Updated on 2022/05/13

写真a

 
WAKE Hiroaki
 
Organization
Graduate School of Medicine Program in Integrated Medicine Anatomy and Cell Biology Professor
Graduate School
Graduate School of Medicine
Undergraduate School
School of Medicine Department of Medicine
Title
Professor

Degree 1

  1. 医学博士 ( 2007.3   名古屋市立大学 ) 

Research Interests 6

  1. 脳梗塞

  2. 神経-グリア相関

  3. 生体

  4. ミクログリア

  5. シナプス

  6. 2光子励起顕微鏡

Research Areas 5

  1. Life Science / Clinical pharmacy

  2. Life Science / Neuroscience-general

  3. Life Science / Neuroscience-general

  4. Life Science / Neuroscience-general

  5. Life Science / Physiology

Research History 2

  1. Nagoya University   Professor

    2019.11

  2. Kobe University   Graduate School of Medicine   Professor

    2016.4 - 2019.10

Education 1

  1. 名古屋市立大学 大学院医学研究科博士課程生体情報機能制御医学専攻修了

    - 2007.3

Awards 1

  1. 神戸大学優秀若手研究賞・学長賞

    2017   神戸大学   高次脳機能の解明と操作に光を当てる

    WAKE HIROAKI

 

Papers 36

  1. Lighting up cosmic neuronal networks with transformative in vivo calcium imaging.

    Murayama M, Wake H

    Neuroscience research     2022.4

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    DOI: 10.1016/j.neures.2022.04.007

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  2. Elucidation of the neurological effects of clothianidin exposure at the no-observed-adverse-effect level (NOAEL) using two-photon microscopy <i>in vivo</i> imaging

    NISHI Misaki, SUGIO Shouta, HIRANO Tetsushi, KATO Daisuke, WAKE Hiroaki, SHODA Asuka, MURATA Midori, IKENAKA Yoshinori, TABUCHI Yoshiaki, MANTANI Youhei, YOKOYAMA Toshifumi, HOSHI Nobuhiko

    Journal of Veterinary Medical Science   Vol. 84 ( 4 ) page: 585 - 592   2022.4

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    Language:English   Publisher:JAPANESE SOCIETY OF VETERINARY SCIENCE  

    DOI: 10.1292/jvms.22-0013

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  3. Ca<sup>2+</sup> imaging with two-photon microscopy to detect the disruption of brain function in mice administered neonicotinoid insecticides.

    Hirai A, Sugio S, Nimako C, Nakayama SMM, Kato K, Takahashi K, Arizono K, Hirano T, Hoshi N, Fujioka K, Taira K, Ishizuka M, Wake H, Ikenaka Y

    Scientific reports   Vol. 12 ( 1 ) page: 5114   2022.3

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    Neonicotinoid pesticides are a class of insecticides that reportedly have harmful effects on bees and dragonflies, causing a reduction in their numbers. Neonicotinoids act as neuroreceptor modulators, and some studies have reported their association with neurodevelopmental disorders. However, the precise effect of neonicotinoids on the central nervous system has not yet been identified. Herein, we conducted in vivo Ca2+ imaging using a two-photon microscope to detect the abnormal activity of neuronal circuits in the brain after neonicotinoid application. The oral administration of acetamiprid (ACE) (20 mg/kg body weight (BW) in mature mice with a quantity less than the no-observed-adverse-effect level (NOAEL) and a tenth or half of the median lethal dose (LD50) of nicotine (0.33 or 1.65 mg/kg BW, respectively), as a typical nicotinic acetylcholine receptor (nAChR) agonist, increased anxiety-like behavior associated with altered activities of the neuronal population in the somatosensory cortex. Furthermore, we detected ACE and its metabolites in the brain, 1 h after ACE administration. The results suggested that in vivo Ca2+ imaging using a two-photon microscope enabled the highly sensitive detection of neurotoxicant-mediated brain disturbance of nerves.

    DOI: 10.1038/s41598-022-09038-7

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  4. A Piezo1/KLF15/IL-6 axis mediates immobilization-induced muscle atrophy.

    Hirata Y, Nomura K, Kato D, Tachibana Y, Niikura T, Uchiyama K, Hosooka T, Fukui T, Oe K, Kuroda R, Hara Y, Adachi T, Shibasaki K, Wake H, Ogawa W

    The Journal of clinical investigation     2022.3

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    DOI: 10.1172/JCI154611

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  5. Construction of a Multidimensional Brain andBiological Imaging Center for the Creation of a Healthy Society andInternational Collaboration

    Hiroaki Wake

    Proceedings for Annual Meeting of The Japanese Pharmacological Society   Vol. 95 ( 0 ) page: 2-S17-2   2022

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    Language:Japanese   Publisher:Japanese Pharmacological Society  

    DOI: 10.1254/jpssuppl.95.0_2-s17-2

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  6. Microglial function for synapses and vessels in physiological and pathological brain

    Hiroaki Wake

    Proceedings for Annual Meeting of The Japanese Pharmacological Society   Vol. 95 ( 0 ) page: 3-S31-3   2022

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    Language:Japanese   Publisher:Japanese Pharmacological Society  

    DOI: 10.1254/jpssuppl.95.0_3-s31-3

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  7. Holographic microscope and its biological application. International journal

    Xiangyu Quan, Daisuke Kato, Vincent Daria, Osamu Matoba, Hiroaki Wake

    Neuroscience research     2021.11

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    Holographic structured illumination combined with optogenetics enables patterned stimulation of neurons and glial cells in an intact living brain. Moreover, in vivo functional imaging of cellular activity with recent advanced microscope technologies allows for visualization of the cellular responses during learning, emotion and cognition. Integrating these techniques can be used to verify the link between cell function and behavior output. However, there are technical limitations to stimulate multiple cells with high spatial and temporal resolution with available techniques of optogenetic stimulation. Here, we summarized a two-photon microscope combined with holographic system to stimulate multiple cells with high spatial and temporal resolution for living mice and their biological application.

    DOI: 10.1016/j.neures.2021.10.012

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  8. [Microglial Regulation of Blood Brain Barrier, the Neuro-Immunological Interface].

    Ako Ikegami, Hiroaki Wake

    Brain and nerve = Shinkei kenkyu no shinpo   Vol. 73 ( 8 ) page: 913 - 919   2021.8

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    The central nervous system (CNS) is an immune-privileged area. The blood-brain barrier (BBB) is thought to separate the CNS from any systemic inflammatory states to maintain homeostasis within this specialized, vulnerable organ. However, accumulating studies have challenged this concept by demonstrating systemic inflammatory effects on brain. Moreover, the coronavirus disease pandemic caused by severe acute respiratory syndrome coronavirus 2 in 2019 has rapidly evoked attention toward the BBB as the systemic-CNS immunological interface. In this review, we focus on microglia, the sole immune cells in the CNS, and briefly introduce our new findings regarding microglial BBB regulation in systemic inflammation. With a close eye on associated literature, we carefully rethink the traditional immune system in the CNS and suggest a new possible mechanism of systemic-CNS immune cell interaction, while an understanding of the BBB develops.

    DOI: 10.11477/mf.1416201861

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  9. [A New Outlook on Mental Disorders: Pathological Dynamics of Glial Cells].

    Yuko Arioka, Daisuke Kato, Hiroaki Wake, Norio Ozaki

    Brain and nerve = Shinkei kenkyu no shinpo   Vol. 73 ( 7 ) page: 787 - 794   2021.7

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    The pathophysiology of mental disorders remains unknown. This causes many gaps in pathophysiology, diagnosis, and treatment of mental disorders. To close these gaps, a new perspective, which is not bound by the existing diagnostic classifications or pathological hypotheses for mental disorders, is required. Recently, it has been reported that glial cells play active roles in normal brain function and circuit formation, and their disruption results in the onset of mental disorders. Here, we discuss mental disorders from the perspective of glial cell-related pathophysiology, along with our current efforts and research.

    DOI: 10.11477/mf.1416201836

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  10. Myelin plasticity modulates neural circuitry required for learning and behavior. International journal

    Daisuke Kato, Hiroaki Wake

    Neuroscience research   Vol. 167   page: 11 - 16   2021.6

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    Oligodendrocytes, which form the myelin sheaths that insulate axons, regulate conduction velocity. Myelinated axons make up the brain's white matter and contribute to the efficiency of information processing by regulating the timing of neural activity. Traditionally, it has been thought that myelin is a static, inactive insulator around the axon. However, recent studies in humans using magnetic resonance imaging have shown that structural changes in the white matter occur during learning and training, suggesting that 1) white matter change depends on neural activity and 2) activity-dependent changes in white matter are essential for learning and behavior. Furthermore, suppression of oligodendrocytes and their progenitor cells leads to deficits in motor learning and remote fear memory consolidation, suggesting a causal relationship between glial function and the learning process. However, for technical reasons, it remains unclear how myelin-generating glia modulate neural circuitry and what underlying mechanisms they employ to affect learning and behavior. Recent advances in optical and genetic techniques have helped elucidate this mechanism. In this review, we highlight evidence that neural activities regulated by myelin plasticity play a pivotal role in learning and behavior and provide further insight into possible therapeutic targets for treating diseases accompanied by myelin impairment.

    DOI: 10.1016/j.neures.2020.12.005

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  11. Pain induces stable, active microcircuits in the somatosensory cortex that provide a therapeutic target International journal

    Takuya Okada, Daisuke Kato, Yuki Nomura, Norihiko Obata, Xiangyu Quan, Akihito Morinaga, Hajime Yano, Zhongtian Guo, Yuki Aoyama, Yoshihisa Tachibana, Andrew J. Moorhouse, Osamu Matoba, Tetsuya Takiguchi, Satoshi Mizobuchi, Hiroaki Wake

    Science Advances   Vol. 7 ( 12 ) page: eabd8261 - eabd8261   2021.3

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:American Association for the Advancement of Science (AAAS)  

    Sustained neuropathic pain from injury or inflammation remains a major burden for society. Rodent pain models have informed some cellular mechanisms increasing neuronal excitability within the spinal cord and primary somatosensory cortex (S1), but how activity patterns within these circuits change during pain remains unclear. We have applied multiphoton in vivo imaging and holographic stimulation to examine single S1 neuron activity patterns and connectivity during sustained pain. Following pain induction, there is an increase in synchronized neuronal activity and connectivity within S1, indicating the formation of pain circuits. Artificially increasing neuronal activity and synchrony using DREADDs reduced pain thresholds. The expression of N-type voltage-dependent Ca<sup>2+</sup> channel subunits in S1 was increased after pain induction, and locally blocking these channels reduced both the synchrony and allodynia associated with inflammatory pain. Targeting these S1 pain circuits, via inhibiting N-type Ca<sup>2+</sup> channels or other approaches, may provide ways to reduce inflammatory pain.

