi, K Uetsuka, H Nakayama, K Doi

    EXPERIMENTAL AND TOXICOLOGIC PATHOLOGY   56 ( 1-2 )   1 - 7   2004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:URBAN & FISCHER VERLAG  

    Hlydroxyurea (HU), a ribonucleotide reductase inhibitor, induces morphological anomalies in the central nervous system, craniofacial tissues and limb buds in animals, and neonatal respiratory distress in humans. The neonates and offspring of pregnant mice treated with 400 or 800 mg/kg of HU on day 13 of gestation were examined at 0 day and 10 weeks after birth to find a clue for clarifying the relationship between HU-induced apoptosis in the fetal tissues and teratogenicity. The offspring from dams treated with HU were retarded in growth compared with controls. But there was no significant difference in the body weight gain between the 400 and 800 mg/kg groups. In the teratologic changes, microencephaly, hydrocephalus and curved coccygeal vertebrae were observed in the offspring, and the incidence of these teratologic changes was similar but their degree was more severe in the 800 mg/kg group than in the 400 mg/kg group. Based on the above-mentioned previous and present studies of ours, we suggest that HU-induced apoptosis in fetal tissues may play an important role in the development of anomalies in the corresponding tissues of offspring. (C) 2004 Elsevier GmbH. All rights reserved.

    DOI: 10.1016/j.etp.2004.04.011

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  • Involvement of p53 in 1-beta-D-arabinofuranosylcytosine-induced rat fetal brain lesions 査読

    H Yamauchi, K Katayama, M Ueno, K Uetsuka, H Nakayama, K Doi

    NEUROTOXICOLOGY AND TERATOLOGY   26 ( 4 )   579 - 586   2004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)   出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD  

    1-beta-D-Arabiiioftiranosylcytosine (Ara-C), a cytidine analogue cytotoxic to proliferating cells, has a teratogenic effect in the brain of experimental animals and causes neural cell apoptosis in vitro and in vivo. In the present study, pregnant rats were injected with Ara-C on Day 13 of gestation and the fetal brain was collected from 1 to 48 It after treatment. Histopathological examinations revealed marked induction of apoptotic cell death and decrease of mitosis in neuroepithelial cells in the brain of Ara-C-treated fetus, and these changes were most prominent from 9 to 12 h. Expression of p53 protein, which mediates apoptosis and cell cycle arrest after DNA damage, was elevated remarkably and peaked at 3 h. p21, a cyclin-dependent kinase inhibitor responsible for p53-mediated cell cycle arrest, showed intense overexpression in protein and mRNA levels following the increase of p53 protein. The mRNA expressions of other p53 transcriptional target genes, bax, cyclinG1, and fas, also significantly increased and peaked at around 9 h. In conclusion, prenatal treatment of Ara-C is thought to induce apoptosis and inhibition of cell proliferation mediated by p53 and its target genes in the fetal brain. (C) 2004 Elsevier Inc. All rights reserved.

    DOI: 10.1016/j.ntt.2004.03.010

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  • Involvement of p53 in 1-beta-D-arabinofuranosylcytosine-induced trophoblastic cell apoptosis and impaired proliferation in rat placenta 査読

    H Yamauchi, K Katayama, M Ueno, K Uetsuka, H Nakayama, K Doi

    BIOLOGY OF REPRODUCTION   70 ( 6 )   1762 - 1767   2004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:SOC STUDY REPRODUCTION  

    1-beta-D-Arabinofuranosyicytosine (Ara-C), a DNA-damaging agent, severely inhibits fetal growth and has teratogenicity. Recently, we reported that Ara-C also causes placental growth retardation and increases placental apoptosis. The aim of the present study is to elucidate the mechanisms of placental injury induced by genotoxic stress and involvement of p53, which mediates apoptosis and cell-cycle arrest after DNA damage. We injected Ara-C into pregnant rats on Day 13 of gestation and examined the placentas from 1 to 48 h after the administration. Terminal deoxynucleotidyltransferase-mediated dUTP end-labeling (TUNEL) revealed that the apoptosis of trophoblastic cells in the placental labyrinth zone increased from 3 h after the treatment and peaked at 6 h before returning to control levels at 48 h. An increase in cleaved caspase-3 immunoreactivity was also detected at 6 h. Proliferative activity as measured by immunohistochemistry for topoisomerase IIalpha and by mitotic index significantly decreased after the treatment in the labyrinth zone. Immunoreactivity for p53 protein in the placental labyrinth zone was remarkably enhanced and peaked at 3 h after treatment, although no increase in p53 mRNA expression was detected with a reverse transcription-polymerase chain reaction. Regarding p53 target genes, p21, cyclinG1, and fas mRNA levels increased significantly and peaked at around 9 h after the treatment. These results indicate that Ara-C would induce apoptosis and impair cell proliferation in the placental labyrinth zone, and p53 and its transcriptional target genes may play an important role in the pathogenesis of the Ara-C-induced placental toxicity.

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  • Age-dependent susceptibility to MPTP neurotoxicity in C57BL mice: A tyrosine hydroxylase-immunohistochemical evaluation 査読

    Xi Jun He, Hiroyuki Nakayama, Masaki Ueno, Kunio Doi

    Journal of Toxicologic Pathology   17 ( 4 )   239 - 244   2004年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The present study was designed to evaluate dopaminergic neuronal loss in the substantia nigra pars compact (SNpc) with immunohistochemical staining. C57BL/6 mice were intraperitoneally injected four times with 15 mg/kg 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), at 2 h intervals on 10 and 21 days, and 6, 12, 24 and 48 weeks of age. Animals were sacrificed 48 hours after the last injection. No change in the number of tyrosine hydroxylase (TH)-positive neurons was observed in 10- and 21-day-old mice after MPTP treatment compared with their corresponding controls. In contrast, MPTP produced a loss of 20.3% of TH-positive neurons in 6 week-old mice, and further decreases with advancing age, i.e., 35.8%, 39.9% and 56.2% TH-positive neuronal loss at 12, 24 and 48 weeks of age, respectively. These results provide evidence of age-related susceptibility of C57BL/6 mice to MPTP using TH immunohistochemistry. However, we failed to observe apoptosis of neurons in SNpc of mice of all ages after a subacute protocol of MPTP treatment (30 mg/kg/day x 5days).

