Updated on 2025/10/14

写真a

 
ZHOU Zhiwen
 
Organization
Research Institute of Environmental Medicine Division of Stress Recognition and Response Assistant Professor
Graduate School
Graduate School of Medicine
Title
Assistant Professor
External link

Degree 1

  1. 博士(薬科学) ( 2019.3   東京大学 ) 

Research Interests 3

  1. Astrocyte

  2. Microglia

  3. Memory

Research Areas 3

  1. Life Science / Neuroscience - general

  2. Life Science / Neuroscience - general

  3. Life Science / Pharmacology

Research History 12

  1. Nagoya University   Research Institute of Environmental Medicine Division of Stress Recognition and Response   Assistant Professor

    2025.4

  2. Nagoya University   Research Institute of Environmental Medicine

    2025.4

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  3. Nagoya University   Researcher

    2024.6 - 2025.3

  4. Nagoya University   Graduate School of Science   Researcher

    2024.6 - 2025.3

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  5. Hokkaido University   Assistant Professor

    2021.6 - 2024.5

  6. Hokkaido University   Assistant Professor

    2021.6 - 2024.5

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  7. The University of Tokyo

    2019.9 - 2021.5

  8. The University of Tokyo   Graduate School of Pharmaceutical Sciences

    2019.9 - 2021.5

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  9. The University of Tokyo

    2019.4 - 2019.8

  10. The University of Tokyo   Graduate School of Pharmaceutical Sciences

    2019.4 - 2019.8

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  11. The University of Tokyo

    2016.4 - 2019.3

  12. The University of Tokyo   Graduate School of Pharmaceutical Sciences

    2016.4 - 2019.3

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Papers 20

  1. Astrocytic cAMP modulates memory via synaptic plasticity. Reviewed International journal Open Access

    Zhiwen Zhou, Kazuki Okamoto, Junya Onodera, Toshimitsu Hiragi, Megumi Andoh, Masahito Ikawa, Kenji F Tanaka, Yuji Ikegaya, Ryuta Koyama

    Proceedings of the National Academy of Sciences of the United States of America   Vol. 118 ( 3 )   2021.1

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)  

    Astrocytes play a key role in brain homeostasis and functions such as memory. Specifically, astrocytes express multiple receptors that transduce signals via the second messenger cAMP. However, the involvement of astrocytic cAMP in animal behavior and the underlying glial-neuronal interactions remains largely unknown. Here, we show that an increase in astrocytic cAMP is sufficient to induce synaptic plasticity and modulate memory. We developed a method to increase astrocytic cAMP levels in vivo using photoactivated adenylyl cyclase and found that increased cAMP in hippocampal astrocytes at different time points facilitated memory formation but interrupted memory retention via NMDA receptor-dependent plasticity. Furthermore, we found that the cAMP-induced modulation of memory was mediated by the astrocyte-neuron lactate shuttle. Thus, our study unveils a role of astrocytic cAMP in brain function by providing a tool to modulate astrocytic cAMP in vivo.

    DOI: 10.1073/pnas.2016584118

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  2. The Astrocytic cAMP Pathway in Health and Disease. Invited Reviewed International journal

    Zhiwen Zhou, Yuji Ikegaya, Ryuta Koyama

    International journal of molecular sciences   Vol. 20 ( 3 )   2019.2

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    Astrocytes are major glial cells that play critical roles in brain homeostasis. Abnormalities in astrocytic functions can lead to brain disorders. Astrocytes also respond to injury and disease through gliosis and immune activation, which can be both protective and detrimental. Thus, it is essential to elucidate the function of astrocytes in order to understand the physiology of the brain to develop therapeutic strategies against brain diseases. Cyclic adenosine monophosphate (cAMP) is a major second messenger that triggers various downstream cellular machinery in a wide variety of cells. The functions of astrocytes have also been suggested as being regulated by cAMP. Here, we summarize the possible roles of cAMP signaling in regulating the functions of astrocytes. Specifically, we introduce the ways in which cAMP pathways are involved in astrocyte functions, including (1) energy supply, (2) maintenance of the extracellular environment, (3) immune response, and (4) a potential role as a provider of trophic factors, and we discuss how these cAMP-regulated processes can affect brain functions in health and disease.

