Updated on 2022/02/24

写真a

 
FUKUSHIMA Akihiro
 
Organization
Graduate School of Medicine Center for Research of Laboratory Animals and Medical Research Engineering Division for Advanced Medical Research Assistant Professor
Graduate School
Graduate School of Medicine
Undergraduate School
School of Medicine Department of Medicine
Title
Assistant Professor

Degree 3

  1. 博士(医学) ( 2010.4   東京大学 ) 

  2. 修士(薬学) ( 2005.3   名古屋市立大学 ) 

  3. 学士(薬学) ( 2003.3   名古屋市立大学 ) 

Current Research Project and SDGs 1

  1. Central nervous system for homeostatic regulation

 

Papers 8

  1. Intracerebroventricular Treatment with Resiniferatoxin and Pain Tests in Mice Reviewed

    Fukushima A, Fujii M, Ono H

    Journal of visualized experiments   ( 163 )   2020.9

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    Language:English  

    DOI: 10.3791/57570

    PubMed

  2. Impairment of spatial memory accuracy improved by Cbr1 copy number resumption and GABAB receptor-dependent enhancement of synaptic inhibition in Down syndrome model mice Reviewed

    Fumiko Arima-Yoshida, Matthieu Raveau, Atsushi Shimohata, Kenji Amano, Akihiro Fukushima, Masashi Watanave, Shizuka Kobayashi, Satoko Hattori, Masaya Usui, Haruhiko Sago, Nobuko Mataga, Tsuyoshi Miyakawa, Kazuhiro Yamakawa, Toshiya Manabe

    Scientific Reports   Vol. 10 ( 1 ) page: 14187   2020.8

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

    Down syndrome is a complex genetic disorder caused by the presence of three copies of the chromosome 21 in humans. The most common models, carrying extra-copies of overlapping fragments of mouse chromosome 16 that is syntenic to human chromosome 21, are Ts2Cje, Ts1Cje and Ts1Rhr mice. In electrophysiological analyses using hippocampal slices, we found that the later phase of the depolarization during tetanic stimulation, which was regulated by GABAB receptors, was significantly smaller in Ts1Cje and Ts2Cje mice than that in WT controls but not in Ts1Rhr mice. Furthermore, isolated GABAB receptor-mediated inhibitory synaptic responses were larger in Ts1Cje mice. To our knowledge, this is the first report that directly shows the enhancement of GABAB receptor-mediated synaptic currents in Ts1Cje mice. These results suggest that GABAB receptor-mediated synaptic inhibition was enhanced in Ts1Cje and Ts2Cje mice but not in Ts1Rhr mice. The Cbr1 gene, which is present in three copies in Ts1Cje and Ts2Cje but not in Ts1Rhr, encodes carbonyl reductase that may facilitate GABAB-receptor activity through a reduction of prostaglandin E2 (PGE2). Interestingly, we found that a reduction of PGE2 and an memory impairment in Ts1Cje mice were alleviated when only Cbr1 was set back to two copies (Ts1Cje;Cbr1+/+/-). However, the GABAB receptor-dependent enhancement of synaptic inhibition in Ts1Cje was unaltered in Ts1Cje;Cbr1+/+/- mice. These results indicate that Cbr1 is one of the genes responsible for DS cognitive impairments and the gene(s) other than Cbr1, which is included in Ts1Cje but not in Ts1Rhr, is responsible for the GABAB receptor-dependent over-inhibition.

    DOI: 10.1038/s41598-020-71085-9

    Web of Science

    Scopus

    PubMed

    Other Link: http://www.nature.com/articles/s41598-020-71085-9

  3. Oxytocinergic Neurons in the Hypothalamic Paraventricular Nucleus Stimulate Brown Adipose Tissue Thermogenesis through Rostral Medullary Raphe

    Fukushima Akihiro, Nakamura Kazuhiro

    FASEB JOURNAL   Vol. 33   2019.4

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    Language:Japanese  

    Web of Science

  4. Similarity of Clinically Significant Neuropsychiatric Adverse Reactions Listed in Package Inserts between the Anti-influenza Drugs Oseltamivir and Amantadine (Possibility Attributable to Common Pharmacological Effects) Reviewed