    DOI: 10.1293/tox.17.239

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  • Ethylnitrosourea-induced apoptosis in primordial germ cells of the rat fetus 査読

    K Katayama, M Ueno, H Yamauchi, H Nakayama, K Doi

    EXPERIMENTAL AND TOXICOLOGIC PATHOLOGY   54 ( 3 )   193 - 196   2002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:URBAN & FISCHER VERLAG  

    Ethylnitrosourea (ENU) is a simple alkylating agent. It induces gene mutations in fetal primordial germ cells (PGCs), and a high incidence of congenital malformations is also found in the offspring of male mice treated with ENU at the embryonic stage. It is also reported that decreases in the fertility rate and weights of the testis and ovary were found in the offspring from dams treated with ENU. In this study, we analyzed the occurrence of apoptotic cell death and the expression of p53 protein which is thought to play an important role in the DNA damage-induced apoptosis after administration of ENU to pregnant rats on day 13 of gestation to obtain a clue for clarifying the toxic effect of ENU on PGCs. Apoptotic cells increased in PGCs in fetal gonads from 3 h after treatment. The number of apoptotic PGCs peaked at 6 h and gradually decreased towards 24 h after treatment. On the other hand, p53-positive PGCs increased from 1 h after treatment, prior to the induction of apoptosis. The number of p53-positive PGCs peaked at 3 h and returned to the control level at 24 h after treatment. These results suggest that ENU induces apoptosis in rat fetal PGCs immediately after its administration to dams and excess cell death by apoptosis may have a close relation to the later occurrence of decreases in the fertility rate and gonadal weight. Moreover, a possible involvement of p53 is suggested in the ENU-induced apoptosis in PGCs.

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  • 5-azacytidine (5AzC)-induced histopathological changes in the central nervous system of rat fetuses 査読

    M Ueno, K Katayama, A Yasoshima, H Nakayama, K Doi

    EXPERIMENTAL AND TOXICOLOGIC PATHOLOGY   54 ( 2 )   91 - 96   2002年8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:URBAN & FISCHER VERLAG  

    5-Azacytidine (5AzC) is a cytidine analogue which possesses nitrogen atom instead of carbon atom at the position 5 of the pyrimidine ring. In this study, detailed histopathological changes were sequentially examined in the rat fetal brain obtained from dams treated with 5AzC (10 mg/kg) on day 13 of gestation (GD13). At 6 hours after treatment (HAT), a prominent accumulation of neuroepithelial cells showing pleomorphic mitotic figures were observed in the telencephalic wall. The mitosis-index peaked at 6 HAT, and decreased thereafter. Neuroepithelial cells positive for nick end labeling (TUNEL) method, which is widely used for the detection of apoptotic cells, prominently increased at 9 HAT, and the TUNEL-index peaked at 12 HAT. TUNEL-positive cells showed ultrastructural characteristics of apoptosis. At 24 HAT, the formation of rosette-like structures was observed in the fetal brain. From the results of the present study, it was evident that abnormal mitosis and neuronal apoptosis were induced in the rat fetal brain following 5AzC-administration to dams on GD13. In addition, it is suggested that 5AzC-induced apoptosis might occur mainly in the post mitotic phase of cell cycle.

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  • Ethylnitrosourea induces apoptosis and growth arrest in the trophoblastic cells of rat placenta 査読

    K Katayama, M Ueno, H Takai, N Ejiri, K Uetsuka, H Nakayama, K Doi

    BIOLOGY OF REPRODUCTION   67 ( 2 )   431 - 435   2002年8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 STUDY REPRODUCTION  

    Ethyl nitrosourea (ENU), a well known alkylating agent, induces congenital anomalies in fetuses when it is administered to pregnant animals. In previous studies, we reported that ENU induced apoptosis and growth arrest in fetal tissues and organs immediately after its administration to pregnant rats. In the present study, we investigated the histopathological changes of the placenta after ENU administration to pregnant rats on Day 13 of gestation (GD13) to obtain a clue for clarifying the role of the placenta in the process of fetal developmental disability induced by genotoxic stress. Apoptotic cells increased and DNA-replicating cells decreased in the trophoblastic cells in the placental labyrinth zone of the ENU-treated group by 3 h after treatment. The number of apoptotic cells peaked at 6 h after treatment and returned to control levels at 48 h after treatment. The number of DNA-replicating cells reached minimum levels at 6 h after treatment and returned to control levels at 48 h after treatment. By immunohistochemistry, p53-positive signals were observed in trophoblastic cells in the labyrinth zone of the ENU-treated group from 3 to 6 h after treatment. Significant decreases in fetal and placental weights were observed in the ENU-treated group at 2 days (GD15) and 8 days (GD21) after treatment. A reduction in the thickness of the labyrinth zone was histopathologically significant in the ENU-treated group. These results indicate that ENU induces apoptosis and growth arrest not only in fetal tissues, but also in trophoblastic cells in the rat placental labyrinth zone, and these placental changes may have roles in the induction of fetotoxicity and teratogenicity of ENU. Moreover, a possible involvement of p53 in the induction of apoptosis and growth arrest is suggested.