    DOI: 10.3390/ijms20030779

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  3. Photoactivated adenylyl cyclase (PAC) reveals novel mechanisms underlying cAMP-dependent axonal morphogenesis. Reviewed International journal Open Access

    Zhiwen Zhou, Kenji F Tanaka, Shigeru Matsunaga, Mineo Iseki, Masakatsu Watanabe, Norio Matsuki, Yuji Ikegaya, Ryuta Koyama

    Scientific reports   Vol. 5   page: 19679 - 19679   2016.1

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    Spatiotemporal regulation of axonal branching and elongation is essential in the development of refined neural circuits. cAMP is a key regulator of axonal growth; however, whether and how intracellular cAMP regulates axonal branching and elongation remain unclear, mainly because tools to spatiotemporally manipulate intracellular cAMP levels have been lacking. To overcome this issue, we utilized photoactivated adenylyl cyclase (PAC), which produces cAMP in response to blue-light exposure. In primary cultures of dentate granule cells transfected with PAC, short-term elevation of intracellular cAMP levels induced axonal branching but not elongation, whereas long-term cAMP elevation induced both axonal branching and elongation. The temporal dynamics of intracellular cAMP levels regulated axonal branching and elongation through the activation of protein kinase A (PKA) and exchange protein directly activated by cAMP (Epac), respectively. Thus, using PAC, our study for the first time reveals that temporal cAMP dynamics could regulate axonal branching and elongation via different signaling pathways.

    DOI: 10.1038/srep19679

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  4. Sleep homeostasis in lizards and the role of the cortex. Reviewed International journal

    Sena Hatori, Sho T Yamaguchi, Riho Kobayashi, Kazuki Okamoto, Zhiwen Zhou, Koki T Kotake, Futaba Matsui, Hiroyuki Hioki, Hiroaki Norimoto

    Proceedings of the National Academy of Sciences of the United States of America   Vol. 122 ( 16 ) page: e2415929122   2025.4

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    Slow-wave sleep (SWS) and rapid eye movement sleep are the two primary components of electrophysiological sleep (e-sleep) in mammals and birds. Slow waves in the cortex not only characterize SWS but are also used as biological markers for sleep homeostasis, given their rebound after sleep deprivation (SD). Recently, it has been reported that the Australian dragon Pogona vitticeps exhibits a two-stage sleep pattern in the dorsal ventricular ridge (DVR), which includes a homologue of the mammalian claustrum (CLA). It remains unclear whether reptilian e-sleep, which has been characterized by activity outside the cortex, compensates for sleep loss, as observed in mammals. We here report a significant rebound in the local field potential (LFP) after 7 h of SD. Meanwhile, the mean bout length of each sleep state remained unaffected. We further investigated a possible role of the cortex in e-sleep regulation and homeostasis in Pogona and found that although a corticotomy had no obvious effect on the LFP features of baseline sleep, it abolished LFP power rebound in the CLA/DVR after SD. These findings suggest that e-sleep homeostasis is a common feature in amniotes and that the cortex is involved in regulating activity rebounds in reptiles and mammals.

    DOI: 10.1073/pnas.2415929122

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  5. Diversity of REM sleep Invited Reviewed Open Access

    Sho T Yamaguchi, Zhiwen Zhou, Hiroaki Norimoto

    Current Opinion in Behavioral Sciences   Vol. 60   page: 101457 - 101457   2024.12

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Elsevier BV  

    DOI: 10.1016/j.cobeha.2024.101457

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  6. Transient Cooling Resets Circadian Rhythms of Locomotor Activity in Lizards Reviewed Open Access