    Ono Hideki, Okamura Maya, Fukushima Akihiro

    YAKUGAKU ZASSHI   Vol. 138 ( 9 ) page: 1201 - 1215   2018.9

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:公益社団法人 日本薬学会  

    <bibitem lang="en">  The anti-influenza virus drug oseltamivir has been reported to have several pharmacological actions including blocking of nicotinic acetylcholine receptor channels and activation of the dopaminergic system. These pharmacological actions highly overlap those of amantadine, another anti-influenza virus drug authorized in Japan, and ester-type local anesthetics. Moreover, oseltamivir and amantadine can clinically induce similar adverse neuropsychiatric reactions. In the present study, from the database of the Pharmaceuticals and Medical Devices Agency (PMDA), we surveyed 2,576 drugs for which neuropsychiatric side effects similar to those of oseltamivir, amantadine and local anesthetics (abnormal behavior, confusion, consciousness disturbance, convulsion, delirium, delusion, hallucination, myoclonus, tremor) are listed as “clinically significant adverse reactions”, and found 327 that had at least one of these adverse reactions. Other neuraminidase inhibitors (laninamivir, peramivir and zanamivir) did not elicit such adverse reactions. By discussing the pharmacological effects of drugs that elicit these adverse reactions, we propose that the similarity of adverse neuropsychiatric reactions between oseltamivir and amantadine is possibly attributable to their common pharmacological effects.<br>

    DOI: 10.1248/yakushi.18-00022

    PubMed

  5. The anti-influenza drug oseltamivir evokes hypothermia in mice through dopamine D2 receptor activation via central actions Reviewed

    Akihiro Fukushima, Arisa Fukui, Yuki Takemura, Yasuhiro Maeda, Hideki Ono

    Journal of Pharmacological Sciences   Vol. 136 ( 1 ) page: 39 - 41   2018.1

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:Japanese Pharmacological Society  

    Oseltamivir has a hypothermic effect in mice when injected intraperitoneally (i.p.) and intracerebroventricularly (i.c.v.). Here we show that the hypothermia evoked by i.c.v.-oseltamivir is inhibited by non-selective dopamine receptor antagonists (sulpiride and haloperidol) and the D2-selective antagonist L-741,626, but not by D1/D5-selective and D3-selective antagonists (SCH-23390 and SB-277011-A, respectively). The hypothermic effect of i.p.-administered oseltamivir was not inhibited by sulpiride, haloperidol, L-741,626 and SCH-23390. In addition, neither sulpiride, haloperidol nor SCH-23390 blocked hypothermia evoked by i.c.v.-administered oseltamivir carboxylate (a hydrolyzed metabolite of oseltamivir). These results suggest that oseltamivir in the brain induces hypothermia through activation of dopamine D2 receptors.

    DOI: 10.1016/j.jphs.2017.12.005

    Web of Science

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    Other Link: http://orcid.org/0000-0003-4465-7445

  6. Supraspinal-selective TRPV1 desensitization induced by intracerebroventricular treatment with resiniferatoxin Reviewed

    Akihiro Fukushima, Kizuku Mamada, Aki Iimura, Hideki Ono

    SCIENTIFIC REPORTS   Vol. 7 ( 1 ) page: 12452   2017.9

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:NATURE PUBLISHING GROUP  

    The transient receptor potential vanilloid type 1 (TRPV1) is a thermosensitive cation channel that triggers heat pain in the periphery. Long-term desensitization of TRPV1, which can be induced by excess amounts of agonists, has been a method for investigating the physiological relevance of TRPV1 containing neuronal circuits, and desensitization induced by various routes of administration, including systemic, intrathecal and intraganglionic, has been demonstrated in rodents. In the present study, we examined the effect of intracerebroventricular (i.c.v.) treatment with an ultrapotent TRPV1 agonist, resiniferatoxin (RTX), on nociception and the analgesic effect of acetaminophen, which is known to mediate the activation of central TRPV1. I.c.v. administration of RTX a week before the test did not affect the licking/biting response to intraplantar injection of RTX (RTX test), suggesting that such i.c.v. treatment spares the function of TRPV1 at the hindpaw. Mice that had been i.c.v.-administered RTX also exhibited normal nociceptive responses in the formalin test and the tail pressure test, but acetaminophen failed to induce analgesia in those mice in any of the tests. These results suggest that i.c.v. administration of RTX leads to brain-selective TRPV1 desensitization in mice.