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  • Mechanisms of 5-azacytidine (5AzC)-induced toxicity in the rat foetal brain 査読

    M Ueno, KI Katayama, H Nakayama, K Doi

    INTERNATIONAL JOURNAL OF EXPERIMENTAL PATHOLOGY   83 ( 3 )   139 - 150   2002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:BLACKWELL PUBLISHING LTD  

    Mechanisms of 5-azacytidine (5AzC)-induced toxicity in the rat foetal brain were investigated. 5AzC (10 mg/kg) was injected into pregnant rats on day 13 of gestation and the protein and mRNA expressions of p53 and its transcriptional target genes, p21 , bax , cyclin G1 , fas , and gadd45 , were examined in the foetal brain. The number of p53-positive cells peaked at 9 h after treatment (HAT) and those of apoptotic cells and p21-positive cells peaked at 12 HAT. The expressions of p21 , bax , cyclin G1 , and fas mRNAs were significantly elevated from 9 to 12 HAT. From the experiments using 5-bromo-2'-deoxyuridine (BrdU), as compared with controls, the migration of neuroepithelial cells significantly delayed and BrdU-positive signals were observed in many apoptotic cells from 9 to 24 HAT in the 5AzC-group. In addition, the number of S phase cells significantly decreased at 12 HAT. The present results indicate that 5AzC induced apoptosis and cell cycle arrest probably at G1 phase in the rat foetal brain and they might be mediated by p53 in response to DNA damage.

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  • Expression of ribosomal protein L4 (rpL4) during neurogenesis and 5-azacytidine (5AzC)-induced apoptotic process in the rat 査読

    Masaki Ueno, H. Nakayama, S. Kajikawa, K. Katayama, K. Suzuki, K. Doi

    Histology and Histopathology   17 ( 3 )   789 - 798   2002年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    5-Azacytidine (5AzC) induces neuronal apoptosis in rat and mouse fetuses. 5AzC also induces apoptosis in undifferentiated PC12 cells, and ribosomal protein L4 (rpL4) mRNA expression increases prior to apoptosis. To clarify the roles of rpL4 during neurogenesis, we first examined the distribution of rpL4 mRNA in the developing rat brain by in situ hybridization and RT-PCR, and compared the results to the distribution of TUNEL- or PCNA-positive cells. rpL4 mRNA expression was strong in the ventricular zone (VZ), subventricular zone (SVZ), cortical plate (CP), cerebral cortex, granule cell layer (GCL), pyramidal cell layer (Py) and external granular layer (EGL) during embryonic and early postnatal days, and it was remarkably weakened thereafter. A lot of PCNA-positive cells were observed in VZ, SVZ, and EGL during embryonic and early postnatal days, and such distribution of PCNA-positive cells was almost identical to rpL4 mRNA distribution. Only few TUNEL-positive cells were observed in VZ, SVZ, cerebral cortex, EGL, and hippocampus during embryonic and early postnatal days, and the regions with TUNEL-positive cells were not identical to rpL4 mRNA distribution. Next, the changes of rpL4 mRNA expression in the brain of 5AzC-treated rat fetuses were examined by in situ hybridization and RT-PCR. Apoptotic cells appeared at 9 to 24 hours after treatment (HAT). However, the rpL4 mRNA expression was unchanged during the apoptotic process. From the results, it is suggested that rpL4 would have certain roles in cell proliferation and differentiation during neurogenesis, but have no roles in 5AzC-induced apoptosis in the fetal brain.

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  • 脊髄損傷にともなう自律神経の病態と回路再建 招待 査読

    上野将紀

    自律神経   60 ( 3 )   110 - 114   2023年9月

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    担当区分:筆頭著者   記述言語:日本語   掲載種別:記事・総説・解説・論説等(学術雑誌)  

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  • 脳損傷における自発的・継続的な運動は加齢で低下する概日リズムと神経修復力を高める 招待 査読

    田中貴士, 浦大樹, 前田拓哉, 柳田寧々, 三次恭平, 古木ほたる, 上野将紀

    基礎理学療法学   advpub   2023年7月

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    担当区分:最終著者   記述言語:日本語   出版者・発行元:一般社団法人 日本基礎理学療法学会  

    脳が損傷を受けると重篤な機能障害が生じる。脳損傷患者の多くは高齢者であるが,高齢なモデル動物を用いた研究はほとんど進んでいない。本研究では,高齢期の脳損傷モデルマウスにおいて,自発的かつ継続的な走行運動がもたらす皮質脊髄路の神経発芽や運動回復への効果を検証した。高齢マウスでは,若齢期にみられる脳損傷後の脊髄内での皮質脊髄路の発芽が生じず,運動機能が回復しない一方,自発的運動が発芽を増大させることが明らかになった。また,高齢期における脳損傷前後の運動が誘発する運動野の遺伝子変化を網羅的に解析した結果,運動群では概日時計関連遺伝子が増加することが示された。さらに,自発的運動の継続が高齢マウスの昼夜の活動リズムを若齢期に類似したパターンに回復させることも明らかになった。自発的かつ継続的な運動は,加齢により乱れる概日リズムを調整し,失われていた脳損傷後の神経修復力を回復させる可能性が示された。

    DOI: 10.24780/jjptf.jjptf_2023-06

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  • 脳脊髄液接触ニューロン 脳脊髄液センサーとしての可能性を探る 招待

    中村 由香, 上野 将紀

    細胞   55 ( 5 )   308 - 312   2023年4月

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    担当区分:最終著者, 責任著者   記述言語:日本語   出版者・発行元:(株)ニュー・サイエンス社  

    脳脊髄液接触ニューロン(Cerebrospinal Fluid-contacting Neurons:CSF-cNs)は,脊髄中心管に沿って存在し,樹状突起を脳脊髄液と接するユニークな神経細胞である。近年,ゼブラフィッシュやヤツメウナギでは,脳脊髄液のpHや構成成分を化学受容するとともに,脳脊髄液の流れや脊髄の動きを機械受容し,遊泳運動や姿勢を制御することが明らかになってきた。一方哺乳類では,CSF-cNsのもつ構造や接続,機能は多くが不明である。筆者らは,アデノ随伴ウイルスを脳室内投与すると,マウスのCSF-cNsを特異的に標識できることを偶然見出した。この手法は,遺伝学的な標識や活動操作を可能とする点で画期的であり,CSF-cNsが脊髄の前後軸に沿って回路網をつくり,歩行運動を制御することが明らかとなった。本稿では,この不思議な細胞の脳脊髄液/脊髄内センサーとしての役割を論じたい。(著者抄録)