    DOI: 10.1126/sciadv.abd8261

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  12. Novel in vivo imaging method to evaluate "Don't eat me" signal of tumor against microglia Reviewed International journal

    Tsuji Takahiro, Wake Hiroaki, Shindo Mariko, Yamazoe Masatoshi, Ajimizu Hitomi, Yasuda Yuto, Funazo Tomoko, Yoshida Hironori, Sakamori Yuichi, Kim Young Hak, Katoh Daisuke, Ozasa Hiroaki, Hirai Toyohiro

    CANCER SCIENCE   Vol. 112   page: 193 - 193   2021.2

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  13. Detection of brain function disruption caused by nicotinic acetylcholine receptor agonists using Ca<sup>2+</sup> imaging with two-photon microscopy

    HIRAI Anri, SUGIO Shouta, NIMAKO Collins, NAKAYAMA Shouta M.M., KATO Keisuke, TAKAHASHI Keisuke, ARIZONO Koji, HIRANO Tetsushi, HOSHI Nobuhiko, FUJIOKA Kazutoshi, TAIRA Kumiko, ISHIZUKA Mayumi, WAKE Hiroaki, IKENAKA Yoshinori

    Annual Meeting of the Japanese Society of Toxicology   Vol. 48.1 ( 0 ) page: P-37E   2021

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    Language:Japanese   Publisher:The Japanese Society of Toxicology  

    <p>Neonicotionoid pesticides are insecticides which have been thought to be one of the causes of Colony Collapse Disorder. They were considered to be less toxic to mammals than insects, but some of the recent studies suggested their association with disruption of higher brain fuction in mammals. Nevertheless, it is still unclear how neonicotionoids affect on the central nervous system. Here, we propose the use of in vivo Ca<sup>2+</sup> imaging with two-photon microscope to detect abnormal activity of neuronal circuits in brain with the application of neonicotionoids.</p><p>In this study, a less than the no-observed-adverse-effect level (NOAEL) of acetamiprid (20 mg/kg bw); and a tenth or half of the median lethal doses of nicotine (0.33 or 1.65 mg/kg bw respectively) were orally administered to mice. They were subjected to elevated plus maze test and Ca<sup>2+</sup> imaging by two-photon microscope in the somatosensory cortex. We further detected acetamiprid and metabolites in brain and blood an hour after the administration.</p><p>Mice exposed to acetamiprid or nicotine exhibited an increase in anxiety-like behavior that associated with the altered activities of the neuronal population in the somatosensory cortex. Although the dose of acetamiprid used in the current study was below the NOAEL, both acetamiprid and nicotine affected the behavior and the neuronal activity in the somatosensory cortex. The results suggested that in vivo Ca<sup>2+</sup> imaging using two-photon microscope enabled highly sensitive detection of brain neurodisruption by neurotoxicants.</p>

    DOI: 10.14869/toxpt.48.1.0_p-37e

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  14. Maternal immune activation induces sustained changes in fetal microglia motility. Reviewed International journal

    Kana Ozaki, Daisuke Kato, Ako Ikegami, Akari Hashimoto, Shouta Sugio, Zhongtian Guo, Midori Shibushita, Tsuyako Tatematsu, Koichiro Haruwaka, Andrew J Moorhouse, Hideto Yamada, Hiroaki Wake

    Scientific reports   Vol. 10 ( 1 ) page: 21378 - 21378   2020.12

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    Maternal infection or inflammation causes abnormalities in brain development associated with subsequent cognitive impairment and in an increased susceptibility to schizophrenia and autism spectrum disorders. Maternal immune activation (MIA) and increases in serum cytokine levels mediates this association via effects on the fetal brain, and microglia can respond to maternal immune status, but consensus on how microglia may respond is lacking and no-one has yet examined if microglial process motility is impaired. In this study we investigated how MIA induced at two different gestational ages affected microglial properties at different developmental stages. Immune activation in mid-pregnancy increased IL-6 expression in embryonic microglia, but failed to cause any marked changes in morphology either at E18 or postnatally. In contrast MIA, particularly when induced earlier (at E12), caused sustained alterations in the patterns of microglial process motility and behavioral deficits. Our research has identified an important microglial property that is altered by MIA and which may contribute to the underlying pathophysiological mechanisms linking maternal immune status to subsequent risks for cognitive disease.

    DOI: 10.1038/s41598-020-78294-2

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  15. Negative feedback control of neuronal activity by microglia. Reviewed International journal

    Ana Badimon, Hayley J Strasburger, Pinar Ayata, Xinhong Chen, Aditya Nair, Ako Ikegami, Philip Hwang, Andrew T Chan, Steven M Graves, Joseph O Uweru, Carola Ledderose, Munir Gunes Kutlu, Michael A Wheeler, Anat Kahan, Masago Ishikawa, Ying-Chih Wang, Yong-Hwee E Loh, Jean X Jiang, D James Surmeier, Simon C Robson, Wolfgang G Junger, Robert Sebra, Erin S Calipari, Paul J Kenny, Ukpong B Eyo, Marco Colonna, Francisco J Quintana, Hiroaki Wake, Viviana Gradinaru, Anne Schaefer

    Nature   Vol. 586 ( 7829 ) page: 417 - +   2020.10

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    Microglia, the brain's resident macrophages, help to regulate brain function by removing dying neurons, pruning non-functional synapses, and producing ligands that support neuronal survival1. Here we show that microglia are also critical modulators of neuronal activity and associated behavioural responses in mice. Microglia respond to neuronal activation by suppressing neuronal activity, and ablation of microglia amplifies and synchronizes the activity of neurons, leading to seizures. Suppression of neuronal activation by microglia occurs in a highly region-specific fashion and depends on the ability of microglia to sense and catabolize extracellular ATP, which is released upon neuronal activation by neurons and astrocytes. ATP triggers the recruitment of microglial protrusions and is converted by the microglial ATP/ADP hydrolysing ectoenzyme CD39 into AMP; AMP is then converted into adenosine by CD73, which is expressed on microglia as well as other brain cells. Microglial sensing of ATP, the ensuing microglia-dependent production of adenosine, and the adenosine-mediated suppression of neuronal responses via the adenosine receptor A1R are essential for the regulation of neuronal activity and animal behaviour. Our findings suggest that this microglia-driven negative feedback mechanism operates similarly to inhibitory neurons and is essential for protecting the brain from excessive activation in health and disease.

    DOI: 10.1038/s41586-020-2777-8

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  16. ニコチン性アセチルコリン受容体アゴニストによるシグナル毒性と2光子顕微鏡を用いた検出手法の開発

    平井 杏梨, 杉尾 翔太, 池中 良徳, Collins Nimako, 中山 翔太, 星 信彦, 和氣 弘明, 石塚 真由美

    The Journal of Toxicological Sciences   Vol. 45 ( Suppl. ) page: S86 - S86   2020.6

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  17. Transient microglial absence assists postmigratory cortical neurons in proper differentiation. Reviewed International journal

    Yuki Hattori, Yu Naito, Yoji Tsugawa, Shigenori Nonaka, Hiroaki Wake, Takashi Nagasawa, Ayano Kawaguchi, Takaki Miyata

    Nature communications   Vol. 11 ( 1 ) page: 1631 - 1631   2020.4

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    In the developing cortex, postmigratory neurons accumulate in the cortical plate (CP) to properly differentiate consolidating subtype identities. Microglia, despite their extensive surveying activity, temporarily disappear from the midembryonic CP. However, the mechanism and significance of this absence are unknown. Here, we show that microglia bidirectionally migrate via attraction by CXCL12 released from the meninges and subventricular zone and thereby exit the midembryonic CP. Upon nonphysiological excessive exposure to microglia in vivo or in vitro, young postmigratory and in vitro-grown CP neurons showed abnormal differentiation with disturbed expression of the subtype-associated transcription factors and genes implicated in functional neuronal maturation. Notably, this effect is primarily attributed to interleukin 6 and type I interferon secreted by microglia. These results suggest that "sanctuarization" from microglia in the midembryonic CP is required for neurons to appropriately fine-tune the expression of molecules needed for proper differentiation, thus securing the establishment of functional cortical circuit.

    DOI: 10.1038/s41467-020-15409-3

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  18. YAP1 mediates survival of ALK-rearranged lung cancer cells treated with alectinib via pro-apoptotic protein regulation. Reviewed International journal

    Takahiro Tsuji, Hiroaki Ozasa, Wataru Aoki, Shunsuke Aburaya, Tomoko Yamamoto Funazo, Koh Furugaki, Yasushi Yoshimura, Masatoshi Yamazoe, Hitomi Ajimizu, Yuto Yasuda, Takashi Nomizo, Hironori Yoshida, Yuichi Sakamori, Hiroaki Wake, Mitsuyoshi Ueda, Young Hak Kim, Toyohiro Hirai

    Nature communications   Vol. 11 ( 1 ) page: 74 - 74   2020.1

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:Springer Science and Business Media {LLC}  

    Despite the promising clinical efficacy of the second-generation anaplastic lymphoma kinase (ALK) inhibitor alectinib in patients with ALK-rearranged lung cancer, some tumor cells survive and eventually relapse, which may be an obstacle to achieving a cure. Limited information is currently available on the mechanisms underlying the initial survival of tumor cells against alectinib. Using patient-derived cell line models, we herein demonstrate that cancer cells survive a treatment with alectinib by activating Yes-associated protein 1 (YAP1), which mediates the expression of the anti-apoptosis factors Mcl-1 and Bcl-xL, and combinatorial inhibition against both YAP1 and ALK provides a longer tumor remission in ALK-rearranged xenografts when compared with alectinib monotherapy. These results suggest that the inhibition of YAP1 is a candidate for combinatorial therapy with ALK inhibitors to achieve complete remission in patients with ALK-rearranged lung cancer.

    DOI: 10.1038/s41467-019-13771-5

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  19. Motor learning requires myelination to reduce asynchrony and spontaneity in neural activity. Reviewed International journal

    Daisuke Kato, Hiroaki Wake, Philip R Lee, Yoshihisa Tachibana, Riho Ono, Shouta Sugio, Yukio Tsuji, Yasuyo H Tanaka, Yasuhiro R Tanaka, Yoshito Masamizu, Riichiro Hira, Andrew J Moorhouse, Nobuaki Tamamaki, Kazuhiro Ikenaka, Noriyuki Matsukawa, R Douglas Fields, Junichi Nabekura, Masanori Matsuzaki

    Glia   Vol. 68 ( 1 ) page: 193 - 210   2020.1

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    Myelination increases the conduction velocity in long-range axons and is prerequisite for many brain functions. Impaired myelin regulation or impairment of myelin itself is frequently associated with deficits in learning and cognition in neurological and psychiatric disorders. However, it has not been revealed what perturbation of neural activity induced by myelin impairment causes learning deficits. Here, we measured neural activity in the motor cortex during motor learning in transgenic mice with a subtle impairment of their myelin. This deficit in myelin impaired motor learning, and was accompanied by a decrease in the amplitude of movement-related activity and an increase in the frequency of spontaneous activity. Thalamocortical axons showed variability in axonal conduction with a large spread in the timing of postsynaptic cortical responses. Repetitive pairing of forelimb movements with optogenetic stimulation of thalamocortical axon terminals restored motor learning. Thus, myelin regulation helps to maintain the synchrony of cortical spike-time arrivals through long-range axons, facilitating the propagation of the information required for learning. Our results revealed the pathological neuronal circuit activity with impaired myelin and suggest the possibility that pairing of noninvasive brain stimulation with relevant behaviors may ameliorate cognitive and behavioral abnormalities in diseases with impaired myelination.