    Sakimi Nagashima, Sho T. Yamaguchi, Zhiwen Zhou, Hiroaki Norimoto

    Journal of Biological Rhythms   Vol. 39 ( 6 ) page: 607 - 613   2024.9

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

    Animals frequently experience temperature fluctuations in their natural life cycle, including periods of low temperatures below their activity range. For example, poikilothermic animals are known to enter a hibernation-like state called brumation during transient cooling. However, the knowledge regarding the physiological responses of brumation is limited. Specifically, the impact of exposure to low-temperature conditions outside the range of temperature compensation on the subsequent circadian behavioral rhythms remains unclear. In this study, we investigated the effects of transient cooling on the behavioral circadian rhythm in the non-avian reptile, the bearded dragon ( Pogona vitticeps). Under constant light (LL) conditions at 30 °C, the animals exhibited a free-running rhythm, and exposure to low temperatures (4 °C) caused a complete cessation of locomotion. Furthermore, we revealed that the behavioral rhythm after rewarming is determined not by the circadian phase at the onset or the duration of cooling, but by the timing of cooling cessation.

    DOI: 10.1177/07487304241273190

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    Other Link: https://journals.sagepub.com/doi/full-xml/10.1177/07487304241273190

  7. Yawning and Its Temperature-Dependent Modulation in Leopard Geckos Reviewed

    Koki T. Kotake, Sho T. Yamaguchi, Yasutaka Mukai, Zhiwen Zhou, Hiroaki Norimoto

    Zoological Science   Vol. 42 ( 1 )   2024.9

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Zoological Society of Japan  

    DOI: 10.2108/zs230123

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  8. Microglia mediate the increase in slow-wave sleep associated with high ambient temperature Reviewed Open Access

    Sena Hatori, Futaba Matsui, Zhiwen Zhou, Hiroaki Norimoto

    The Journal of Physiological Sciences   Vol. 74 ( 1 ) page: 37   2024.7

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    Authorship:Corresponding author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:Elsevier BV  

    Abstract

    An increase in ambient temperature leads to an increase in sleep. However, the mechanisms behind this phenomenon remain unknown. This study aimed to investigate the role of microglia in the increase of sleep caused by high ambient temperature. We confirmed that at 35 °C, slow-wave sleep was significantly increased relative to those observed at 25 °C. Notably, this effect was abolished upon treatment with PLX3397, a CSF1R inhibitor that can deplete microglia, while sleep amount at 25 °C was unaffected. These observations suggest that microglia play a pivotal role in modulating the homeostatic regulation of sleep in response to the fluctuations in ambient temperature.

    DOI: 10.1186/s12576-024-00929-0

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    Other Link: https://link.springer.com/article/10.1186/s12576-024-00929-0/fulltext.html

  9. CSF1R inhibitor PLX3397 depletes microglia in Mongolian gerbil Meriones unguiculatus, but not in syrian hamster Mesocricetus auratus Reviewed Open Access

    Ren Y. Sato, Yumin Zhang, Koki T. Kotake, Hiraku Onishi, Shiho Ito, Hiroaki Norimoto, Zhiwen Zhou

    Journal of Pharmacological Sciences   Vol. 155 ( 2 ) page: 29 - 34   2024.6

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    Authorship:Last author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:Elsevier BV  

    DOI: 10.1016/j.jphs.2024.03.003

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  10. Circadian control of sleep-related neuronal activity in lizards. Reviewed Open Access

    Sho T Yamaguchi , Sena Hatori , Koki T Kotake , Zhiwen Zhou , Kazuhiko Kume , Sam Reiter , Hiroaki Norimoto

    PNAS nexus   Vol. 3 ( 1 ) page: pgad481   2024.1

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    DOI: 10.1093/pnasnexus/pgad48

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  11. Circadian control of sleep-related neuronal activity in lizards. Reviewed International journal

    Sho T Yamaguchi, Sena Hatori, Koki T Kotake, Zhiwen Zhou, Kazuhiko Kume, Sam Reiter, Hiroaki Norimoto

    PNAS nexus   Vol. 3 ( 1 ) page: pgad481   2024.1

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    Although diurnal animals displaying monophasic sleep patterns exhibit periodic cycles of alternating slow-wave sleep (SWS) and rapid eye movement sleep (REMS), the regulatory mechanisms underlying these regular sleep cycles remain unclear. Here, we report that in the Australian dragon Pogona vitticeps exposed to constant darkness (DD), sleep behavior and sleep-related neuronal activity emerged over a 24-h cycle. However, the regularity of the REMS/SWS alternation was disrupted under these conditions. Notably, when the lizards were then exposed to 12 h of light after DD, the regularity of the sleep stages was restored. These results suggest that sleep-related neuronal activity in lizards is regulated by circadian rhythms and that the regularity of REMS and SWS cycling is influenced by daytime light exposure.