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  • 中枢神経の障害にともなう皮質脊髄路の再編 招待

    井上 貴博, 上野 将紀

    神経心理学   39 ( 1 )   30 - 39   2023年3月

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    担当区分:最終著者, 責任著者   記述言語:日本語   出版者・発行元:日本神経心理学会  

    皮質脊髄路は随意運動の制御に重要な役割を果たしており,脳卒中や脊髄損傷などで損傷を受けると重篤な運動障害が引き起こされる.一方で,脳や脊髄には可塑性があり,失われた機能は時間を経て回復あるいは増悪するなどしばしば変容することが知られる.近年の研究成果から,こうした機能の変容は,障害をのがれた回路網の代償的なはたらきや再編に起因することが明らかとなりつつある.本総説では,げっ歯類の基礎研究から明らかになってきた皮質脊髄路の構造や機能,障害パターンに応じた再編様式について概説し,中枢神経障害後の回路再編と機能回復を促進しうる有望な治療アプローチと今後の課題について述べていく.(著者抄録)

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  • TDP-43 differentially propagates to induce degeneration in the motor circuit

    坪口晋太朗, 中村由香, 石原智彦, 加藤泰介, 佐藤時春, 小山哲秀, 森秀樹, 小池佑佳, 小野寺理, 小野寺理, 上野将紀

    Dementia Japan   37 ( 4 )   2023年

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  • TDP-43変異型により異なる病態進展特性の解析

    森秀樹, 坪口晋太朗, 佐藤時春, 中村由香, 加藤泰介, 須貝章弘, 小野寺理, 上野将紀

    Dementia Japan   37 ( 4 )   2023年

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  • リハビリテーションと分子標的の併用による脳損傷後の機能回復 招待

    田中 貴士, 上野 将紀

    基礎理学療法学   25 ( 1 )   43 - 49   2022年10月

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    担当区分:最終著者   記述言語:日本語   出版者・発行元:(一社)日本基礎理学療法学会  

    脳損傷はしばしば重篤な運動機能障害を引き起こし,自立した社会生活を困難にする。傷害された神経回路の再編は機能回復に重要であるが,成体の中枢神経における再編能力は限定的である。脳損傷後において,神経分子を標的とした治療やリハビリテーション等,様々なアプローチが試行されてきたが,未だ十分な機能回復は達成されていない。したがって,再編と機能回復を強化する新しいコンセプトの治療法が求められている。例えば我々は,神経軸索の伸長を阻害しているチロシン脱リン酸化酵素(src homology 2-containing phosphatase-1:以下,SHP-1)に着目し,遺伝学的なSHP-1の欠損と自発的運動の併用が脳損傷モデルマウスの神経回路の再編や機能回復を相乗的に高めることを報告してきた。本稿では,中枢神経損傷のモデル動物における神経回路の再編についての知見を整理し,リハビリテーションや分子標的がもたらす再編や機能回復への効果とその機序について概説する。(著者抄録)

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    その他リンク: https://search.jamas.or.jp/default/link?pub_year=2022&ichushi_jid=J07591&link_issn=&doc_id=20221220310006&doc_link_id=%2Fch1ufund%2F2022%2F002501%2F006%2F0043-0049%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fch1ufund%2F2022%2F002501%2F006%2F0043-0049%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

  • 脳・脊髄障害後の神経回路再編の可視化 招待

    佐藤時春, 上野将紀

    Clinical Neuroscience   40 ( 6 )   746 - 749   2022年6月

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    担当区分:最終著者, 責任著者   記述言語:日本語   掲載種別:記事・総説・解説・論説等(学術雑誌)  

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  • 中枢神経の障害がもたらす免疫系の変容と病態 招待

    上野将紀

    生体の科学   72 ( 5 )   409 - 411   2021年10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:記事・総説・解説・論説等(学術雑誌)  

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  • 中枢神経障害による免疫系の変容 招待

    上野将紀

    医学のあゆみ   277 ( 13 )   1104 - 1107   2021年6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:記事・総説・解説・論説等(学術雑誌)  

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  • 中枢神経障害による神経回路の再編と機能回復 招待

    上野将紀

    新潟医学会雑誌   134 ( 1 )   7 - 12   2020年12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:速報,短報,研究ノート等(学術雑誌)  

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  • 随意運動をになう神経回路の再建 〜基礎研究の現状と課題〜 招待

    上野将紀

    新潟県医師会報   842   2 - 7   2020年5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:記事・総説・解説・論説等(学術雑誌)  

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  • 動きを生み出す脳の仕組みと謎 招待

    上野将紀

    脳研コラム   2020年3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:記事・総説・解説・論説等(その他)  

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  • 脊髄損傷と自律神経-臓器-免疫連関 招待

    上野将紀

    実験医学   36 ( 3 )   370 - 376   2019年7月

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    記述言語:日本語   掲載種別:記事・総説・解説・論説等(学術雑誌)  

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  • 脳・脊髄の障害による神経‒免疫制御システムの破綻 招待

    上野将紀

    実験医学   36 ( 3 )   370 - 376   2018年1月

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    記述言語:日本語   掲載種別:記事・総説・解説・論説等(学術雑誌)  

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  • ミクログリアと脳発達 招待

    上野将紀

    Brain and Nerve   69 ( 9 )   985 - 997   2017年9月

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    記述言語:日本語   掲載種別:記事・総説・解説・論説等(学術雑誌)  

    Scopus

    PubMed

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  • 障害による神経回路の再編と機能の回復 招待 査読

    上野将紀

    ライフサイエンス領域融合レビュー   6   e003   2017年6月

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    記述言語:日本語   掲載種別:記事・総説・解説・論説等(商業誌、新聞、ウェブメディア)  