    DOI: 10.1002/glia.23713

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  20. Signal toxicity caused by nicotinic acetylcholine receptor agonist and development of detection method using two-photon microscope

    HIRAI Anri, SUGIO Shouta, IKENAKA Yoshinori, COLLINS Nimako, NAKAYAMA Shouta M.M, HOSHI Nobuhiko, WAKE Hiroaki, ISHIZUKA Mayumi

    Annual Meeting of the Japanese Society of Toxicology   Vol. 47 ( 0 ) page: P - 4S   2020

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    Publisher:The Japanese Society of Toxicology  

    <p> By acting on receptors in the brain, some chemicals exhibit "signal toxicity" that disrupts intracellular and intercellular signaling, causing unexpected effects. In particular, in brain function, a complex signal network between neurons and glial cells is formed, and disruption of this network can be a critical endpoint of signal toxicity. However, "disruption of brain function" due to signal toxicity is often not accompanied by cell death and accompanying brain tissue degeneration, and cannot be detected by current neurotoxicity test methods. In this study, we used neonicotinoids (NNs) and nicotine, which are agonists of the nicotinic acetylcholine receptor (nAChR), as model compounds, and detected changes in neuronal activity in the somatosensory cortex using a two-photon microscope. The aim was to detect disruption of brain function associated with signal toxicity.</p><p> C57BL/6N were orally administered ACE at 20 mg/kg (with reference to LOAEL in general pharmacology test of the central nervous system) and their blood was collected over time. It was analyzed quantitatively using LC-MS/MS. Then, we exposed mice to ACE at 20 mg/kg or 7.1 mg/kg (with reference to NOAEL to rats), and their behavior was observed using openfield (OF) test 1 hour after the administration at the former concentration, and using elevated plus maze (EPM) test 1 hour after the administration at the latter concentration. In addition, C57BL/6J were administered ACE at 30 mg/kg (with reference to NOAEL in the subacute toxicity test) and Nicotine, which is the typical agonist of nAChR, at 1.6 mg/kg (with reference to 1/2 LD50), and the neuronal activity in somatosensory cortex was observed over time by using two-photon microscope. </p><p> As a result, ACE absorbed quickly and the Tmax of ACE was around 25 minutes after administration. In comparison, dm-ACE, which is one of its major metabolites, absorbed a bit slower and the Tmax was around 150 minutes. An hour after the administration, the activity of mice decreased, and the anxiety-like behavior increased. In the somatosensory cortex, the firing frequency of nerve cells decreased, and the synchronous firing increased, 1 hour and 2.5 hour after ACE administration. Similarly, the firing frequency tended to decrease, and the synchronous firing increased, 5 minutes and 30 minutes after the administration of Nicotine. This suggest that changes in neuronal activity after administration of ACE are the result of ACE acting as a ligand for nAChR because we can see the same trends between ACE and Nicotine. In summary, it was observed that administration of ACE at a concentration that is originally non-toxic, such as NOAEL, affects the behavior and neural activities. This suggests that cranial nerve activity is responsible for changes in behavior.</p>

    DOI: 10.14869/toxpt.47.1.0_P-4S

  21. Dual microglia effects on blood brain barrier permeability induced by systemic inflammation. Reviewed International journal

    Koichiro Haruwaka, Ako Ikegami, Yoshihisa Tachibana, Nobuhiko Ohno, Hiroyuki Konishi, Akari Hashimoto, Mami Matsumoto, Daisuke Kato, Riho Ono, Hiroshi Kiyama, Andrew J Moorhouse, Junichi Nabekura, Hiroaki Wake

    Nature communications   Vol. 10 ( 1 ) page: 5816 - 5816   2019.12

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    Microglia survey brain parenchyma, responding to injury and infections. Microglia also respond to systemic disease, but the role of blood-brain barrier (BBB) integrity in this process remains unclear. Using simultaneous in vivo imaging, we demonstrated that systemic inflammation induces CCR5-dependent migration of brain resident microglia to the cerebral vasculature. Vessel-associated microglia initially maintain BBB integrity via expression of the tight-junction protein Claudin-5 and make physical contact with endothelial cells. During sustained inflammation, microglia phagocytose astrocytic end-feet and impair BBB function. Our results show microglia play a dual role in maintaining BBB integrity with implications for elucidating how systemic immune-activation impacts neural functions.

    DOI: 10.1038/s41467-019-13812-z

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  22. Oral splint ameliorates tic symptoms in patients with tourette syndrome. Reviewed International journal

    Jumpei Murakami, Yoshihisa Tachibana, Shigehisa Akiyama, Takafumi Kato, Aya Taniguchi, Yoshiaki Nakajima, Mao Shimoda, Hiroaki Wake, Yukiko Kano, Masahiko Takada, Atsushi Nambu, Atsushi Yoshida

    Movement disorders : official journal of the Movement Disorder Society   Vol. 34 ( 10 ) page: 1577 - 1578   2019.10

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    DOI: 10.1002/mds.27819

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  23. Regulation of myelin structure and conduction velocity by perinodal astrocytes (vol 115, pg 11832, 2018)

    Dutta Dipankar J., Woo Dong Ho, Lee Philip R., Pajevic Sinisa, Bukalo Olena, Huffman William C., Wake Hiroaki, Basser Peter J., SheikhBahaei Shahriar, Lazarevic Vanja, Smith Jeffrey C., Fields R. Douglas

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   Vol. 116 ( 25 ) page: 12574 - 12574   2019.6

  24. Microglia: Lifelong modulator of neural circuits. Reviewed International journal

    Ako Ikegami, Koichiro Haruwaka, Hiroaki Wake

    Neuropathology : official journal of the Japanese Society of Neuropathology   Vol. 39 ( 3 ) page: 173 - 180   2019.6

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    Microglia, the sole immune cells in the brain, are the key player for synaptic regulation required for our brain function in both developing and adult brain. They have highly motile processes to detect synaptic functions. Recent accumulated studies have unveiled the mechanism underlying synapse detection and pruning / formation by microglia. In this review, we summarize the current knowledge of various microglial machinery recruited in synaptic modulation in the different life stages and contexts.

    DOI: 10.1111/neup.12560

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  25. Activity-Dependent Myelination. Reviewed International journal

    Daisuke Kato, Hiroaki Wake

    Advances in experimental medicine and biology   Vol. 1190   page: 43 - 51   2019

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    Oligodendrocyte form myelin around the axons to regulate the conduction velocity. Myelinated axons are composed of white matter to act as cables to connect distinct brain regions. Recent human MRI studies showed that the signal from white matter change in the people with special skills such as taxi driver, piano player, and juggling. The change of the white matter suggested that (1) The plasticity of myelination depends on neuronal activity (activity-dependent myelination) and (2) White matter plasticity is essential for brain functions. In this session, we discussed that how the un-electrical components, oligodendrocytes, and its precursor cells receive the signal from electrically active neurons and differentiate, proliferate, and myelinate the axons to modulate the activity of neuronal circuits, ultimately affect on their behaviors. In this review, we highlight the physiological functions of oligodendrocyte and their neuronal activity-dependent functions and thus show new insight for their contribution to brain functions.

    DOI: 10.1007/978-981-32-9636-7_4

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  26. In Vivo Two-Photon Imaging of Microglial Synapse Contacts. Reviewed International journal

    Daisuke Kato, Ako Ikegami, Hiroshi Horiuchi, Andrew J Moorhouse, Junichi Nabekura, Hiroaki Wake

    Methods in molecular biology (Clifton, N.J.)   Vol. 2034   page: 281 - 286   2019

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    Language:Japanese   Publishing type:Research paper (scientific journal)  

    Microglia are traditionally known as immune sentinels of the brain and as key player in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease, Parkinson disease, or amyotrophic lateral sclerosis. Recently, they were also identified as synaptic organizer, promoting formation and maturation of synapses as well as modifying synaptic activity. Interestingly, microglia-mediated synaptic pruning and microglia-mediated changes in synaptic plasticity were observed both during brain development and in neurodegenerative diseases, stressing the key role of microglia-synapse interaction in these processes. Here we descried a technique for noninvasive in vivo monitoring of microglia-synapse interactions by means of two-photon microscopy.

    DOI: 10.1007/978-1-4939-9658-2_20

    Web of Science

    PubMed

  27. Physiological Implications of Microglia-Synapse Interactions. Reviewed International journal

    Hiroaki Wake, Hiroshi Horiuchi, Daisuke Kato, Andrew J Moorhouse, Junichi Nabekura

    Methods in molecular biology (Clifton, N.J.)   Vol. 2034   page: 69 - 80   2019

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    Language:Japanese   Publishing type:Research paper (scientific journal)  

    Microglia are the sole immune responding cells in the central nervous system. Their role as neuroimmune cells in the pathogenesis of various neurodegenerative and infectious diseases of the brain have been extensively studied. Upon brain disease and infection, they adopt an activated phenotype associated with the release of cytokines and neurotrophic factors and resulting in neuroprotective or neurotoxic outcomes. However, microglia are resident also in the healthy or physiological brain, but much less is known about their role(s) in the healthy brain, partly due to technical limitations regarding investigation of these highly reactive cells in the intact brain. Recent developments in molecular probes and in vivo optical imaging techniques has now helped to characterize microglia in the physiological or healthy brain. In vivo two-photon imaging of fluorescently labeled microglia have revealed that they are highly motile cells in the healthy brain, extending and retracting their processes that extend from a largely stationary cell soma. In this chapter, we briefly summarize some of the physiological functions of microglia in the uninjured brain, with a focus on interactions they have with synapses.

    DOI: 10.1007/978-1-4939-9658-2_6

    Web of Science

    PubMed

  28. Regulation of myelin structure and conduction velocity by perinodal astrocytes. Reviewed International journal

    Dipankar J Dutta, Dong Ho Woo, Philip R Lee, Sinisa Pajevic, Olena Bukalo, William C Huffman, Hiroaki Wake, Peter J Basser, Shahriar SheikhBahaei, Vanja Lazarevic, Jeffrey C Smith, R Douglas Fields

    Proceedings of the National Academy of Sciences of the United States of America   Vol. 115 ( 46 ) page: 11832 - 11837   2018.11

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    Language:Japanese   Publishing type:Research paper (scientific journal)  

    The speed of impulse transmission is critical for optimal neural circuit function, but it is unclear how the appropriate conduction velocity is established in individual axons. The velocity of impulse transmission is influenced by the thickness of the myelin sheath and the morphology of electrogenic nodes of Ranvier along axons. Here we show that myelin thickness and nodal gap length are reversibly altered by astrocytes, glial cells that contact nodes of Ranvier. Thrombin-dependent proteolysis of a cell adhesion molecule that attaches myelin to the axon (neurofascin 155) is inhibited by vesicular release of thrombin protease inhibitors from perinodal astrocytes. Transgenic mice expressing a dominant-negative fragment of VAMP2 in astrocytes, to reduce exocytosis by 50%, exhibited detachment of adjacent paranodal loops of myelin from the axon, increased nodal gap length, and thinning of the myelin sheath in the optic nerve. These morphological changes alter the passive cable properties of axons to reduce conduction velocity and spike-time arrival in the CNS in parallel with a decrease in visual acuity. All effects were reversed by the thrombin inhibitor Fondaparinux. Similar results were obtained by viral transfection of tetanus toxin into astrocytes of rat corpus callosum. Previously, it was unknown how the myelin sheath could be thinned and the functions of perinodal astrocytes were not well understood. These findings describe a form of nervous system plasticity in which myelin structure and conduction velocity are adjusted by astrocytes. The thrombin-dependent cleavage of neurofascin 155 may also have relevance to myelin disruption and repair.

    DOI: 10.1073/pnas.1811013115

    Web of Science

    PubMed

  29. Three-dimensional stimulation and imaging-based functional optical microscopy of biological cells. Reviewed International journal

    Xiangyu Quan, Manoj Kumar, Osamu Matoba, Yasuhiro Awatsuji, Yoshio Hayasaki, Satoshi Hasegawa, Hiroaki Wake

    Optics letters   Vol. 43 ( 21 ) page: 5447 - 5450   2018.11

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    Language:Japanese   Publishing type:Research paper (scientific journal)  

    A new type of functional optical microscope system called three-dimensional (3D) stimulation and imaging-based functional optical microscopy (SIFOM) is proposed, to the best of our knowledge. SIFOM can precisely stimulate user-defined targeted biological cells and can simultaneously record the volumetric fluorescence distribution in a single acquisition. Precise and simultaneous stimulation of fluorescent-labeled biological cells is achieved by multiple 3D spots generated by digital holograms displayed on a phase-mode spatial light modulator. Single-shot 3D acquisition of the fluorescence distribution is accomplished by common-path off-axis incoherent digital holographic microscopy in which a diffraction grating with a focusing lens is displayed on another phase-mode spatial light modulator. The effectiveness of the proposed functional microscope system was verified in experiments using fluorescent microbeads and human lung cancer cells located at various defocused positions. The system can be used for manipulating the states of cells in optogenetics.

