2022/12/01 更新

写真a

ナカムラ ユカ
中村 由香
Nakamura Yuka
所属
脳研究所 特任助手
職名
特任助手
外部リンク

代表的な業績

    • 【論文】 Olig2-Induced Semaphorin Expression Drives Corticospinal Axon Retraction After Spinal Cord Injury.  2020年10月

    • 【論文】 Corticospinal Circuits from the Sensory and Motor Cortices Differentially Regulate Skilled Movements through Distinct Spinal Interneurons.  2018年5月

    • 【論文】 Silencing spinal interneurons inhibits immune suppressive autonomic reflexes caused by spinal cord injury.  2016年6月

学位

  • 学士 ( 1999年3月 )

研究キーワード

  • 神経回路

  • 神経再生

研究分野

  • ライフサイエンス / 神経形態学

経歴

  • 新潟大学   脳研究所   特任助手

    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   特任助手

    2019年4月 - 2020年3月

 

論文

  • Modulation of Both Intrinsic and Extrinsic Factors Additively Promotes Rewiring of Corticospinal Circuits after Spinal Cord Injury. 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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  • Lesion Area in the Cerebral Cortex Determines the Patterns of Axon Rewiring of Motor and Sensory Corticospinal Tracts After Stroke. 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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  • Olig2-Induced Semaphorin Expression Drives Corticospinal Axon Retraction After Spinal Cord Injury. 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10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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  • Ghrelin-insulin-like growth factor-1 axis is activated via autonomic neural circuits in the non-alcoholic fatty liver disease. 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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  • NASHモデルマウスにおける自律神経系を介した消化管ホルモンの関与

    名古屋 拓郎, 上村 顕也, 井上 良介, 酒井 規裕, 後藤 諒, 高 昌良, 丹羽 佑輔, 坂牧 僚, 中村 由香, 上野 将紀, 寺井 崇二

    日本消化器病学会雑誌   115 ( 臨増大会 )   A732 - A732   2018年10月

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    記述言語:日本語   出版者・発行元:(一財)日本消化器病学会  

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

    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   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)  

    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.

    DOI: 10.1016/j.celrep.2018.03.137

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  • Silencing spinal interneurons inhibits immune suppressive autonomic reflexes caused by spinal cord injury. 国際誌

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

    Nature neuroscience   19 ( 6 )   784 - 7   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)  

    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.

    DOI: 10.1038/nn.4289

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  • Erratum: Ecto-domain phosphorylation promotes functional recovery from spinal cord injury(Scientific Reports 4(4972) 10.1038/srep04972) 査読

    Kenji Suehiro, Yuka Nakamura, Shuai Xu, Youichi Uda, Takafumi Matsumura, Yoshiaki Yamaguchi, Hitoshi Okamura, Toshihide Yamashita, Yoshinori Takei

    Scientific Reports   5   2015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:Nature Publishing Group  

    DOI: 10.1038/srep11780

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  • Ecto-domain phosphorylation promotes functional recovery from spinal cord injury. 国際誌

    Kenji Suehiro, Yuka Nakamura, Shuai Xu, Youichi Uda, Takafumi Matsumura, Yoshiaki Yamaguchi, Hitoshi Okamura, Toshihide Yamashita, Yoshinori Takei

    Scientific reports   4   4972 - 4972   2014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)  

    Inhibition of Nogo-66 receptor (NgR) can promote recovery following spinal cord injury. The ecto-domain of NgR can be phosphorylated by protein kinase A (PKA), which blocks activation of the receptor. Here, we found that infusion of PKA plus ATP into the damaged spinal cord can promote recovery of locomotor function. While significant elongation of cortical-spinal axons was not detectable even in the rats showing enhanced recovery, neuronal precursor cells were observed in the region where PKA plus ATP were directly applied. NgR1 was expressed in neural stem/progenitor cells (NSPs) derived from the adult spinal cord. Both an NgR1 antagonist NEP1-40 and ecto-domain phosphorylation of NgR1 promote neuronal cell production of the NSPs, in vitro. Thus, inhibition of NgR1 in NSPs can promote neuronal cell production, which could contribute to the enhanced recovery of locomotor function following infusion of PKA and ATP.