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  • 脊髄損傷後の自律神経回路の再編成による免疫機能低下のメカニズム 招待

    上野将紀, Phillip G Popovich, 吉田富

    実験医学   34 ( 14 )   2328 - 2331   2016年8月

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  • The brain immune network in spinal cord injury 招待

    Masaki Ueno, Toshihide Yamashita

    Neurodegenerative Disorders as Systemic Diseases   41 - 66   2015年1月

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    記述言語:英語   出版者・発行元:Springer Japan  

    Diseases or injuries in the central nervous system (CNS) often cause robust immune responses, which significantly affect the recovery process. Here we review recent knowledge about brain-immune system interactions, which occur during degenerative and reparative processes, and focus mainly on spinal cord injury (SCI). Immune system-brain inflammatory responses involve multiple cell types that originate in the bloodstream and reside in the brain. Studies indicate that these cells have bidirectional destructive and supportive effects on the repair of damaged neural tissue after SCI. These opposing roles likely depend on the types of cells and their state of activation. Further detailed investigations on the mechanisms and function of their interactions are required to ultimately reduce the toxicity and enhance the trophic effects of the immune system. This would lead to the development of novel strategies to enhance recovery after SCI. The recent discovery of neural circuits that directly regulate immune responses has further highlighted brain-immune system communication. In this regard, signals from the brain to the immune system should also be considered to understand the whole pathology of SCI. In this review, we aim to emphasize that cell-cell and system-system interactions are important concepts for understanding the complex reactions that occur in the degenerating CNS.

    DOI: 10.1007/978-4-431-54541-5_3

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  • 脳発達期においてミクログリアは大脳皮質第5層神経細胞の生存に寄与する

    上野将紀, 藤田幸, 山下俊英

    ライフサイエンス 新着論文レビュー   16 ( 5 )   543 - 551   2013年5月

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  • 研コミュ白書 第9回 UC-Tomorrow: シンシナティから発する明日のサイエンスへの光ー遥かなる上を目指してー

    山田宗茂, 合山進, 上野将紀, 佐々木敦朗

    細胞工学   32 ( 11 )   1174 - 1177   2013年

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    記述言語:日本語   出版者・発行元:学研メディカル秀潤社 ; 1982-  

    CiNii Article

    CiNii Books

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  • 脳損傷後の皮質脊髄路再編成におけるSHP-1シグナル抑制の効果

    田中貴士, 藤田幸, 上野将紀, 山下俊英, 田中貴士, 藤田幸, 上野将紀, 山下俊英

    理学療法学   39   2012年

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▶ 全件表示

共同研究・競争的資金等の研究

  • 化学遺伝学を用いた下降性疼痛抑制系の操作で慢性疼痛治療薬のシードを探す

    研究課題/領域番号:22H03167

    2022年4月 - 2026年3月

    制度名:科学研究費助成事業

    研究種目:基盤研究(B)

    提供機関:日本学術振興会

    紙谷 義孝, 佐々木 美佳, 倉部 美起, 大西 毅, 上野 将紀

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    配分額:16510000円 ( 直接経費:12700000円 、 間接経費:3810000円 )

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  • リハビリテーションが誘導する障害後の皮質脊髄路可塑性の分子基盤の解明

    研究課題/領域番号:21H05683

    2021年9月 - 2023年3月

    制度名:科学研究費助成事業

    研究種目:学術変革領域研究(A)

    提供機関:日本学術振興会

    上野 将紀

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    配分額:7800000円 ( 直接経費:6000000円 、 間接経費:1800000円 )

    リハビリテーションは、中枢神経障害後の機能回復の促進に広く用いられ、回路の可塑性と再編がその機序の根幹に存在することが示唆されている。しかし、リハビリテーションがどのように可塑性を高め、回路再編と機能回復を促すのか、その神経・分子基盤の理解は進んでいない。本研究では、運動によるリハビリテーションが、脳障害後に可塑性を誘導し、随意運動を担う皮質脊髄路の再編を引き起こすメカニズムを明らかにすることで、リハビリテーションによる回路再編と機能回復の分子神経基盤を解明することを目的とする。本年度はまず、Rose Bengalを用いた光血栓形成により、大脳皮質に梗塞を起こす脳障害モデルを確立し、残存した皮質脊髄路の回路網における再編様式の挙動を解析した。まず大脳皮質の各領野特異的に梗塞が起こった場合の再編様式を探索したところ、脳梗塞の起こる部位により皮質脊髄路が異なる様式で再編することが明らかとなった。さらに運動を一定時間行わせるリハビリテーションにより、脳梗塞後、皮質脊髄路の再編が促進されるかを解剖学的に解析した。その結果、運動リハビリテーションにより皮質脊髄路の軸索の伸長が増加し、再編が促進されることがわかった。さらに脳梗塞後、再編する回路網において誘導される遺伝子発現の変動を調べた。その結果、梗塞後、経時的に変動する遺伝子発現のデータを取得することができた。得られた成果は、リハビリテーションによる皮質脊髄路の再編機序の理解へつながるものと期待される。

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  • 自律神経調節による非アルコール性脂肪性肝疾患の治療への基盤研究

    研究課題/領域番号:21K19478

    2021年7月 - 2024年3月

    制度名:科学研究費助成事業

    研究種目:挑戦的研究(萌芽)

    提供機関:日本学術振興会

    寺井 崇二, 上村 顕也, 上野 将紀, 松井 秀彰

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    配分額:6500000円 ( 直接経費:5000000円 、 間接経費:1500000円 )