    DOI: 10.1364/OL.43.005447

    Web of Science

    PubMed

  30. Microglia mediate non-cell-autonomous cell death of retinal ganglion cells. Reviewed International journal

    Akiko Takeda, Youichi Shinozaki, Kenji Kashiwagi, Nobuhiko Ohno, Kei Eto, Hiroaki Wake, Junichi Nabekura, Schuichi Koizumi

    Glia   Vol. 66 ( 11 ) page: 2366 - 2384   2018.11

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    Language:Japanese   Publishing type:Research paper (scientific journal)  

    Excitotoxicity is well known in the neuronal death in the brain and is also linked to neuronal damages in the retina. Recent accumulating evidence show that microglia greatly affect excitotoxicity in the brain, but their roles in retina have received only limited attention. Here, we report that retinal excitotoxicity is mediated by microglia. To this end, we employed three discrete methods, that is, pharmacological inhibition of microglia by minocycline, pharmacological ablation by an antagonist for colony stimulating factor 1 receptor (PLX5622), and genetic ablation of microglia using Iba1-tTA::DTAtetO/tetO mice. Intravitreal injection of NMDA increased the number of apoptotic retinal ganglion cells (RGCs) followed by reduction in the number of RGCs. Although microglia did not respond to NMDA directly, they became reactive earlier than RGC damages. Inhibition or ablation of microglia protected RGCs against NMDA. We found up-regulation of proinflammatory cytokine genes including Il1b, Il6 and Tnfa, among which Tnfa was selectively blocked by minocycline. PLX5622 also suppressed Tnfa expression. Tumor necrosis factor α (TNFα) signals were restricted in microglia at very early followed by spreading into other cell types. TNFα up-regulation in microglia and other cells were significantly attenuated by minocycline and PLX5622, suggesting a central role of microglia for TNFα induction. Both inhibition of TNFα and knockdown of TNF receptor type 1 by siRNA protected RGCs against NMDA. Taken together, our data demonstrate that a phenotypic change of microglia into a neurotoxic one is a critical event for the NMDA-induced degeneration of RGCs, suggesting an importance of non-cell-autonomous mechanism in the retinal neuronal excitotoxicity.

    DOI: 10.1002/glia.23475

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    PubMed

  31. Cortical astrocytes prime the induction of spine plasticity and mirror image pain. Reviewed International journal

    Tatsuya Ishikawa, Kei Eto, Sun Kwang Kim, Hiroaki Wake, Ikuko Takeda, Hiroshi Horiuchi, Andrew J Moorhouse, Hitoshi Ishibashi, Junichi Nabekura

    Pain   Vol. 159 ( 8 ) page: 1592 - 1606   2018.8

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    Language:Japanese   Publishing type:Research paper (scientific journal)  

    Peripheral nerve injury causes maladaptive plasticity in the central nervous system and induces chronic pain. In addition to the injured limb, abnormal pain sensation can appear in the limb contralateral to the injury, called mirror image pain. Because synaptic remodeling in the primary somatosensory cortex (S1) has critical roles in the induction of chronic pain, cortical reorganization in the S1 ipsilateral to the injured limb may also accompany mirror image pain. To elucidate this, we conducted in vivo 2-photon calcium imaging of neuron and astrocyte activity in the ipsilateral S1 after a peripheral nerve injury. We found that cross-callosal inputs enhanced the activity of both S1 astrocytes and inhibitory neurons, whereas activity of excitatory neurons decreased. When local inhibitory circuits were blocked, astrocyte-dependent spine plasticity and allodynia were revealed. Thus, we propose that cortical astrocytes prime the induction of spine plasticity and mirror image pain after peripheral nerve injury. Moreover, this result suggests that cortical synaptic rewiring could be sufficient to cause allodynia on the uninjured periphery.

    DOI: 10.1097/j.pain.0000000000001248

    Web of Science

    PubMed

  32. Activity-dependent functions of non-electrical glial cells. Reviewed International journal

    Daisuke Kato, Kei Eto, Junichi Nabekura, Hiroaki Wake

    Journal of biochemistry   Vol. 163 ( 6 ) page: 457 - 464   2018.6

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    Language:Japanese   Publishing type:Research paper (scientific journal)  

    Electrical activity is essential for brain function. However, neurons, the electrically active cells, are less numerous than the non-electrical glial cells in the central nervous system. The non-electrical components modify the function of neural circuits, depending on the electrical neuronal activity, by wrapping synapses, myelinating axons and phagocytozing the neuronal components. Moreover, recent evidence has suggested that they contribute to neurological and psychiatric disease by regulating neuronal circuits, ultimately affecting their behaviour. In this review, we highlight the physiological functions of glial cells, particularly the electrical activity-dependent processes, to provide further insight into their role in brain function.

    DOI: 10.1093/jb/mvy023

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    Scopus

    PubMed

  33. Microglia Enhance Synapse Activity to Promote Local Network Synchronization Reviewed International journal

    Akiyoshi R, Wake Hiroaki, Kato D, Horiuchi H, Ono R, Ikegami A, Haruwaka K, Omori T, Tachibana Y, Moorhouse AJ, Nabekura J

    eNeuro   Vol. 5 ( 5 )   2018

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    Language:Japanese   Publishing type:Research paper (scientific journal)  

    DOI: 10.1523/ENEURO.0088-18.2018

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    PubMed

  34. Three-dimensional stimulation and imaging-based functional optical microscopy of biological cells Reviewed International journal

    Xiangyu Quan, Manoj Kumar, MATOBA Osamu, Yasuhiro Awatsuji, Yoshio Hayasaki, Satoshi Hasegawa, WAKE Hiroki

    Optics Letters   Vol. Vol. 43 ( No. 21 ) page: pp. 5447 - 5480   2018

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    Language:English   Publishing type:Research paper (scientific journal)  

  35. High temporal and spatial pattern stimulation to manipulate brain function

    Wake Hiroaki, Haruwaka Koichiro, Zen Kogyoku, Matoba Osamu

    BIOMEDICAL IMAGING AND SENSING CONFERENCE   Vol. 10711   2018

  36. Reduced Mastication Impairs Memory Function Reviewed International journal

    Y. Fukushima-Nakayama, Takehito Ono, M. Hayashi, M. Inoue, H. Wake, Takashi Ono, T. Nakashima

    JOURNAL OF DENTAL RESEARCH   Vol. 96 ( 9 ) page: 1058 - 1066   2017.8

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:SAGE PUBLICATIONS INC  

    Mastication is an indispensable oral function related to physical, mental, and social health throughout life. The elderly tend to have a masticatory dysfunction due to tooth loss and fragility in the masticatory muscles with aging, potentially resulting in impaired cognitive function. Masticatory stimulation has influence on the development of the central nervous system (CNS) as well as the growth of maxillofacial tissue in children. Although the relationship between mastication and cognitive function is potentially important in the growth period, the cellular and molecular mechanisms have not been sufficiently elucidated. Here, we show that the reduced mastication resulted in impaired spatial memory and learning function owing to the morphological change and decreased activity in the hippocampus. We used an in vivo model for reduced masticatory stimuli, in which juvenile mice were fed with powder diet and found that masticatory stimulation during the growth period positively regulated long-term spatial memory to promote cognitive function. The functional linkage between mastication and brain was validated by the decrease in neurons, neurogenesis, neuronal activity, and brain-derived neurotrophic factor (BDNF) expression in the hippocampus. These findings taken together provide in vivo evidence for a functional linkage between mastication and cognitive function in the growth period, suggesting a need for novel therapeutic strategies in masticatory function-related cognitive dysfunction.

    DOI: 10.1177/0022034517708771

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▼display all

MISC 5

  1. オリゴデンドロサイトおよびその前駆細胞の生体内カルシウムイメージング

    尾野里穂, 加藤大輔, 杉尾翔太, 橘吉寿, 和氣弘明

    日本生理学雑誌(Web)   Vol. 82 ( 1 )   2020

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  2. 行動毒性試験および二光子イメージングによるアセタミプリドの神経毒性評価

    平井杏梨, 杉尾翔太, 池中良徳, COLLINS Nimako, 中山翔太, 星信彦, 和氣弘明, 石塚真由美

    日本獣医学会学術集会講演要旨集   Vol. 163rd   2020

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  3. Real-time visualization of brain metastasis in vivo Reviewed International journal

    Takahiro Tsuji, Hiroaki Wake, Hiroaki Ozasa, Koichiro Haruwaka, Hitomi Ajimizu, Yuto Yasuda, Yuichi Sakamori, Takashi Nomizo, Young Hak Kim, Toyohiro Hirai

    AACR Annual Meeting 2019   Vol. April 1, 2019   2019.4

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    Language:English   Publishing type:Research paper, summary (international conference)  

  4. Simple intensity equalization methods in SLM generated multispots

    Xiangyu Quan, Manoj Kumar, Osamu Matoba, Yasuhiro Awatsuji, Hiroaki Wake

    Proceedings of SPIE - The International Society for Optical Engineering   Vol. 11140   2019

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    © 2019 SPIE. Multispots in three-dimensions generated by phase mode spatial light modulators (SLMs) are very useful in laser processing or light induced biological treatments, such as optogenetics. So far, the intensity of the focus spots varies depending to the distance from optical axis. In order to equalize intensities in all generated spots, simple feedback method was applied. Further, look up table was created by dividing imaging area in sectors. Experiment results show improvement in the random spots at some degree, however, further analyzation is required.

    Scopus

  5. イオンイメージセンサによる脳内pHイメージング

    堀内浩, 石田順子, 中村友亮, 稲田浩之, 揚妻正和, 和氣弘明, 澤田和明, 鍋倉淳一

    日本生理学雑誌(Web)   Vol. 80 ( 1 ) page: WEB ONLY   2018.2

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    Language:Japanese  

    J-GLOBAL

Presentations 87

  1. 2光子励起を用いたホログラフィック光刺激の現状:生体試料への適用を目指して

    SUGIO SHOUTA, TACHIBANA YOSHIHISA, WAKE HIROAKI

    CREST第2回シンポジウム  2018.12 

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    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:西尾  

  2. 2光子励起を用いたホログラフィック光刺激法の開発:現状と展望

    SUGIO SHOUTA, TACHIBANA YOSHIHISA, WAKE HIROAKI

    シグナル伝達医学研究展開センター若手道場  2019.1 

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    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:淡路  

  3. 2光子顕微鏡による生体イメージング

    Wake Hiroaki

    京都大学呼吸器内科  2017.9 

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    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:京都  

  4. 2光子顕微鏡による生体イメージング

    Wake Hiroaki

    京都大学セミナー  2017.8 

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    Language:Japanese   Presentation type:Public lecture, seminar, tutorial, course, or other speech  

    Venue:京都  

  5. A New Type of Microscopy for Light Stimulation and 3D Imaging; Invited International conference

    Xiangyu Quan, Manoj Kumar, MATOBA Osamu, Yasuhiro Awatsuji, Yoshio Hayasaki, Satoshi Hasegawa, WAKE Hiroaki, Mitsuhiro Morita

    International Workshop on Holography and Related Technologies 2018 (IWH2018)  2018.11  IWH2018

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    Language:English   Presentation type:Oral presentation (invited, special)  

    Venue:Suzhou; China;  

  6. Abnormal Behavior and Malformation of Microglia in Schizophrenic Mice International conference

    Ako Ikegami, Koichiro Haruwaka, Wake Hiroaki

    第2回神戸大学・ワシントン大学・オスロ大学国際合同シンポジウム  2018.3 

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    Language:English   Presentation type:Poster presentation  

    Venue:ハワイ, 米国  

  7. Activity dependent myelin regulation in information processing

    Wake Hiroaki

    第115回IIISセミナー  2017.8 

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    Venue:茨城  

  8. Ca2+ imaging of oligodendrocyte and oligodendrocyte precursor cell in vivo

    Riho Ono, Shouta Sugio, Yoshihisa Tachibana, Hiroaki Wake

    新学術領域研究 スクラップ&ビルドによる脳機能の動的制御 第3回領域会議  2018.11 

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    Language:Japanese   Presentation type:Poster presentation  

    Venue:大阪  

  9. Change of lipid profile in myelin associated with motor learning affect on neuronal activity pattern in primary motor cortex.