    DOI: 10.1038/s41598-017-12717-5

    Web of Science

    PubMed

  7. Serotonergic System Does Not Contribute to the Hypothermic Action of Acetaminophen Reviewed

    Akihiro Fukushima, Wakana Sekiguchi, Kizuku Mamada, Yumi Tohma, Hideki Ono

    BIOLOGICAL & PHARMACEUTICAL BULLETIN   Vol. 40 ( 2 ) page: 227 - 233   2017.2

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:PHARMACEUTICAL SOC JAPAN  

    Acetaminophen (AcAP), a widely-used antipyretic and analgesic drug, has been considered to exert its effects via central mechanisms, and many studies have demonstrated that the analgesic action of AcAP involves activation of the serotonergic system. Although the serotonergic system also plays an important role in thermoregulation, the contribution of serotonergic activity to the hypothermic effect of AcAP has remained unclear. In the present study, we examined whether the serotonergic system is involved in AcAP-induced hypothermia. In normal mice, AcAP (300 mg/kg, intraperitoneally (i.p.)) induced marked hypothermia (ca. -4 degrees C). The same dose of AcAP reduced pain response behavior in the formalin test. Pretreatment with the serotonin synthesis inhibitor DL-p-chlorophenylalanine (PCPA, 300 mg/kg/d, i.p., 5 consecutive days) substantially decreased serotonin in the brain by 70% and significantly inhibited the analgesic, but not the hypothermic action of AcAP. The same PCPA treatment significantly inhibited the hypothermia induced by the selective serotonin reuptake inhibitor fluoxetine hydrochloride (20mg/kg, i.p.) and the serotonin 5-HT2 receptor antagonist cyproheptadine hydrochloride (3 mg/kg, i.p.). The lower doses of fluoxetine hydrochloride (3 mg/kg, i.p.) and cyproheptadine hydrochloride (0.3 mg/kg, i.p.) did not affect the AcAP-induced hypothermia. These results suggest that, in comparison with its analgesic effect, the hypothermic effect of AcAP is not mediated by the serotonergic system.

    DOI: 10.1248/bpb.b16-00728

    Web of Science

    Scopus

    PubMed

    Other Link: http://orcid.org/0000-0003-4465-7445

  8. Oseltamivir produces hypothermic and neuromuscular effects by inhibition of nicotinic acetylcholine receptor functions: comparison to procaine and bupropion Reviewed

    Fukushima A, Chazono K, Hashimoto Y, Iwajima Y, Yamamoto S, Maeda Y, Ohsawa M, Ono H

    European journal of pharmacology   Vol. 762   page: 275 - 282   2015.9

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

    DOI: 10.1016/j.ejphar.2015.06.004

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Presentations 23

  1. A central oxytocin neural pathway that regulates metabolism

    Akihiro Fukushima, Kazuhiro Nakamura

    The 3rd CIBoG Retreat  2022.2.19 

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    Event date: 2022.2

    Language:English   Presentation type:Oral presentation (general)  

  2. Oxytocinergic pathway stimulating brown adipose tissue thermogenesis

    Fukushima A, Nakamura K

    the 126th Annual Meeting of The Japanese Association of Anatomists / the 98th Annual Meeting of The Physiological Society of Japan  2021.3.29 