    本研究では、NASHにおける自律神経が繋ぐ多臓器連関の仕組みを解明し、その調節によってNASHの治療法を開発することを目的としている。
    今年度は、NASHの病態と自律神経が繋ぐ多臓器連関を解明するために、視床下部の4型メラノコルチン受容体(MC4R)のノックアウトマウス、高脂肪食給餌マウス、メチオニンコリン欠乏食給餌マウスをNASHモデルマウスとして、経時的な病態変化に伴う自律神経系のシグナル伝達と肝臓、脳、消化管における液性因子を検証した。
    また、多臓器の連関を検討する目的で、メダカ高脂肪食給餌によるNASHモデルでの心臓、腎臓での組織学的検証と種々の代謝経路を標的とした治療法による改善効果を検討し、自律神経経路を介したNASHの治療標的の検討を行った。

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  • 脳内修復におけるミクログリアによるタウ排泄機序の解明

    研究課題/領域番号:21K19441

    2021年7月 - 2024年3月

    制度名:科学研究費助成事業

    研究種目:挑戦的研究(萌芽)

    提供機関:日本学術振興会

    金澤 雅人, 田井中 一貴, 清水 宏, 上野 将紀

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    配分額:6240000円 ( 直接経費:4800000円 、 間接経費:1440000円 )

    認知症の原因となるタウ蛋白蓄積が生じる能血管障害モデルをもとに,タウ蓄積とその排泄に関して機序の解明を行う.脳血管障害に伴うタウ蛋白蓄積を解明することのみならず,その障害の基盤を解明する研究である.ミクログリアで,タウ蓄積を軽減し,認知機能を改善することができれば,高血圧,糖尿病,高脂血症治療薬を用いて,ミクログリアを保護的に修飾し,タウ排泄促進するかを検討する.これにて,ドラッグ・リポジショニングの応用が可能である.さらに,異常蛋白蓄積による神経変性疾患にも応用可能な提案であり,他の蛋白排泄機序の解明につながり,他の神経疾患研究にも展開する.

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  • 脳-脊髄をつなぐ運動性下行路再編の統合的解析

    研究課題/領域番号:21H02590

    2021年4月 - 2024年3月

    制度名:科学研究費助成事業

    研究種目:基盤研究(B)

    提供機関:日本学術振興会

    上野 将紀

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    配分額:17290000円 ( 直接経費:13300000円 、 間接経費:3990000円 )

    本研究では、脳障害後におこる、脳-脊髄をつなぐ運動下行路の再編様式を明らかにし、障害部位別に起こる再編のパターンとその機能を体系化することを目的とする。脳の障害は、神経回路を破綻させ、運動をはじめとする神経機能の低下をもたらす。一方、失われた機能は、自然回復あるいは増悪したりと変容することが知られ、この機能の変化は、障害から逃れ残存した神経回路の可塑的、代償的な変化により起こると近年示されている。申請者はこれまで、脳障害後に運動機能を担う下行路の1つである皮質脊髄路が再編することを見出し、残された神経の可塑的変化が、機能の回復を導く鍵となる現象であると示してきた。適切な回路の可塑性を増強し治療標的とするには、多様な脳障害部位に応じて再編し機能回復をもたらす神経回路の局在やその挙動の理解が求められており、本研究ではその体系化を試みる。本年度は、光血栓形成により任意の大脳皮質領域に梗塞を引き起こすモデルを確立し、障害を逃れた大脳皮質の残存領域から伸びる皮質脊髄路が脊髄で再編する様式の変化を解析した。これまでマウスでは、頸髄に投射する皮質脊髄路ニューロンは大脳皮質の大きく3ヶ所 (運動野(CFA,RFA),感覚野S1)に分布することを見出していることから、この各脳領域が障害されるモデルを確立した。これらのモデルのうち、広範に脳梗塞を起こした場合には、障害対側の皮質脊髄路が頸髄において出芽・伸長して再編することがわかった。一方、やや小型の脳梗塞(RFA+S1領域)を起こした場合には、障害同側の皮質脊髄路が再編することがわかった。さらに、見出した再編軸索の接続や機能を解析する実験にも取り組み、その接続様式や機能が見えはじめた。得られた成果は、脳障害後におこる運動下行路の再編様式と機序の理解へつながるものと期待される。

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  • 光遺伝学を利用した青斑核ニューロン制御による全身麻酔薬作用機序の解明

    研究課題/領域番号:21K08943

    2021年4月 - 2024年3月

    制度名:科学研究費助成事業

    研究種目:基盤研究(C)

    提供機関:日本学術振興会

    倉部 美起, 佐々木 美佳, 上野 将紀

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    配分額:4160000円 ( 直接経費:3200000円 、 間接経費:960000円 )

    全身麻酔薬の作用機序は現代においても未解明である。睡眠・覚醒と密接な関わりを持つ、“青斑核”を起始核とするノルアドレナリン(NA)ニューロンが全身麻酔時の意識消失や覚醒にも関与していると考えられているが、詳細は不明である。近年、青斑核ニューロンが一様ではなく、NAニューロン以外にGABA(gamma-Aminobutyric acid)ニューロンを含み、相互作用していることが明らかになったことから、GABAニューロンとNAニューロンとの相互の関係性が、全身麻酔薬の作用機序に大きく関与しているのではないかと考えた。そこで、全身麻酔時の青斑核NA/GABAニューロンの活動が果たす機能的役割とそれぞれの神経の相互関連性を、光遺伝学的手法を用いて解明することを目的とした。
    初年度は光遺伝学的手法の導入と確認を組織学的・生理学的両面から行った。青斑核NAニューロンを特異的に操作するために、NAニューロン特異的プロモーターPRSx8下でチャネルロドプシン・アーキロドプシンを発現するアデノ随伴ウイルスを作製し、C57BL/6マウス青斑核に脳定位固定装置を用いて投与した。免疫組織学的に、青斑核ニューロンに特異的に発現することを確認した。さらにこれらのマウスから青斑核スライス標本を作製し近赤外線
    微分干渉顕微鏡を用いて可視下にホールセルパッチクランプ記録を行った。NAニューロンは電流固定モード下で3~4Hzの活動電位を発していた。また、光刺激によって活動電位の発火頻度が増加あるいは減少することを確認した。
    これらの結果を基に、次年度はNA/GABAニューロン制御下に電気生理学解析を進め、無麻酔状態のマウスからの脳波・行動解析を行う予定である。