    Kazuki Nishida, Yoshihisa Tachibana, Shumpei Sato, Fumiyoshi Yamazaki, Mitsutoshi Setou, Hiroaki Wake

    第23 回グリア研究会  2018.12 

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    Venue:名古屋  

  10. Ca2+ imaging of oligodendrocyte and oligodendrocyte precursor cell in vivo

    Shouta Sugio, Riho Ono, Yoshihisa Tachibana, Hiroaki Wake

    次世代脳プロジェクト 冬のシンポジウム  2018.12 

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    Language:English   Presentation type:Poster presentation  

    Venue:東京  

  11. Fetal microglia changes by maternal immune activation

    Kana Ozaki, Wake Hiroaki, Hideto Yamada

    第70回日本産科婦人科学会学術講演会  2018.5 

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    Venue:仙台  

  12. High Temporal and Spatial Pattern Stimulation to Manipulate Brain Function Invited International conference

    Hiroaki Wake

    International Workshop on Bioimaging2019  2019.2 

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    Language:English   Presentation type:Oral presentation (invited, special)  

    Venue:宇都宮  

  13. High Temporal and Spatial Pattern Stimulation to Manipulate Brain Function International conference

    Hiroaki Wake

    ABiS International Symposium  2019.2 

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    Venue:岡崎  

  14. High Temporal and Spatial Pattern Stimulation to Manipulate Brain Function International conference

    Hiroaki Wake, Koichiro Haruwaka, Xiangyu Quan, Osamu Matoba

    OPIC2018  2018.4 

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    Venue:横浜  

  15. High Temporal and Spatial Pattern Stimulation to Manipulate Brain Function International conference

    WAKE Hiroaki, Koichiro Haruwaka, Xiangyu Quan, MATOBA Osamu

    BISC  2018.4  OPIC2018

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    Venue:神奈川、横浜  

  16. In vivo tracing of single neuron activity with Ca2+ imaging of primary somatosensory cortex in mouse models of postoperative pain and inflammatory pain International conference

    Takuya Okada, Yoshihisa Tachibana, Yuki Nomura, Norihiko Obata, Satoshi Mizobuchi, Hiroaki Wake

    Neuroscience 2018  2018.11 

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    Language:English   Presentation type:Poster presentation  

    Venue:San Diego, CA  

  17. Microglia and Synapses Invited International conference

    Hiroaki Wake

    ICN2018 世界神経病理学会  2018.9 

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    Language:English   Presentation type:Symposium, workshop panel (nominated)  

    Venue:東京  

  18. Lipid composition of frontal white matter is altered with motor learning.

    Yukio Tsuji, Tachibana Yoshihisa, Fumiyoshi Yamazaki, Daisuke Kato, Shinohara Masakazu, Miyamoto Akiko, Ikuko Yao, Toda Tatsushi, Mitsutoshi Setou, Wake Hiroaki

    第40回日本神経科学大会  2017.7 

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    Venue:千葉  

  19. In vivo tracing of single neuron activity with Ca2+ imaging of primary somatosensory cortex in mouse models of postoperative pain and inflammatory pain International conference

    岡田 卓也, 橘 吉寿, NOMURA YUKI, OBATA NORIHIKO, MIZOBUCHI SATOSHI, WAKE HIROAKI

    Cold Spring Harbor Asia Confference  2018.9 

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    Venue:淡路  

  20. Microglia in health and disease -lesson from schizophreniamodel mice Invited

    WAKE HIROAKI

    第41回日本神経科学大会  2018.7 

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    Venue:神戸  

  21. Microglia in physiological brain—Focusing on microglia—synapse interactions Invited International conference

    Hiroaki Wake

    Cold Spring Harbor Asia Conferences  2018.12 

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    Language:English   Presentation type:Oral presentation (invited, special)  

    Venue:蘇州  

  22. Microglia in Health and Disease.- Interaction with synapses- Invited

    Hiroaki Wake

    日本生化学大会  2018.9 

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    Venue:京都  

  23. Microglia sense systemic immune status to modify activity of neuronal circuit

    Koichiro Haruwaka, Wake Hiroaki, Junichi Nabekura

    Life Science Retreat 2017  2017.10 

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    Venue:山梨  

  24. Microglia sense systemic immune status to modify activity of neuronal circuit; 免疫状態依存的なミクログリアによる神経回路活動の制御

    Koichiro Haruwaka, Wake Hiroaki, Junichi Nabekura

    第40回日本神経科学大会  2017.7 

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    Venue:千葉  

  25. Microglial contribute to dendritic spine formation in postnatal mice somatosensory cortex Invited

    Miyamoto Akiko, Wake Hiroaki, Ayako Ishikawa, Hideji Murakoshi, Kei Eto, Yumiko Yoshimura, Junichi Nabekura

    日本神経化学学会  2017.9 

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    Language:English   Presentation type:Symposium, workshop panel (nominated)  

    Venue:仙台  

  26. Myelination for information processing

    Wake Hiroaki

    第90回日本神経化学会大会  2017.9 

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    Venue:仙台  

  27. Multimodal Digital Holographic Microscopy Invited International conference

    Xiangyu Quan, Manoj Kumar, MATOBA Osamu, Yasuhiro Awatsuji, Yoshio Hayasaki, Satoshi Hasegawa, WAKE Hiroaki, Mitsuhiro Morita

    The 8th Japana-Korea workshop on digital holography and information photonics (DHIP 2018)  2018.11  DHIP2018

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    Language:English   Presentation type:Oral presentation (invited, special)  

    Venue:Osaka; Japan  

  28. Neurochemistry of neuron-glia interaction Invited International conference

    Hiroaki Wake

    WFSBP2018 The ISN-JSN  2018.9 

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    Language:English   Presentation type:Symposium, workshop panel (nominated)  

    Venue:神戸  

  29. oligodendrocyte and myelin remodeking in information processing

    Wake Hiroaki

    第2回「スクラップビルド」領域会議  2017.8 

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    Venue:山梨  

  30. Physiclogocal function of microglia and their role for disease formation

    WAKE HIROAKI

    武田薬品社内シンポジウム  2018.12 

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    Language:Japanese   Presentation type:Public lecture, seminar, tutorial, course, or other speech  

    Venue:藤沢  

  31. Physiology of microglia -New Insights- Invited International conference

    Wake Hiroaki

    Physiology of microglia XXIII World Congres of Neurology  2017.9 

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    Language:English   Presentation type:Symposium, workshop panel (nominated)  

    Venue:京都  

  32. Physiology of microglia Invited

    Wake Hiroaki

    九州大学歯学部  2017.9 

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    Language:English   Presentation type:Oral presentation (invited, special)  

    Venue:福岡  

  33. Physiologiacl function of microglia and their effect on neuronal circuits International conference

    Hiroaki Wake

    第9回アジアオセアニア生理学会(神戸市)  2019.3 

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    Venue:神戸  

  34. The response to whisker stimulation in the visual cortex of monocular deprived mice in vivo International conference

    橋本 明香里, MIYAMOTO AKIKO, TACHIBANA YOSHIHISA, 春若航一路, WAKE HIROAKI

    9th FAOPS  2019.3 

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    Language:English   Presentation type:Poster presentation  

    Venue:神戸  

  35. Two-photon in vivo imaging of oligodendrocyte Ca2+ activity in mice International conference

    Riho Ono, Shouta Sugio, Yoshihisa Tachibana, Hiroaki Wake

    Young glia  2018.10 

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    Language:English   Presentation type:Poster presentation  

    Venue:シュパイヤー  

  36. The scrap and build of oligodendrocyte function and myelin components

    WAKE HIROAKI

    スクラップ&ビルド領域会議  2018.11 

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    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:大阪  

  37. Visualization and manipulation of glial cell functions in vivo International conference

    Hiroaki Wake

    glial heterogeneity SPP1757  2018.10 

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    Venue:シュパイヤー  

  38. What we see in microglia about schizophrenia

    池上暁湖, 春若航一路, TACHIBANA YOSHIHISA, WAKE HIROAKI

    第5回先進イメージング医学研究会  2018.8 

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    Venue:京都  

  39. オリゴデンドロサイトおよびその前駆細胞のin vivo カルシウムイメージング

    尾野 里穂, SUGIO SHOUTA, TACHIBANA YOSHIHISA, WAKE HIROAKI

    シグナル伝達医学研究展開センター若手道場  2019.1 

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    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:淡路  

  40. ミクログリアの生理機能とその破綻による疾患について

    WAKE HIROAKI

    東京女子医科大セミナー  2018.10 

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    Language:Japanese   Presentation type:Public lecture, seminar, tutorial, course, or other speech  

    Venue:東京  

  41. ミクログリアの生理・病態を踏まえた認知症治療戦略 Invited

    WAKE HIROAKI

    第37回日本認知症学会学術集会  2018.10 

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    Language:Japanese   Presentation type:Symposium, workshop panel (nominated)  

    Venue:札幌  

  42. ミクログリアの新規生理機能の可視化

    WAKE HIROAKI

    北海道大学医学部免疫代謝内科学セミナー  2019.2 

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    Language:Japanese   Presentation type:Public lecture, seminar, tutorial, course, or other speech  

    Venue:札幌  

  43. ミクログリアの新規生理機能とその破綻による病態の表出

    WAKE HIROAKI

    第11回先端脳科学セミナー  2019.2 

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    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:中央  

  44. ミクログリアによる神経機能修飾

    WAKE HIROAKI

    Neurovascular Unit研究会2019  2019.1 

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    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:東京  

  45. ホログラフィック光照射による蛍光励起の強度均一化"

    小管啓仁, Xiangyu Quan, MATOBA Osamu, 早崎芳夫, 粟辻安浩, WAKE Hiroaki

    日本光学会年次学術講演会(Optics & Photonics Japan 2018)  2018.11 

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    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:筑波大学東京キャンパス文京校舎,東京  

  46. グリア細胞の生理機能と神経回路機能

    WAKE HIROAKI

    第48回小児神経セミナー  2018.11 

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    Language:Japanese   Presentation type:Oral presentation (invited, special)  

    Venue:大阪  

  47. グリアの生理機能とその破綻による精神疾患の可能性

    WAKE HIROAKI

    動的恒常性研究会  2018.6 

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    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:東京  

  48. 中枢神経系免疫細胞ミクログリアの新規生理機能とその病態への関与

    WAKE HIROAKI

    日本薬学会北陸支部特別講演会  2018.12 

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    Language:Japanese   Presentation type:Public lecture, seminar, tutorial, course, or other speech  

    Venue:金沢  

  49. 統合失調症モデルマウスにおけるミクログリア動態・形態の変容

    Ako Ikegami, Koichiro Haruwaka, Wake Hiroaki

    第7回ニューロサイエンス研究会  2017.12 

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    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:兵庫  

  50. 統合失調症モデルマウスにおけるミクログリア動態・形態の変容

    Ako Ikegami, Koichiro Haruwaka, Wake Hiroaki

    第110回近畿生理学談話会  2017.11 

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    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:兵庫  