    DOI: 10.1038/srep04972

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  • Layer V cortical neurons require microglial support for survival during postnatal development. 国際誌

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

    Nature neuroscience   16 ( 5 )   543 - 51   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.

    DOI: 10.1038/nn.3358

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

    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.

    DOI: 10.1016/j.neures.2011.07.1830

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  • RGMa modulates T cell responses and is involved in autoimmune encephalomyelitis. 国際誌

    Rieko Muramatsu, Takekazu Kubo, Masahiro Mori, Yuka Nakamura, Yuki Fujita, Tsugio Akutsu, Tatsusada Okuno, Junko Taniguchi, Atsushi Kumanogoh, Mari Yoshida, Hideki Mochizuki, Satoshi Kuwabara, Toshihide Yamashita

    Nature medicine   17 ( 4 )   488 - 94   2011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)  

    In multiple sclerosis, activated CD4(+) T cells initiate an immune response in the brain and spinal cord, resulting in demyelination, degeneration and progressive paralysis. Repulsive guidance molecule-a (RGMa) is an axon guidance molecule that has a role in the visual system and in neural tube closure. Our study shows that RGMa is expressed in bone marrow-derived dendritic cells (BMDCs) and that CD4(+) T cells express neogenin, a receptor for RGMa. Binding of RGMa to CD4(+) T cells led to activation of the small GTPase Rap1 and increased adhesion of T cells to intracellular adhesion molecule-1 (ICAM-1). Neutralizing antibodies to RGMa attenuated clinical symptoms of mouse myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) and reduced invasion of inflammatory cells into the CNS. Silencing of RGMa in MOG-pulsed BMDCs reduced their capacity to induce EAE following adoptive transfer to naive C57BL/6 mice. CD4(+) T cells isolated from mice treated with an RGMa-specific antibody showed diminished proliferative responses and reduced interferon-γ (IFN-γ), interleukin-2 (IL-2), IL-4 and IL-17 secretion. Incubation of PBMCs from patients with multiple sclerosis with an RGMa-specific antibody reduced proliferative responses and pro-inflammatory cytokine expression. These results demonstrate that an RGMa-specific antibody suppresses T cell responses, and suggest that RGMa could be a promising molecular target for the treatment of multiple sclerosis.

    DOI: 10.1038/nm.2321

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  • Paired immunoglobulin-like receptor B knockout does not enhance axonal regeneration or locomotor recovery after spinal cord injury. 国際誌

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

    The Journal of biological chemistry   286 ( 3 )   1876 - 83   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)  

    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 wild-type 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 knock-out is not sufficient to induce extensive axonal regeneration after spinal cord injury.

    DOI: 10.1074/jbc.M110.163493

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  • Peptides derived from repulsive guidance molecule act as antagonists. 国際誌

    Masayoshi Suda, Katsuhiko Hata, Aika Sawada, Yuka Nakamura, Takekazu Kubo, Atsushi Yamaguchi, Toshihide Yamashita

    Biochemical and biophysical research communications   371 ( 3 )   501 - 4   2008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)  

    Repulsive guidance molecule (RGM) is a membrane-bound protein that was originally identified as an axon guidance molecule in the visual system [T. Yamashita, B.K. Mueller, K. Hata, Neogenin and RGM signaling in the central nervous system, Curr. Opin. Neurobiol. 17 (2007) 29-34]. Functional studies in Xenopus and chick embryos have revealed the roles of RGM in axon guidance and laminar patterning, while those in mouse embryos have demonstrated its function in regulating the cephalic neural tube closure. Importantly, RGM inhibition enhanced the growth of injured axons and promoted functional recovery after spinal cord injury in rats. Here, we identified two RGMa-derived peptides that functioned as antagonists against RGMa. The peptides studied in vitro dose-dependently suppressed the neurite growth inhibition and growth cone collapse induced by RGMa. Thus, these peptides are promising reagents to treat injuries of the central nervous system.

    DOI: 10.1016/j.bbrc.2008.04.114

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