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  • 脳脊髄液を探知する神経回路の機能の解明

    研究課題/領域番号:20K21460

    2020年7月 - 2023年3月

    制度名:科学研究費助成事業

    研究種目:挑戦的研究(萌芽)

    提供機関:日本学術振興会

    上野 将紀

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    配分額:6500000円 ( 直接経費:5000000円 、 間接経費:1500000円 )

    本研究では、脳脊髄液に接する未知の細胞である脳脊髄液接触ニューロンのもつ細胞構造や神経回路網、機能の解明を目的に研究を進めている。本細胞は、脳脊髄液と接する特徴的な構造を有することから、脳内外の生体環境の情報を有する脳脊髄液の情報を感知し、中枢神経系の神経回路内へ伝達する重要な細胞群であることが想定される。しかし、その機能や実体はほとんどわかっていないのが現状である。本年度は、前年度までに確立した同ニューロンを蛍光標識などで可視化する方法を用いて、同ニューロンが構成している神経回路網の様式を解明する研究に取り組んだ。各種の遺伝子改変マウスや神経トレーサーを駆使して、多様に存在する脊髄ニューロン種との接続様式の解析を進めた。解剖・組織学的な実験を進めた結果、同ニューロンは、特定の脊髄ニューロンとシナプス接続をしている可能性を見出した。一部の接続は、電子顕微鏡を用いた観察によっても確かめられた。次に、同ニューロンやその回路網が持っている機能を探索する研究への展開を試みた。そのため、同ニューロンの選択的な除去や神経活動の操作をすることにより、機能を特異的に阻害する方法の検討を行った。検討を行った中、一部の方法を用いることにより、同ニューロンの機能を阻害できる可能性を見出した。この方法論は、同ニューロンの機能の解明を目指した研究へ有用になると考えられる。ここで得られた成果は、生体-神経をつなぐ新たな細胞・生体メカニズムの理解へ貢献すると期待される。

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  • 高齢期の認知機能におけるチロシン脱リン酸化酵素SHP-1の機能解析

    研究課題/領域番号:20K11222

    2020年4月 - 2024年3月

    制度名:科学研究費助成事業

    研究種目:基盤研究(C)

    提供機関:日本学術振興会

    田中 貴士, 加藤 伸郎, 上野 将紀

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    配分額:4420000円 ( 直接経費:3400000円 、 間接経費:1020000円 )

    アルツハイマー型認知症に対する有効な治療法は未だ確立されていない。認知症の改善のためには、海馬における神経新生を増加させること、脳に蓄積したアミロイドβなどの代謝廃棄物の除去を促すこと、の2点が重要である。本研究で着目しているチロシン脱リン酸化酵素(SHP-1)は、神経新生やミクログリアによる代謝廃棄物の貪食を阻害することが報告されている。そこで、SHP-1の抑制がアルツハイマー病の予防・改善に有効であるのではないかと仮説を立て、研究を進めている。
    本研究で用いるアルツハイマー型認知症マウスは、成長早期から脳内にアミロイドβの顕著な蓄積がみられ、認知症を示すマウスである。アルツハイマー型認知症マウスとSHP-1欠損マウスを交配させることで、SHP-1が減少したアルツハイマー型認知症マウスを作製し、20月齢まで成長させた。このマウスにおいて、脳内のアミロイドβの蓄積をタンパク質及び組織学的に解析した結果、特に海馬におけるアミロイドβの蓄積が緩和され、認知機能の低下が改善されるデータを積み重ねることができている。また、SHP-1欠損のアルツハイマー型認知症マウスの海馬における神経新生の評価を開始しており、統計学的な解析を進めているところである。

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  • 特定神経ネットワークの人工的制御技術を駆使した全身麻酔薬の作用機序の解明

    研究課題/領域番号:19K22652

    2019年6月 - 2022年3月

    制度名:科学研究費助成事業

    研究種目:挑戦的研究(萌芽)

    提供機関:日本学術振興会

    紙谷 義孝, 佐々木 美佳, 倉部 美起, 上野 将紀

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    配分額:6240000円 ( 直接経費:4800000円 、 間接経費:1440000円 )

    本研究の目的は、化学遺伝学的手法を用いて青斑核ノルアドレナリン(NA)神経を制御し、NA神経の全身麻酔時の意識消失・覚醒に果たす役割を明らかにすることである。アデノ随伴ウイルス(AAV1-PRSx8-hM3Dq-HA)を作製し、青斑核NA神経を特異的に制御可能なラットを作製した。NA神経活性化によって揮発性麻酔薬による麻酔導入・覚醒時間はわずかに変化するのみであったが、静脈麻酔薬による麻酔導入・覚醒時間は著明に変化した。さらにfree moving下で電気生理学的解析・脳波解析を行う手法を確立し、NA神経制御下に記録を行うことが可能となった。

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  • 脳-腸-肝ネットワークによる新規肝再生治療法の開発

    研究課題/領域番号:18K19537

    2018年6月 - 2020年3月

    制度名:科学研究費助成事業

    研究種目:挑戦的研究(萌芽)

    提供機関:日本学術振興会

    寺井 崇二, 上村 顕也, 上野 将紀

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    配分額:6240000円 ( 直接経費:4800000円 、 間接経費:1440000円 )

    本研究では肝障害モデルマウスを対象として、神経ネットワークによる消化管ホルモンの分泌、肝再生への影響、神経系を介したフィードバック機構による肝再生シグナルの制御機構を解明することを課題とした。経シナプスウィルストレーサーによる肝障害に関与する自律神経ネットワークの可視化に成功し、化学遺伝学的手法による腸、肝を結ぶ脳神経経路の活動の特異的な促進あるいは抑制により、肝障害時に神経ネットワークを介して活性化する消化管ホルモンの動態を解明できた。