  51. Optical control of neuron and glial cells by the 3D multi-points stimulation

    春若 航一路, 全 香玉, 森田 光洋, Miyamoto Akiko, 的場 修, Wake Hiroaki

    CREST「光の特性を活用した生命機能の時空間制御技術の開発と応用」研究領域 第2回領域会議  2018.1 

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    Language:Japanese   Presentation type:Poster presentation  

    Venue:東京  

  52. 生体イメージング最前線

    WAKE HIROAKI

    小野薬品工業「脳移転治療について考える会」  2018.9 

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    Language:Japanese   Presentation type:Public lecture, seminar, tutorial, course, or other speech  

    Venue:京都  

  53. 生体イメージングが明らかにする脳-免疫系の相互作用

    春若 航一路, 鍋倉 淳一, Wake Hiroaki

    岡崎信用金庫先端奨学金制度 成果発表会  2018.2 

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    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:愛知  

  54. 生体 in Vivoイメージング

    WAKE HIROAKI

    第2回ニコンイメージングフォーラム  2019.2 

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    Language:Japanese   Presentation type:Symposium, workshop panel (nominated)  

    Venue:東京  

  55. 大脳皮質感覚野の生体イメージングによる疼痛発症機構解明へのアプローチ

    岡田 卓也, TACHIBANA YOSHIHISA, NOMURA YUKI, OBATA NORIHIKO, MIZOBUCHI SATOSHI, WAKE HIROAKI

    第111回 近畿生理学談話会  2018.11 

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    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:和歌山  

  56. 単眼遮蔽による視覚野のヒゲ刺激への応答変化のin vivoイメージング

    橋本 明香里, MIYAMOTO AKIKO, TACHIBANA YOSHIHISA, 春若航一路, WAKE HIROAKI

    関西5医科大学コンソーシアム合宿  2018.9 

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    Language:Japanese   Presentation type:Poster presentation  

    Venue:大阪  

  57. 単眼遮蔽による、高次視覚野のヒゲ刺激への応答変化のin vivo イメージング

    橋本 明香里, MIYAMOTO AKIKO, TACHIBANA YOSHIHISA, 春若航一路, WAKE HIROAKI

    第41回日本神経科学大会  2018.7 

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    Language:English   Presentation type:Poster presentation  

    Venue:神戸  

  58. 全身炎症時におけるミクログリアによる血液脳関門の制御

    春若航一路, WAKE HIROAKI

    シグナル伝達医学研究展開センター若手道場  2019.1 

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    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:淡路  

  59. 全身炎症時におけるミクログリアによる血液脳関門の制御

    春若航一路, WAKE HIROAKI

    第6回先進イメージング医学研究会・学術集会  2019.1 

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    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:神戸  

  60. Microglia sense systemic immune status to modify activity of neuronal circuit

    Koichiro Haruwaka, Junichi Nabekura, Wake Hiroaki

    第95回日本生理学会大会  2018.3 

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    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:香川  

  61. 光による高次脳機能の計測と操作を目指して

    WAKE HIROAKI

    レーザー学会第39回年次大会  2019.1 

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    Language:Japanese   Presentation type:Oral presentation (invited, special)  

    Venue:東京  

  62. 光で迫る脳免疫細胞の機能について Invited

    Wake Hiroaki

    第49回藤田学園医学会シンポジウム(愛知県豊名市)  2017.10 

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    Language:Japanese   Presentation type:Oral presentation (invited, special)  

    Venue:愛知  

  63. 光で迫る脳免疫細胞の機能 Invited

    Wake Hiroaki

    第40回日本神経科学大会  2017.7 

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    Language:Japanese   Presentation type:Symposium, workshop panel (nominated)  

    Venue:千葉  

  64. 光で迫る脳免疫細胞の機能

    Wake Hiroaki

    脳科学の達人2017  2017.6 

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    Language:Japanese   Presentation type:Symposium, workshop panel (public)  

    Venue:東京  

  65. 光で照らし出すグリアの新機能および脳機能表出

    Wake Hiroaki

    Glial assembly, The 5th Summer Workshop  2017.6 

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    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:新潟  

  66. 光で照らし出すグリアの新機能および脳機能への寄与 Invited

    Wake Hiroaki

    (株)ファイザー 第12回緑内障若手研究者の会(東京)  2017.10 

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    Language:Japanese   Presentation type:Oral presentation (invited, special)  

    Venue:東京  

  67. Microglia sense systemic immune activation in autoimmune disease model.

    Koichiro Haruwaka, Junichi Nabekura, Wake Hiroaki

    次世代脳冬のシンポジウム  2017.12 

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    Language:Japanese   Presentation type:Poster presentation  

    Venue:東京  

  68. 自己免疫疾患におけるミクログリアの変化

    春若 航一路, 鍋倉 淳一, Wake Hiroaki

    第111回近畿生理学談話会  2017.11 

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    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:兵庫  

  69. 脳科学について

    WAKE HIROAKI

    santec社内講演会  2018.10 

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    Language:Japanese   Presentation type:Public lecture, seminar, tutorial, course, or other speech  

    Venue:小牧  

  70. 統合失調症モデルマウスにおけるミクログリア動態・形態の変容

    Ako Ikegami, Koichiro Haruwaka, Wake Hiroaki

    新学術領域 S&B第2回班会議  2017.8 

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    Language:Japanese   Presentation type:Poster presentation  

    Venue:山梨  

  71. 統合失調症モデルマウスにおけるミクログリア動態・形態の変容

    Ako Ikegami, Koichiro Haruwaka, Wake Hiroaki

    次世代脳冬のシンポジウム  2017.12 

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    Language:Japanese   Presentation type:Poster presentation  

    Venue:東京  

  72. 術後痛モデルマウスにおける第一次体性感覚野 in vivo カルシウムイメージング

    岡田 卓也, 橘 吉寿, NOMURA YUKI, OBATA NORIHIKO, MIZOBUCHI SATOSHI, WAKE HIROAKI

    第41回日本神経科学大会  2018.7 

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    Language:Japanese   Presentation type:Poster presentation  

    Venue:神戸  

  73. 髄鞘制御不全による情報処理異常の可視化 Invited

    Wake Hiroaki

    神経組織培養研究会  2017.10 

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    Language:Japanese   Presentation type:Oral presentation (invited, special)  

    Venue:愛知  

  74. 髄鞘制御不全による情報処理異常の可視化

    Wake Hiroaki

    大阪大学生命機能セミナー  2017.7 

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    Venue:大阪  

  75. 髄鞘のスクラップアンドビルドによる脳情報処理の効率化

    Wake Hiroaki

    次世代脳冬のシンポジウム  2017.12 

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    Venue:東京  

  76. 運動学習と関連した白質における脂質の変化が一次運動野の神経活動に及ぼす影響

    西田 一貴, TACHIBANA YOSHIHISA, 佐藤 駿平, 山崎 文義, 瀬藤 光利, WAKE HIROAKI

    第111回 近畿生理学談話会  2018.11 

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    Venue:和歌山  

  77. 身体疾患で惹起される免疫変容が起こす神経回路恒常性の破綻と精神症状の解明

    Wake Hiroaki

    さきがけ領域会議  2017.6 

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    Venue:秋田  

  78. 術後痛モデルマウスにおける第一次体性感覚野のin vivoカルシウムイメージング

    岡田 卓也, TACHIBANA YOSHIHISA, NOMURA YUKI, OBATA NORIHIKO, MIZOBUCHI SATOSHI, WAKE HIROAKI

    第41回日本神経科学大会  2018.7 

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    Language:English   Presentation type:Poster presentation  

    Venue:神戸  

  79. 術後痛モデルマウスにおける第一次体性感覚野 in vivo カルシウムイメージング

    岡田 卓也, 橘 吉寿, NOMURA YUKI, OBATA NORIHIKO, MIZOBUCHI SATOSHI, WAKE HIROAKI

    第5回イメージング数理研究会  2018.7 

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    Venue:神戸  

  80. 高次脳機能に関わる中枢神経系免疫細胞の生理機能 Invited

    Wake Hiroaki

    東京大学大学院医学研究科  2017.11 

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    Venue:東京  

  81. 高精度時空間分解能を持つ光刺激法による脳機能操作

    Wake Hiroaki

    第14回生体イメージング研究会  2017.8 

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    Venue:京都  

  82. 高精度時空間分解能を持つ光による脳機能計測・操作を目指して

    WAKE HIROAKI

    イメージング数理研究会  2018.7 

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    Venue:神戸  

  83. 髄鞘制御不全による情報処理異常の可視化 Invited

    Wake Hiroaki

    第29回臨床MR脳機能研究会  2017.4 

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    Venue:東京  

  84. 革新的予防・診断・治療法開発に向けたシグナル伝達医学研究

    Wake Hiroaki

    神戸大学先端融合研究環新規プロジェクトキックオフシンポジウム  2017.5 

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    Venue:神戸  

  85. 生体適合性マイクロチップレーザーを用いた高次脳機能の4次元操作

    Wake Hiroaki

    融合発展促進研究プロジェクト中間実績報告会  2017.4 

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    Venue:東京  

  86. 横浜市立大学「神経医科学序説」における講義

    Wake Hiroaki

    神経医科学序説  2017.5 

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    Venue:横浜  

  87. Microglia Sense Systemic Immune Status to Modify Activity of Neuronal Circuit

    Koichiro Haruwaka, Wake Hiroaki, Junichi Nabekura

    Glial assembly, The 4th Summer Workshop  2017.6 

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    Venue:新潟  

▼display all

KAKENHI (Grants-in-Aid for Scientific Research) 20

  1. ミクログリアによる感覚モダリティーの制御と精神病態への寄与

    Grant number:21H02662  2021.4 - 2024.3

    日本学術振興会  科学研究費助成事業  基盤研究(B)

    和氣 弘明

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    Authorship:Principal investigator 

    Grant amount:\17550000 ( Direct Cost: \13500000 、 Indirect Cost:\4050000 )

    本研究では感覚領域間の機能的結合に着目し、感覚喪失時に引き起こされる異種感覚の可塑性のメカニズムをミクログリアのシナプス修飾の観点から明らかにする。視覚遮断マウスモデルを用いて、第一次感覚野→高次視覚野の機能的結合に着目し、その機能的結合および高次視覚野内で起こる神経回路再編のメカニズムをミクログリアの観点から分子基盤を明らかにする。

  2. 脳と免疫系相互作用の観点からの多階層的研究による精神疾患病態解明

    Grant number:21H04815  2021.4 - 2024.3

    日本学術振興会  科学研究費助成事業  基盤研究(A)

    尾崎 紀夫, 和氣 弘明, 野田 幸裕, 大野 欽司, 財津 桂

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    Authorship:Coinvestigator(s) 

    脳と免疫系相互作用の観点から精神疾患病態解明の達成を目指し、ゲノム変異を同定した患者由来試料と同一変異に基づくモデル細胞・マウスを用いた多階層的研究を実施する。具体的には、患者ゲノム解析及びゲノム変異患者由来末梢血・腸内細菌・死後脳の解析及びiPS細胞由来神経細胞・オルガノイドの解析。新生仔期免疫活性化状態を経た遺伝子改変マウスの行動解析。ミクログリアと神経細胞の相互作用による神経回路病態解明を目指した、モデルマウスのin vivoイメージング解析。腸内細菌と脳の連関解明を目指した、ヒト・マウスの解析。脳病態と末梢病態との関係の明確化を目指した、ヒト・マウスのインフラマソーム解析。

  3. 母体低栄養が新発見のGABA作動性CRH放出経路を介して仔の脳発達に与える影響

    Grant number:21H02661  2021.4 - 2024.3

    日本学術振興会  科学研究費助成事業  基盤研究(B)

    福田 敦夫, 才津 浩智, 和氣 弘明

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    Authorship:Coinvestigator(s) 