    DOI: 10.1093/pnasnexus/pgad481

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  12. Methyl vinyl ketone impairs spatial memory and activates hippocampal glial cells in mice Reviewed Open Access

    Ren Y. Sato, Koki Kotake, Yumin Zhang, Hiraku Onishi, Futaba Matsui, Hiroaki Norimoto, Zhiwen Zhou

    PLOS ONE   Vol. 18 ( 8 ) page: e0289714 - e0289714   2023.8

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    Authorship:Last author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:Public Library of Science (PLoS)  

    Memory is a fundamental brain function that can be affected by a variety of external factors including environmental pollutants. One of these pollutants is methyl vinyl ketone (MVK), a hazardous substance found in cigarettes, industrial wastes, and car exhaust. Humans can be exposed to MVK under many circumstances; however, it is unclear whether MVK affects higher-order brain functions such as memory. Here, we examined the memory performances of mice receiving systemic MVK administration. We found that 1 mg/kg of MVK impaired spatial memory. We also showed that 1 mg/kg MVK activated glial cells and altered glial functions in several subregions of the hippocampus, a brain region involved in learning and memory. These results suggest that MVK induces memory deficits and activates glial cells in hippocampal subregions.

    DOI: 10.1371/journal.pone.0289714

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  13. Ablation of microglia does not alter circadian rhythm of locomotor activity. Reviewed International journal Open Access

    Futaba Matsui, Sho T Yamaguchi, Riho Kobayashi, Shiho Ito, Sakimi Nagashima, Zhiwen Zhou, Hiroaki Norimoto

    Molecular brain   Vol. 16 ( 1 ) page: 34 - 34   2023.4

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    Authorship:Corresponding author   Language:English   Publishing type:Research paper (scientific journal)  

    Microglia, as macrophages in the brain, are responsible for immune responses and synaptic remodeling. Although the function of microglia is regulated by circadian rhythms, it is still unclear whether microglia are involved in the generation and light entrainment of circadian rhythms of behavior. Here, we report that microglial depletion does not alter behavioral circadian rhythms. We depleted ~ 95% of microglia in the mouse brain by PLX3397, a CSF1R inhibitor, and analyzed the effect on the spontaneous behaviors of mice. We found that neither the free-running period under constant darkness nor light entrainment under jet-lag circumstances were influenced by the ablation of microglia. Our results demonstrate that the circadian rhythms of locomotor activity, an important output of the circadian clock in the brain, are likely a phenomenon not produced by microglia.

    DOI: 10.1186/s13041-023-01021-1

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  14. Sleep sharp wave ripple and its functions in memory and synaptic plasticity Invited Reviewed Open Access

    Zhiwen Zhou, Hiroaki Norimoto

    Neuroscience Research   Vol. 189   page: 20 - 28   2023.4

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    Authorship:Lead author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:Elsevier BV  

    DOI: 10.1016/j.neures.2023.01.011

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  15. Methyl vinyl ketone disrupts neuronal survival and axonal morphogenesis Reviewed

    Hiromu Sugawara, Hiroaki Norimoto, Zhiwen Zhou

    The Journal of Toxicological Sciences   Vol. 47 ( 9 ) page: 375 - 380   2022

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    Authorship:Last author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:Japanese Society of Toxicology  

    DOI: 10.2131/jts.47.375

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  16. The use of photoactivated adenylyl cyclase (PAC) to investigate the function of astrocytes