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    Event date: 2021.3

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

    Venue:Web  

    Endothermic animals maintain their core body temperature by controlling skin vasomotion and brown adipose tissue (BAT) thermogenesis. These thermoregulatory organs are regulated by sympathetic inputs from the hypothalamo-medullary-spinal central pathway. Oxytocin (OXT), a hypothalamic neuropeptide, contributes to a variety of behaviors and stress responses. Impairment of the oxytocinergic (OXTergic) neural system leads to metabolic hypofunction. However, the neuronal pathway underpinning the link between OXT and metabolism has not been determined. To elucidate the mechanism, we performed neural tract tracing and in vivo BAT sympathetic recording in combination with optogenetic stimulation of a specific OXTergic neural pathway, and found that (i) OXT neurons in a dorsocaudal part of the paraventricular hypothalamic nucleus innervate sympathetic premotor neurons in the rostral medullary raphe region (rMR); (ii) the OXTergic input to the rMR stimulates BAT thermogenesis by potentiating glutamatergic transmission onto sympathetic premotor neurons. This OXTergic pathway may underlie etiologies of metabolic disorders, such as Prader-Willi syndrome, and be relevant to emotional responses.

  3. How do emotions impact thermogenic and cardiovascular functions?

    Nakamura K, Kataoka N, Fukushima A

    The 98th Annual Meeting of The Physiological Society of Japan  2021.3.28 

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    Event date: 2021.3

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

    Venue:Web  

    Emotions strongly impact thermogenic and cardiovascular functions by affecting the central sympathetic regulatory system. We have discovered a central neural pathway that mediates psychological stress signaling by connecting the corticolimbic emotion circuit to the hypothalamomedullary autonomic regulatory system. This is a master psychosomatic pathway that drives a variety of sympathetic and behavioral stress responses, such as brown adipose tissue (BAT) thermogenesis, tachycardia, and pressor response. Recently, we have also identified a central circuit mechanism by which the oxytocin nervous system, which is stimulated by emotional cues, impacts metabolic and cardiac functions. In vivo optogenetic and physiological studies revealed that oxytocinergic inputs from the hypothalamus to medullary sympathetic premotor neurons stimulate BAT thermogenic and cardiac responses by potentiating glutamatergic sympathoexcitatory efferent transmission. Based on these findings, we will discuss central psychosomatic circuit mechanisms that underlie a variety of phenomena due to “mind?body” relationship in health and disease.

  4. Oxytocinergic Neurons in the Hypothalamic Paraventricular Nucleus Stimulate Brown Adipose Tissue Thermogenesis through Rostral Medullary Raphe

    Fukushima A, Nakamura K

    2020.10 

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    Event date: 2020.10

    Language:English   Presentation type:Poster presentation  

    Venue:Web  

  5. 視床下部室傍核オキシトシン神経系による褐色脂肪熱産生の促進

    福島章紘,中村和弘

    第10回名古屋大学医学系研究科・生理学研究所合同シンポジウム  2020.9.19 

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    Event date: 2020.9

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:Web  

  6. 視床下部室傍核オキシトシン神経系による褐色脂肪熱産生の促進

    福島章紘,中村和弘

    温熱生理研究会  2020.8.27  生理学研究所

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    Event date: 2020.8

    Presentation type:Oral presentation (general)  

    Venue:Web  

  7. Oxytocinergic Transmission from Paraventricular Hypothalamic Nucleus to Rostral Medullary Raphe Stimulates Brown Adipose Tissue Thermogenesis

    Fukushima A, Nakamura K

    The 97th Annual Meeting of the Physiological Society of Japan  2020.3 

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    Event date: 2020.3

    Language:English   Presentation type:Poster presentation  

  8. Oxytocinergic Transmission from the Paraventricular Hypothalamic Nucleus to Rostral Medullary Raphe Stimulates Brown Adipose Tissue Thermogenesis

    Akihiro Fukushima, Kazuhiro Nakamura

    2020.3.16 

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    Event date: 2020.3

    Presentation type:Oral presentation (general)  

  9. Central Neural Pathways for Thermoregulation and Beyond. Invited

    Akihiro Fukushima

    2019.11.21 

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    Event date: 2019.11

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

  10. Oxytocinergic Neurons in the Hypothalamic Paraventricular Nucleus Stimulate Brown Adipose Tissue Thermogenesis Through Rostral Medullary Raphe