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  • 神経細胞種間を結ぶ脳内機能モジュールの解析手法の開発

    研究課題/領域番号:17K19443

    2017年6月 - 2021年3月

    制度名:科学研究費助成事業

    研究種目:挑戦的研究(萌芽)

    提供機関:日本学術振興会

    上野 将紀

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    配分額:6500000円 ( 直接経費:5000000円 、 間接経費:1500000円 )

    本研究では、神経回路内にある特定の神経細胞同士の接続で構成される内在回路が、どのような接続パターンを持ち、機能に貢献するのか解析を可能とする神経回路解析技術を開発し、その適用を試みることを目的とした。本研究の結果、マウス生体内の特定の神経細胞のシナプスや細胞内小器官の標識、1神経細胞の標識、神経細胞の活動の操作、神経細胞の除去、神経活動の検知、発現分子の機能解析、を可能とするツールを作製でき、神経回路の解析へ適用できることがわかった。この神経の標識や操作を可能とする解析技術のライブラリーは、特定の神経細胞種同士の接続や機能の解明へ大きく貢献すると期待される。

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  • 脳障害による神経回路の再編メカニズムの解明

    研究課題/領域番号:17H04985

    2017年4月 - 2021年3月

    制度名:科学研究費助成事業

    研究種目:若手研究(A)

    提供機関:日本学術振興会

    上野 将紀

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    配分額:23660000円 ( 直接経費:18200000円 、 間接経費:5460000円 )

    外傷や血管障害など中枢神経の障害では、障害から逃れ残存した神経回路が可塑的に再編し、機能を変容させうることがわかってきたが、その実体の理解が進んでいない。本研究では、随意運動を担う皮質脊髄路を対象に、健常時と障害時における回路構造と形成機序、機能を探索し、障害後に起こる回路の再編機序を明らかにすることを目的とした。まず健常時には、皮質脊髄路が多様な内在回路から成り立ち機能することを見出した。さらに脳脊髄の障害時には、残存した皮質脊髄路の軸索が再編する様式と、軸索伸長を促進する標的分子や方法論を見出した。以上から、中枢神経障害後の神経回路の再編機序とそれらを促進する方法論を明らかにした。

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  • 脳障害後の神経回路再編促進モデルによる回路シフトの解析

    研究課題/領域番号:17H05556

    2017年4月 - 2019年3月

    制度名:科学研究費助成事業

    研究種目:新学術領域研究(研究領域提案型)

    提供機関:日本学術振興会

    上野 将紀

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    配分額:7020000円 ( 直接経費:5400000円 、 間接経費:1620000円 )

    脳において神経の軸索の伸長や再生が起こりにくい大きな要因に、①軸索の周囲環境に存在する軸索伸長阻害因子(外的要因)、②軸索伸長をうながす神経細胞内シグナルの枯渇(内的要因)、の2つが示されている。本研究では、これらの外的、内的要因を取り除くことが可能な遺伝子改変マウスによって、障害後の運動回路の再編や機能の回復を促進することができるか検証することを目的とする。特に、大脳皮質と脊髄をつなぎ自発的あるいは巧緻的な運動に必要とされる皮質脊髄路をターゲットとする。本年度は、外的、内的要因を標的としたシングル、ダブル、トリプルノックアウトマウスにおいて、皮質脊髄路の再編が促されるかどうかを検証するため、脊髄損傷モデルを構築した。皮質脊髄路の軸索を順行性神経トレーサーでラベルし、損傷後の軸索の伸長や退縮の度合いを評価した。その結果、外的要因を阻害したマウスでは、損傷による切断後の軸索の退縮が顕著に抑制された。一方、内的要因を克服したマウスでは、損傷による切断後の軸索の伸長が顕著に増加した。こうした変化が、回路の再編を促進するかを明らかにするため、経シナプス逆行性ウイルストレーサーを用いて、神経回路の接続解析を行った。その結果、これらのダブルノックアウトマウスにおいて、筋と大脳皮質を結ぶ回路の再編が増えることが明らかとなった。本研究の結果から、外的、内的要因は、神経回路の再生を阻む異なる過程に関わっていることがわかった。さらにこれらの要因を阻害することで、神経回路の再編を促進することが可能であることが示された。本研究の成果は、脳脊髄の障害に対し、外的、内的要因双方を標的として、機能回復をもたらす治療法の開発に貢献すると期待される。

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  • 中枢神経傷害における神経回路による恒常性機能の破綻と回復メカニズムの解明

    2013年10月 - 2017年3月

    制度名:さきがけ

    提供機関:科学技術振興機構

    上野将紀

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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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  • 脳損傷疾患における代償性神経回路の形成機序の解明

    研究課題/領域番号:21700381

    2009年4月 - 2011年3月

    制度名:科学研究費補助金(若手研究(B))

    研究種目:若手研究(B)

    提供機関:文部科学省

    上野将紀

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    担当区分:研究代表者  資金種別:競争的資金

    脳損傷は神経機能に重篤な障害を及ぼすが、その後機能は一定の自然回復を示す。本研究では、大脳皮質運動野の損傷後、残存した神経回路が新たな回路を形成して、障害された運動機能を自然回復させることをはじめて実証した。さらに、この新規神経回路形成に関わる一連の分子群(BDNF-TrkB、GABA、MAG/Nogo/OMgp-PirB、EphA4-EphrinB3)の働きを明らかにした。

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担当経験のある授業科目(researchmap)

  • 生理学(再生生理)

    2023年9月
    機関名:新潟大学

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  • 発生学

    機関名:大阪大学

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  • 神経解剖学

    機関名:大阪大学

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  • 神経と行動の科学

    機関名:東京大学

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  • 脳と心の医科学

    機関名:新潟大学

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  • ニューロサイエンスコース

    機関名:名古屋大学

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  • 先端医科学研究概説

    機関名:新潟大学

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担当経験のある授業科目

  • 先端医科学研究概説

    2023年
    -
    現在
    機関名:新潟大学