    Zhiwen Zhou, Yuji Ikegaya, Ryuta Koyama

        2020.2

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  17. The Astrocytic cAMP Pathway in Health and Disease Invited Reviewed Open Access

    Zhiwen Zhou , Yuji Ikegaya , Ryuta Koyama

    International journal of molecular sciences   Vol. 20 ( 3 )   2019.2

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    DOI: 10.3390/ijms20030779

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  18. Structural insight into photoactivation of an adenylate cyclase from a photosynthetic cyanobacterium. Reviewed International journal Open Access

    Mio Ohki, Kanako Sugiyama, Fumihiro Kawai, Hitomi Tanaka, Yuuki Nihei, Satoru Unzai, Masumi Takebe, Shigeru Matsunaga, Shin-Ichi Adachi, Naoya Shibayama, Zhiwen Zhou, Ryuta Koyama, Yuji Ikegaya, Tetsuo Takahashi, Jeremy R H Tame, Mineo Iseki, Sam-Yong Park

    Proceedings of the National Academy of Sciences of the United States of America   Vol. 113 ( 24 ) page: 6659 - 64   2016.6

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    Cyclic-AMP is one of the most important second messengers, regulating many crucial cellular events in both prokaryotes and eukaryotes, and precise spatial and temporal control of cAMP levels by light shows great promise as a simple means of manipulating and studying numerous cell pathways and processes. The photoactivated adenylate cyclase (PAC) from the photosynthetic cyanobacterium Oscillatoria acuminata (OaPAC) is a small homodimer eminently suitable for this task, requiring only a simple flavin chromophore within a blue light using flavin (BLUF) domain. These domains, one of the most studied types of biological photoreceptor, respond to blue light and either regulate the activity of an attached enzyme domain or change its affinity for a repressor protein. BLUF domains were discovered through studies of photo-induced movements of Euglena gracilis, a unicellular flagellate, and gene expression in the purple bacterium Rhodobacter sphaeroides, but the precise details of light activation remain unknown. Here, we describe crystal structures and the light regulation mechanism of the previously undescribed OaPAC, showing a central coiled coil transmits changes from the light-sensing domains to the active sites with minimal structural rearrangement. Site-directed mutants show residues essential for signal transduction over 45 Å across the protein. The use of the protein in living human cells is demonstrated with cAMP-dependent luciferase, showing a rapid and stable response to light over many hours and activation cycles. The structures determined in this study will assist future efforts to create artificial light-regulated control modules as part of a general optogenetic toolkit.

    DOI: 10.1073/pnas.1517520113

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  19. [Early childhood stress and neuropsychiatric disease].

    Zhiwen Zhou, Cong Luo, Ryuta Koyama

    Nihon yakurigaku zasshi. Folia pharmacologica Japonica   Vol. 146 ( 5 ) page: 263 - 7   2015.11

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    DOI: 10.1254/fpj.146.263

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  20. [Photoactivated adenylyl cyclase, a new optogenetic tool for neurobiology].

    Zhou Zhiwen, Ryuta Koyama

    Nihon yakurigaku zasshi. Folia pharmacologica Japonica   Vol. 146 ( 2 ) page: 119 - 119   2015.8

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    DOI: 10.1254/fpj.146.119

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Presentations 8

  1. 短期社会的隔離による神経回路の変調へのマイクログリアの関与

    周至文, 伊藤詩歩, 張煜民, 乘本裕明

    第29回海馬と高次脳機能学会  2022.9 

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  2. cAMPによる軸索分枝と伸長の分別制御

    周至文, 田中謙二, 松永茂, 伊関峰生, 渡辺正勝, 松木則夫, 池谷裕二, 小山隆太

    第130回日本薬理学会関東部会  2014.7.5 

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  3. cAMPによる軸索分枝と伸長の独立制御

    周至文, 田中謙二, 松永茂, 伊関峰生, 渡辺正勝, 松木則夫, 池谷裕二, 小山隆太

    第37回日本神経科学大会  2014.9 

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  4. Optogenetic Regulation of cAMP in Brain Cells In vivo Invited

    Zhou, Z., Onodera, J., Hiragi, T., Andoh, M., Tanaka, F, K., Koyama, R., Ikegaya, Y.