    Fukushima A, Nakamura K

    第9回名古屋大学医学系研究科・生理学研究所合同シンポジウム  2019.9.28 

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    Event date: 2019.9

    Language:English   Presentation type:Poster presentation  

  11. Oxytocinergic Neurons in the Hypothalamic Paraventricular Nucleus Stimulate Brown Adipose Tissue Thermogenesis through Rostral Medullary Raphe International conference

    Fukushima A, Nakamura K

    Experimental Biology 2019 Meeting  2019.4 

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    Event date: 2019.4

    Language:English   Presentation type:Poster presentation  

    Venue:Orlando, USA   Country:United States  

    Hypothalamic neurons in the paraventricular nucleus (PVN) produce several neuropeptides, including oxytocin and vasopressin, and send their axons to various brain regions. These PVN neurons have been considered to serve neuroendocrine and autonomic functions, and many studies have demonstrated the involvement of oxytocin in social and emotional behaviors (e.g. maternal and sexual behaviors, and stress responses). Although these behaviors are accompanied with autonomic responses, it is unclear how oxytocin modulates the activities of the autonomic nervous system. To investigate the roles of PVN oxytocinergic neurons in the central regulation of autonomic function, in this study, we first performed neural tract tracing in rats from PVN oxytocinergic neurons to the rostral medullary raphe region (rMR), which contains sympathetic premotor neurons controlling brown adipose tissue (BAT) thermogenesis. In the rMR, oxytocin‐immunoreactive fibers, but not vasopressin‐immunoreactive fibers, were distributed, and oxytocin‐containing terminals were apposed to tryptophan hydroxylase‐expressing (i.e., serotonergic) neurons, potentially BAT sympathetic premotor neurons. Retrograde tracing from the rMR with cholera toxin b‐subunit (CTb) labeled a portion of oxytocinergic neurons in the caudal PVN, but not in the supraoptic nucleus, suggesting that the PVN is a major source of oxytocinergic fibers in the rMR. Then, we performed in vivo BAT sympathetic nerve recording combining optogenetic stimulation of the PVN‐derived oxytocinergic axon terminals in the rMR. Recombinant adeno‐associated viral vectors were injected into the PVN to express the engineered channel rhodopsin variant, ChIEF, under the oxytocin promoter. We confirmed that most of PVN neurons expressing ChIEF‐mCherry contained oxytocin and that their axon fibers were densely distributed in the rMR. Optogenetic stimulation of these fibers evoked BAT sympathetic nerve activities as well as increased expired CO2 and heart rate. Similar thermogenic and cardiac responses were elicited by nanoinjection of oxytocin into the rMR, and these responses were blocked by prior injection of the oxytocin receptor antagonist, L‐368,899 into the rMR. In addition, oxytocin injection into the rMR also potentiated NMDA‐evoked BAT sympathetic nerve activities. These findings indicate that PVN oxytocinergic neurons stimulate thermogenic sympathetic outflow to BAT through activation of rMR neurons. This oxytocinergic pathway may play an important role in emotion‐related autonomic responses.

  12. Raphe-projecting oxytocinergic hypothalamic neurons stimulate brown adipose tissue thermogenesis International conference

    Fukushima A, Nakamura K

    9th Federation of the Asian and Oceanian Physiological Societies Congress (FAOPS2019)  2019.3  Federation of the Asian and Oceanian Physiological Societies (FAOPS)