    ストレスではCRH産生細胞にGABAが逆説的に興奮性に作用する。胎生期ストレスやGABA神経系の異常は精神疾患のリスクだが、胎児の視床下部-下垂体-副腎系(既知HPA軸)やGABA神経系の役割はわかっていない。妊娠中の低栄養も子の精神疾患のリスクなので、まず、申請者が発見した弓状核から正中隆起へ投射する興奮性GABA神経経路(新規HPA)が、低栄養時にCRH分泌を促進し、グルココルチコイド放出を増やすことを証明する。次に母体に食餌制限を行い、母体の新規HPA軸反応と胎仔の神経発達及び生後のフェノタイプを評価し、母体低栄養がどのように仔の精神神経疾患フェノタイプを形成するのかを明らかにする。

  4. Glia decoding: deciphering information critical for brain-body interactions

    Grant number:20H05894  2020.11 - 2025.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Transformative Research Areas (A)

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    Authorship:Coinvestigator(s) 

  5. 全身臓器の生理的・病理的免疫状態遷移の脳による検出機構

    Grant number:20H05899  2020.11 - 2025.3

    日本学術振興会  科学研究費助成事業  学術変革領域研究(A)

    和氣 弘明, 足澤 悦子

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    Authorship:Principal investigator 

    Grant amount:\103220000 ( Direct Cost: \79400000 、 Indirect Cost:\23820000 )

    「全身臓器の情報がグリアインターフェイスによってどのように中枢神経系に伝えられるか」の科学的問いに答えるために脳環境と体循環系環境の境界領域に着目し、境界領域における体循環系免疫細胞と脳免疫細胞の相互作用を生体イメージングを主とした方法で解き明かし、これによって臓器情報がどのように中枢神経系に伝えられるかを明らかにする。
    認知機能・学習・情動などの高次脳機能に障害を呈する発達障害・精神疾患の病態を理解することは喫緊の課題である。近年発達した光学技術によってグリア細胞の新しい生理機能の理解が得られ、高次脳機能とその病態の理解にはグリア細胞は不可欠であるという共通認識が広がりつつある。本研究では本研究では中枢神経系免疫細胞であるミクログリアに着目し、そのシナプスや血管などの脳環境に対する生理機能を明らかにする。さらに遺伝的・環境要因によるミクログリア変容のメカニズム及びその結果として引き起こされる異常による病態を精神疾患と組み合わせて解き明かすことを目的とした。これまでミクログリアは全身炎症時に血管に集積することで、炎症初期にはタイトジャンクション関連分子を発現することで、血管内皮細胞と結合し、血液脳関門の透過性を保護すること、炎症後期にはアストロサイトの足突起を貪食することで血液脳関門を障害することを明らかにした。そこで、さらに体循環系の環境及び脳環境の相互作用を免疫系に着目して、検証するために硬膜及び側脳室脈絡叢に着目した。全身炎症においてはこれらのマクロファージおよびTリンパ球の挙動が変化し、脳内環境と連動することがわかった。そこで、この組織の中に含まれる免疫細胞成分特にTリンパ球の成分に着目して解析を進めている。また神経疾患であるアルツハイマー型認知機能障害や精神疾患である統合失調症などにおいても硬膜及び側脳室脈絡叢の変化さらに中枢神経系との相互作用の解析を進めていく。
    脳境界領域のイメージングが進み、技術的な系の構築が順調である。
    体循環―脳環境の境界領域における体循環系免疫細胞と脳免疫細胞の相互作用を生体イメージングで明らかにし、特異的な応答を引き起こす体循環系免疫細胞をシングルセルトランスクリプトームおよび蛍光活性化セルソーティング(FACS)で同定する(大阪大・石井との共同研究)。また、ミクログリアにカルシウム感受性蛍光タンパク質を発現したマウス(CX3CR1-Cre :: CAG-Flox-GCaMP6マウスおよびIba1-tTa:;TeTo-GCaMP6マウス:入手済み)を用いて、生体でこの同定した免疫細胞と相互作用する際のミクログリアの機能応答の変化を可視化する。そしてその機能応答変化したミクログリアのトランスクリプトームの変化を次世代シークエンス技術(RNA-seq)を用いて、細胞集団・シングルセルレベルで同定し、とくにシナプス・軸索に作用することが知られているP2Y12やMHC受容体などの分子に着目してその発現変動を検証する。さらに機能応答変化を起こしたミクログリアがシナプスおよび軸索活動をどのように修飾し、その修飾様式を変えるのかをシナプス活動もしくは軸索活動と同時にイメージングすることで明らかにするとともに分担者の足澤が電気生理学的に解析する。さらに神経細胞構造およびそれによる神経回路機能変化を検証する(東大・岡部との共同研究)。また臓器由来のエクソソームなどの信号がミクログリアに作用することによって全身臓器の情報をミクログリアが取得する経路を検証するために、蛍光発色したヒト患者由来のエクソソームをマウスの発達期に注入し、このエクソソームを取り込んだミクログリアの活動変化を可視化し、これによるトランスクリプトームの変化をRNA-seqを用いて網羅解析することによって明らかにする(東工大・星野との共同研究)。

  6. 感覚モダリティ理解のためのミクログリア・シナプス接触の多角的解析

    Grant number:20KK0170  2020.10 - 2024.3

    日本学術振興会  科学研究費助成事業  国際共同研究加速基金(国際共同研究強化(B))

    和氣 弘明, 大野 伸彦, 加藤 大輔, 竹田 育子

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    Authorship:Principal investigator 

    Grant amount:\18720000 ( Direct Cost: \14400000 、 Indirect Cost:\4320000 )

    本国際研究では中枢神経系唯一の免疫細胞であるミクログリアに着目し、ミクログリアがシナプスの構造的・機能的可塑性を修飾する背景を踏まえ、多角的階層的な技術を相互補完することによって、ミクログリアのシナプスに対する時間的(発達・成熟)および空間(脳領域)特異的な生理機能を明らかにする。さらにこれを異種感覚の可塑的変化のメカニズムに繋げ、そこから精神病態を考察する。
    認知機能・学習・情動などの高次脳機能に障害を呈する発達障害・精神疾患の病態を理解することは喫緊の課題である。近年発達した光学技術によってグリア細胞の新しい生理機能の理解が得られ、高次脳機能とその病態の理解にはグリア細胞は不可欠であるという共通認識が広がりつつある。本研究では中枢神経系免疫細胞であるミクログリアに着目し、そのシナプスや血管などの脳環境に対する生理機能を明らかにする。さらに遺伝的・環境要因によるミクログリア変容のメカニズム及びその結果として引き起こされる異常による病態を精神疾患と組み合わせて解き明かすことを目的とした。ミクログリアのシナプス活動に対する修飾メカニズムを検証するために、生体イメージングとトランスクリプトーム解析を用いて、シナプスから放出されるATPにミクログリアの突起上のP2YR12を介した応答があることでシナプスに誘引され、その活動を修飾する。てんかんなどの過剰興奮時にはミクログリアがシナプスに誘引されることによってシナプス活動を抑制し、神経保護的作用を示すことを明らかにした。さらにこれらのシナプスの領域間への作用を検証するために、異種感覚の可塑性に着目し、視覚遮断マウスにおける第一次感覚野(S1)から高次視覚野(V2)への投射に着目した。髭に応答するS1軸索はV2においても髭に同期した活動を示し、視覚遮断マウスにおいては複雑な物体提示に対するV2神経細胞の活動上昇が認められ、ミクログリアを遺伝学的に除去することでこの活動上昇が損なわれることがわかった。ミクログリアを解析することで、ミクログリアがV2領域興奮性神経細胞体に存在する抑制性シナプス終末を除去することで、この興奮性上昇が認められ、これが異種感覚領域を用いた学習の向上に寄与することを明らかにした。
    国際共同研究の成果を上げることができ、さらに異種感覚の可塑性に関する研究も予想以上に進捗した。
    感覚除去によってシナプスが除去される過程にミクログリアが関与することも明らかにされてきた。このような感覚除去では異種感覚の可塑性が生じる。また臨床的に先天的盲のヒトは統合失調症発症に対する抵抗性があり、成熟後に視覚が喪失したヒトは幻覚を経験するリスク及び統合失調症を発症するリスクが有意に高いことが知られている。しかしながら、シナプスレベル(ミクロ)から神経回路レベル(マクロ)までの現象を分子から回路までこの感覚除去におけるミクログリアの神経回路に対する役割及びその病態への関与を階層的に検証した研究は未だない。
    1.感覚除去(視覚遮断)に対する脳領域別ミクログリアのシナプスに対する役割を明らかにする。
    2.正常群および統合失調症モデルマウスにおける発達の異なる段階および成熟期における感覚遮断のミクログリアに対する作用を明らかにし、その結果としてのシナプスの変化を抽出する。
    本年度はミクログリアの異種感覚に対する可塑的変化の分子メカニズムを視覚遮断マウスの脳からミクログリア、アストロサイト、神経細胞を抽出し、Dr. Anne Schaeferとともにそのトランスクリプトーム解析を進めることで全容を明らかにし、さらに統合失調症のモデルで視覚遮断を作成することで、統合失調症の発祥の抵抗性を有する分子メカニズムの検索を行う。

  7. Development of cell function editing technology with fast 3D measurement and local-field light perturbation

    Grant number:20K20379  2020.4 - 2022.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Challenging Research (Pioneering)

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    Authorship:Coinvestigator(s) 

  8. Local response of oligodendrocyte progenitor cell regulate axonal activity

    Grant number:19H04753  2019.4 - 2021.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

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    Authorship:Principal investigator 

    Grant amount:\9490000 ( Direct Cost: \7300000 、 Indirect Cost:\2190000 )

  9. 免疫異常の記憶から捉える精神疾患の階層的理解

    Grant number:19H05219  2019.4 - 2021.3

    日本学術振興会  科学研究費助成事業  新学術領域研究(研究領域提案型)

    和氣 弘明

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    Authorship:Principal investigator 

    Grant amount:\7540000 ( Direct Cost: \5800000 、 Indirect Cost:\1740000 )

    大脳皮質感覚野に着目し、各発達期において免疫異常の履歴をもつマウスのエピジェネティックな変化および遺伝子発現の変化を、DNAメチル化に対する検証およびミクログリア特異的遺伝子発現解析法を用いて明らかにし、成熟過程のミクログリアを2光子顕微鏡による機能イメージングと相関づける。続いて、この免疫履歴をもつマウスに対して拘束ストレスを付加し、誘導されるミクログリアの機能変化を検出し、その後表出する遺伝子異常と結びつける。さらにミクログリアの機能変化によって引き起こされる表現型の差異を、特にミクログリアによるシナプス修飾・血液脳関門の透過性制御に着目して、2光子顕微鏡で可視化することで明らかにする。
    本研究ではミクログリアによる精神疾患の関与を解明する研究を行った。ミクログリアはこれまで成熟期においてシナプスなどの恒常性を維持する働きがあることがわかっている。近年全身炎症などが精神症状に寄与することが知られているが、この全身炎症に伴ってミクログリアが血管にCCL5-CCR5のシグナルによって遊走し、炎症早期はCldn5を発現することによって血液脳関門(BBB)の透過性に保護的に作用すること炎症後期においてはCD68を発現することによって、BBBの透過性を増加させることを明らかにした。これによってBBBを介した精神疾患の治療戦略を組み立てることができるようになった。さらに妊娠中のマウスに炎症を引き起こすことで児の自閉症を引き起こすことが知られているが、この際に増加するサイトカインプロファイルを明らかにし、ミクログリアの成熟を促すマーカーの変化を伴うこと、さらにこの極性が行動異常と相関することから、ミクログリアの動態の極性を誘導することで、その生理機能を損なうことを明らかにした。また2Hit論理で統合失調症様症状を発症するモデルマウスの創出に成功し、このマウスにおけるミクログリアのエピゲノム変化が成熟期の発現分子変化およびシナプスに対する作用を変化させることを長期生体イメージングを用いて明らかにし、さらにこのエピゲノムの変化がストレスによって行動異常をもたらす分子基盤及び神経回路基盤を明らかにした。
    令和2年度が最終年度であるため、記入しない。
    令和2年度が最終年度であるため、記入しない。

  10. Microglial contribution on higher order of brain function and their pathology

    Grant number:18H02598  2018.4 - 2021.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    WAKE Hiroaki

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\17420000 ( Direct Cost: \13400000 、 Indirect Cost:\4020000 )

    In this study, we focused on microglia and aimed to elucidate psychiatric pathology from their physiological functions on synapses and blood vessels. Using in vivo imaging, we found that microglia migrate into cerebral blood vessels during systemic inflammation and contribute to the permeability of the blood-brain barrier in a time-specific manner by altering the expression of tight junction-related factors and phagocytic factors. In addition, we found that microglia modulate their synaptic effects by regulating their projection dynamics during higher brain functions (motor learning). These synaptic modulation mechanisms are dependent on the sensory input in the sensory cortex, suggesting a role for microglia in heterogeneous sensory plasticity.