    9th Optogenetics Research Society Japan International Symposium  2017.10 

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  5. The Involvement of microglia in social isolation induced behavioral deficits Invited

    Zhiwen Zhou

    The NIPS Research Meeting 2024  2024.9 

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  6. アストロサイトの光操作による記憶の制御

    周至文, 小野寺純也, 平木俊光, 安藤めぐみ, 田中譲二, 小山隆太, 池谷裕二

    第92回日本薬理学会年会  2019.3 

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  7. 光活性化アデニル酸シクラーゼによる軸索形態形成の解明

    周至文, 田中謙二, 松永茂, 伊関峰生, 渡辺正勝, 松木則夫, 池谷裕二, 小山隆太

    第89回日本薬理学会年会  2016.3 

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  8. 光活性化アデニル酸シクラーゼ(PAC)の利用による脳内回路形成機構の解明

    周至文, 田中謙二, 松永茂, 伊関峰生, 渡辺正勝, 松木則夫, 池谷裕二, 小山隆太

    平成26年度生理学研究所研究会 「グリア細胞機能から迫る脳機能解明」  2014.10 

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KAKENHI (Grants-in-Aid for Scientific Research) 4

  1. Glial Involvement in Neural Alterations Underlying Social Isolation

    Grant number:25K18582  2025.4 - 2027.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Early-Career Scientists

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    Grant amount:\4810000 ( Direct Cost: \3700000 、 Indirect Cost:\1110000 )

  2. The astrocytic modulation of sleep oscillation

    Grant number:22K15369  2022.4 - 2025.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Early-Career Scientists

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

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  3. Suppression of epileptic seizures by regulating astrocytic cAMP signaling

    Grant number:19F19411  2019.10 - 2022.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for JSPS Fellows

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  4. 新規の光感受性タンパク質を利用した神経回路形成メカニズムの解明

    Grant number:16J08137  2016.4 - 2019.3

    日本学術振興会  科学研究費助成事業  特別研究員奨励費

    周 至文

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    Grant amount:\2800000 ( Direct Cost: \2800000 )

    本研究は、申請者が作製に携わり、有用性を検証したアストロサイト特異的に光活性化アデニル酸シクラーゼ(PAC)を発現する遺伝子改変マウスを利用し、海馬に局所的な青色光刺激を与え、海馬のアストロサイトのcAMP濃度を上昇させた場合、海馬の機能へ与える影響を調べた。本研究は、海馬が司る空間記憶およびてんかん発作感受性について検証した。
    空間記憶形成時海馬アストロサイトのcAMP濃度を一時的に上昇させた場合、記憶がより長く保持され、記憶形成が促進されるという結果が得られた。一方、記憶形成した一日後に海馬アストロサイトのcAMPを上昇させた場合、記憶成績が低下し、記憶保持が阻害されるということが示唆された。そのメカニズムを検証した結果、アストロサイトのcAMP上昇によって神経細胞のNMDA受容体が活性化され、神経細胞およびシナプス可塑性が誘導されることが示唆された。この結果はアストロサイトのcAMPシグナルがタイミングによって双方向に記憶に影響することを初めて示した。そして、アストロサイトのcAMPシグナルがNMDA受容体を活性化し、神経活動およびシナプス可塑性を誘導するという新たな経路を同定した。
    また、てんかん発作感受性について調べたところ、海馬アストロサイトのcAMP濃度上昇が薬物によって誘導された急性てんかん発作の程度を軽減したことを発見した。本研究はグリア細胞を急性的に操作することでてんかん発作を抑制する初めて研究となる。この発見はグリア細胞に着目することでてんかん発作の対処法または難治性てんかんの治療に進歩をもたらす可能性を秘めている。
    本研究は、海馬アストロサイトのcAMPシグナルに着目し、光遺伝学的な制御によって海馬の複数の機能に影響与えることを発見した。

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