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    Event date: 2019.3

    Language:English   Presentation type:Poster presentation  

    Venue:Kobe Convention Center  

  13. 視床下部オキシトシン神経系による褐⾊脂肪熱産⽣の誘導

    福島章紘,中村和弘

    第46 回⾃律神経⽣理研究会  2018.12.1 

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    Event date: 2018.12

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:⽇本光電⼯業株式会社本社ビル  

  14. Raphe-Projecting Oxytocinergic Hypothalamic Neurons Stimulate Brown Adipose Tissue Thermogenesis

    Fukushima A, Nakamura K

    2018.11.16 

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    Event date: 2018.11

    Language:Japanese   Presentation type:Poster presentation  

  15. 添付文書における抗インフルエンザウイルス薬オセルタミビルと局所麻酔薬の副作用の類似性

    小野秀樹, 岡村真彩, 福島章紘

    日本薬学会第137年会  2017.3  日本薬学会

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    Event date: 2017.3

    Language:Japanese   Presentation type:Poster presentation  

    Venue:仙台国際センター   Country:Japan  

  16. Intracerebroventricular injection of resiniferatoxin induces brain-selective TRPV1 desensitization in mice

    Fukushima A, Mamada K, Ono H

    第39回日本神経科学大会 

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    Event date: 2016

    Language:English   Presentation type:Poster presentation  

    Country:Japan  

  17. Chemical ablation of TRPV1-expressing cells in the CNS attenuates hypothermic effects of acetaminophen and p-aminophenol

    Fukushima A, Fujii M, Higurashi K and Ono H

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    Event date: 2016

    Language:English   Presentation type:Poster presentation  

    Country:Japan  

  18. Centrally administered oseltamivir evokes hypothermia through dopamine D2 receptor activation in mice

    Fukushima A, Fukui A, Takemura Y, Matsuura N, Maeda Y and Ono H

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    Event date: 2016

    Language:English   Presentation type:Poster presentation  

    Country:Japan  

  19. レシニフェラトキシン中枢投与マウスにおけるアセトアミノフェンの体温低下作用の抑制

    福島章紘, 藤井萌子, 眞々田築, 日暮航平, 小野秀樹

    第133回日本薬理学会関東部会 

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    Event date: 2015

    Language:Japanese   Presentation type:Oral presentation (general)  

    Country:Japan  

  20. オセルタミビルの心血管機能・骨格筋収縮に対する作用:局所麻酔様作用の可能性

    福島章紘, 前田康博, 小野秀樹

    第45回日本神経精神薬理学会・第37回日本生物学的精神医学会 合同年会 

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    Event date: 2015

    Language:Japanese   Presentation type:Poster presentation  

    Country:Japan  

  21. Inhibition of serotonergic system does not contribute to the hypothermic action of acetaminophen

    Fukushima A, Sekiguchi W, Tsuchido Y, Tohma Y, Mamada K, Ono H

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    Event date: 2015

    Language:English   Presentation type:Poster presentation  

    Country:Japan  

  22. Synaptic vesicle pool size affects the frequency dependency of synaptic transmission in the hippocampus

    Fukushima A, Sekino Y and Manabe T

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    Event date: 2008

    Language:English   Presentation type:Poster presentation  

    Country:Japan  

  23. Presynaptic mechanisms of the frequency-dependent depression at perforant path-granule cell synapses in the hippocampus

    Fukushima A, Sekino Y and Manabe T

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    Event date: 2008

    Language:English   Presentation type:Poster presentation  

    Country:Japan  

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KAKENHI (Grants-in-Aid for Scientific Research) 2

  1. 交感神経活動を制御する視床下部オキシトシン神経系の中枢神経回路の解明

    Grant number:19K07300  2019.4 - 2022.3

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    福島 章紘

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    Authorship:Principal investigator 

    Grant amount:\4290000 ( Direct Cost: \3300000 、 Indirect Cost:\990000 )