  11. Therapeutic strategy for the abnormal neuronal circuit activity associated with systemic inflammation

    Grant number:17K19458  2017.6 - 2019.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Research (Exploratory)  Grant-in-Aid for Challenging Research (Exploratory)

    WAKE Hiroaki

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    Authorship:Principal investigator 

    Grant amount:\6500000 ( Direct Cost: \5000000 、 Indirect Cost:\1500000 )

    Microglia survey brain parenchyma and respond to any disruptions. Microglia also respond to systemic disease, but how this relates to blood brain barrier (BBB) integrity is largely unknown. Here we use simultaneous in vivo imaging to demonstrate that systemic inflammation induces migration of brain resident microglia to cerebral vessels. Vessel-associated microglia initially maintain BBB integrity, associated with expression of the tight junction protein Claudin-5. Further sustained inflammation results in microglia phagocytosing astrocytic end-feet and impairing BBB function. Our results show dual microglial role for BBB and have important implications for understanding how systemic immune-activation can impact on neural circuit functions.

  12. オリゴデンドロサイトの制御による神経科回路活動の精緻化

    Grant number:17H05747  2017.4 - 2019.3

    日本学術振興会  科学研究費助成事業 新学術領域研究(研究領域提案型)  新学術領域研究(研究領域提案型)

    和氣 弘明

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\11050000 ( Direct Cost: \8500000 、 Indirect Cost:\2550000 )

    オリゴデンドロサイトは髄鞘を形成する細胞で、これまで神経活動依存的に髄鞘化することが知られている。これまで私たちはオリゴデンドロサイトが神経活動依存的に髄鞘化する分子メカニズムを示し、さらに軸索との結合様式を明らかにしてきた。本研究ではこの神経活動依存的髄鞘化を担う、オリゴデンドロサイトの活動を生体で可視化するとともに、その髄鞘を構成する脂質成分を捉えるべく研究を行った。
    1.生体でオリゴデンドロサイトおよびその前駆細胞を可視化するために、PLPプロモーターの下流にカルシウム感受性蛍光タンパク質がテトラサイクリン依存的に発現するマウスを用いて、これを2光子顕微鏡によって生体覚醒下で可視化した。神経細胞活動を操作するために覚醒下、麻酔下の2条件で比較した。細胞体のカルシウム上昇頻度はオリゴデンドロサイトおよびその前駆細胞すべての例において覚醒下氏比して麻酔下では有意に低下した。さらにその突起の活動も有意に低下することを明らかにした。一方でDREAAD法を用いて神経細胞活動を上昇させたところ細胞体の活動は大きく変化せず、突起活動は突起によるバリエーションを認めた。この中からカルシウム上昇が高頻度に起こる部位をホットスポットと定義し、ホットスポットにおけるカルシウム上昇頻度が有意に上昇するのを認めた。またこのホットスポットが学習などの負荷によって高頻度にターンオーバーすることがわかり、現在結果をまとめている。またこのような髄鞘は脂質で構成されていることが知られている。このような脂質変化を神経回路活動の変化と結びつけるため、マウスにレバー引き水報酬学習を行わせ、神経細胞集団の活動を可視化した後、質量分析顕微鏡で脂質成分の変化を検出し、その相関を得られることができた。
    平成30年度が最終年度であるため、記入しない。
    平成30年度が最終年度であるため、記入しない。

  13. 全身免疫異常に伴う神経回路活動の変容に対する治療戦略

    2017.4 - 2019.3

    学術研究助成基金助成金/挑戦的研究(萌芽) 

    和氣 弘明

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    Authorship:Principal investigator  Grant type:Competitive

  14. ホログラム光刺激による神経回路再編の人為的創出

    2017

    国立研究開発法人科学技術振興機構  戦略的創造研究推進事業(CREST) 

    和氣 弘明

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    Authorship:Principal investigator  Grant type:Competitive

  15. ミクログリアによるシナプス活動修飾と神経回路の空間的活動制御

    Grant number:16H01346  2016.4 - 2018.3

    日本学術振興会  科学研究費助成事業 新学術領域研究(研究領域提案型)  新学術領域研究(研究領域提案型)

    和氣 弘明

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    Authorship:Principal investigator 

    Grant amount:\9490000 ( Direct Cost: \7300000 、 Indirect Cost:\2190000 )

    本課題では、感覚刺激、運動学習において生理学的なミクログリア突起の動きによるシナプスへの接触でシナプス活動ひいては神経回路活動にどのように影響し、シナプス機能、可塑性、数を制御するかを検証する。次にこの制御機構の破綻で発達障害、精神・神経疾患を惹起しうるかを考える。これまで、2光子顕微鏡を用いた生体イメージングによってシナプス活動とミクログリアを同時に可視化し、ミクログリアの接触時にシナプス活動が増加することを示し、さらにこのミクログリアによるシナプス活動の修飾はミクログリアをリポ多糖類で活性化させることで消失することを明らかにした。またミクログリアをジフテリア毒素によって遺伝的に時期特異的に除去できるマウス(Iba1-tTa::TetO-DTA)を用いることで、ミクログリアを除去すると神経細胞活動の同期性が減少することから、ミクログリアによるシナプス活動の修飾は神経細胞集団の同期性に寄与していることを示した(論文投稿中)。またミクログリアがシナプス活動を修飾するのであれば、学習過程によってその動態が変化し、シナプス活動の修飾機構が変化する可能性がある。そこでレバー引きによる水報酬学習を用いてその前後でミクログリア突起の動態の比較をしたところ、学習前に比べて、学習後ではミクログリア突起の動態の複雑性が低下し、より定型的になっていることを明らかにした。またこのようなミクログリア突起動態の変化が精神疾患などのモデルでも認められるかどうか検証するために統合失調症モデル(Shn2-KO)で同様に比較したところ統合失調症モデルではミクログリア突起の動態の複雑性が増していることがわかった。そこで、これらを踏まえ、今後ミクログリアのシナプス修飾機構から精神疾患を考察していく。
    29年度が最終年度であるため、記入しない。
    29年度が最終年度であるため、記入しない。

  16. 身体疾患で惹起される免疫変容が起こす神経回路恒常性の破綻と精神症状の解明

    2016

    国立研究開発法人科学技術振興機構  戦略的創造研究推進事業(さきがけ) 

    和氣 弘明

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    Authorship:Principal investigator  Grant type:Competitive

  17. ミクログリアによるシナプス活動修飾と神経回路の空間的活動制御

    2015.4 - 2018.3

    科学研究費補助金/新学術領域研究 

    和氣 弘明

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    Authorship:Principal investigator  Grant type:Competitive

  18. グリア細胞からみる精神疾患

    Grant number:15H01300  2015.4 - 2017.3

    日本学術振興会  科学研究費助成事業 新学術領域研究(研究領域提案型)  新学術領域研究(研究領域提案型)

    和氣 弘明

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\4680000 ( Direct Cost: \3600000 、 Indirect Cost:\1080000 )

    多様化する現代社会において、高次脳機能に異常を呈する発達障害・精神疾患の病態の解明および治療法の開発は喫緊の課題である。本課題では統合失調症モデルマウスにおける神経回路基盤の変化を脳内免疫と結びつけて検証する。すなわち統合失調症モデルとしてSchnurri-2 欠損マウスを用い、Schnurri-2 欠損マウスの中枢神経系炎症反応の増大の結果としてミクログリアにおけるシナプス制御分子、髄鞘制御分子の変化を検出し、これを、2光子顕微鏡によるin vivoイメージングを組み合わせることにより行動異常と神経回路動作の相関を神経細胞の発火パターン、シナプスの活動パターンを可視化することによって明らかにする。これまでSchnurri-2 欠損マウスにおける神経細胞の発火率、発火パターンを検証するためにカルシウム感受性蛍光タンパク質であるGCaMP6fをコードする遺伝子をアデノ随伴ウィルス(AAV)の大脳皮質感覚野・運動野への注入によって発現させ、その神経細胞集団音発火を解析することによって覚醒下の神経細胞活動の協調性の低下が認められていることを明らかにした。さらに中枢神経系免疫細胞であるミクログリアを免疫染色することによってその突起の短縮および複雑性の低下を認めた。さらにSchnurri-2 欠損マウスのミクログリアにGFPが発現するマウスを作成し、2光子顕微鏡を用いて突起の動きを解析したところ、その動きのランダムさが亢進していることがわかった(Haruwaka et al., in preparation)。これはシナプス活動のランダムさを反映するものであると考えている。今後この変化を担う分子の同定を行うとともに、行動との相関を検証する予定である

  19. The effect of activity dependent myelination on to the neuronal circuit activity

    Grant number:26710004  2014.4 - 2018.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (A)  Grant-in-Aid for Young Scientists (A)

    WAKE Hiroaki

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\24570000 ( Direct Cost: \18900000 、 Indirect Cost:\5670000 )

    Myelination increases conduction velocity and promotes brain functions. Myelin dysregulation is frequently associated with learning and cognition deficits, ultimately causing neurological and psychiatric disorders. However, it has not been revealed what perturbation of neural activity induced by myelin dysregulation impairs learning. Here, we measured neural activity in the motor cortex during motor learning in transgenic mice with a subtle impairment of their myelin regulation.This myelin dysregulation impaired motor learning and was accompanied by a decrease in the amplitude of movement-related activity, an increase in the frequency of spontaneous activity, and a widening in the timing of cortical responses to thalamic stimulation. Repetitive pairing of forelimb movements with optogenetic stimulation of thalamocortical axon terminals partially restored learning.

  20. スキャンレス3D ホログラフィック計測・刺激顕微鏡の開発と生体応用

    国立研究開発法人科学技術振興機構  A-STEP産学共同【本格型】 

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Teaching Experience (Off-campus) 17

  1. 文献解析・プレゼンテーション演習

    Kobe University)

  2. Biomedical ScienceA

    Kobe University)

  3. Basic Course of Bioscience

    Kobe University)

  4. Forefront of Research at Kobe University B

    Kobe University)

  5. 神戸大学の研究最前線B

    Kobe University)

  6. 生理学

    Kobe University)

  7. 医学B

    Kobe University)

  8. 医学A

    Kobe University)

  9. 医学序説

    Kobe University)

  10. バイオメディカルサイエンス特別研究

    Kobe University)

  11. バイオメディカルサイエンスA

    Kobe University)

  12. バイオサイエンス基本実習

    Kobe University)

  13. Research in Biomedical Science

    Kobe University)

  14. Physiology

    Kobe University)

  15. Medical Science B

    Kobe University)

  16. Medical Science A

    Kobe University)

  17. Literature Analysis and Presentation

    Kobe University)

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