    視床下部は体温や血圧など基本的な身体内部状態の維持に加え,情動行動中枢としても機能している.本研究は,視床下部オキシトシンニューロンを活性化する上位中枢領域を単シナプス逆行性トレーシングにより同定し,これらの領域間シナプスの特性を電気生理学的手法および免疫組織化学的手法を用いて明らかにする.さらに覚醒行動下におけるオキシトシンニューロンの活動をインビボカルシウムイメージング法により観察することで,情動行動中に惹起される交感神経反応における視床下部オキシトシン神経系の役割を明らかにする.
    本研究の目的は,情動にともなう交感神経反応表出時におけるオキシトシン神経系の関与を明らかにすることである.喜怒哀楽や緊張,恐怖などの情動が生じる際,血圧・心拍変動をはじめとした自律神経反応も同時に誘導される.交感神経系の活動は延髄縫線核を含む下行性神経路により制御されているが,研究代表者らはこれまでに,オキシトシンニューロン選択的に任意の遺伝子を発現させるアデノ随伴ウイルスを開発・使用することで,視床下部室傍核オキシトシンニューロンが延髄縫線核へ投射していることや,延髄縫線核においてオキシトシン作動性軸索を光遺伝学的に刺激すると褐色脂肪熱産生が誘導されることを見出している.
    今年度は,上記実験で用いたアデノ随伴ウイルスをさらに応用・改変することで,延髄縫線核からの逆行性感染によりオキシトシンニューロン選択的にCreリコンビナーゼ発現を誘導するウイルスの開発を試みた.これまでに6種類のウイルスを作製し,それらの細胞選択性や発現効率を検討してきたが,実用に足るウイルスを見いだせておらず,現在も開発を継続している.同じく今年度に実施を計画していたオキシトシンニューロンに投射するシナプスの電気生理学的解析については,スライスパッチクランプ法の実験系を確立することができた.また本オキシトシン神経系の生理学的意義をさらに検討するため,麻酔下ラット延髄縫線核にてオキシトシン性軸索の光遺伝学的刺激後,興奮性神経伝達物質であるNMDAを同じく延髄縫線核に微量注入する実験をおこない,オキシトシンが延髄縫線核交感神経プレモーターニューロンの興奮性を上げること,すなわち本神経系が他の上位脳領域からの興奮性信号を増強しており,交感神経活動に対して促進的に働くことを示唆する結果を得ることができた.
    今年度の主な研究計画は,延髄縫線核へ投射するオキシトシンニューロンを起点とする単シナプス性逆行標識をおこない.オキシトシンニューロンの活動を制御する脳領域を同定することであった.当初の計画では,すでに作製済みのウイルス(オキシトシンニューロン選択的に緑色蛍光タンパク(GFP)を発現させるアデノ随伴ウイルス)の血清型を改変することで,延髄縫線核からの逆行性感染によりオキシトシンニューロン選択的なCreリコンビナーゼ発現を誘導するウイルスを新たに作製する予定であったが,現在我々が用いている作製方法では,十分なウイルス濃度を確保することが困難であった.次に,解決策として,オキシトシンニューロンには順行性Cre発現ウイルスを感染させ,目的とする遺伝子発現用のウイルスを縫線核から逆行感染させることを計画し,これまで複数種のウイルスを作製したが,オキシトシンニューロン選択的なCre発現の成功には至っていない.
    また今年度は,オキシトシンニューロンからの単シナプス性逆行標識法を確立した後,光遺伝学的手法を用いたシナプス伝達の電気生理学的解析をおこなう予定であったが,単シナプス性逆行標識の確立に至っていなかったため,オキシトシンニューロン選択的に蛍光タンパク標識型光感受性陽イオンチャネル(ChIEF-mCherry)を発現するウイルスを代用することで,ラット視床下部でのスライスパッチクランプ法の準備を進めた.これについては,mCherry発現細胞がオキシトシン陽性であることや,光刺激によって活動電位を発生させることが確認できたことから,スライスパッチクランプ法の実験系は確立できていると考えられ,単シナプス性逆行標識が成功し次第,速やかに着手できる状態にある.以上の進捗状況に鑑み,本研究は現段階ではやや遅れている状態にあると判断する.
    オキシトシンニューロン選択的Cre発現ウイルスの開発は引き続きおこなう予定である.まずは,選択性がありながらも十分な濃度を確保できなかったウイルスについて,作製スケールを大きくすることで濃度を上げることを試みる.また逆行感染型アデノ随伴ウイルス以外にも,同じく逆行性感染が報告されているイヌアデノウイルス(CAV-2)の導入や,Cre/loxPシステムの代替としてFLP/frtシステムへの切り替えも検討する.
    次年度以降に計画していた覚醒下ラットを用いたオキシトシンニューロン活動の観察については,オキシトシンニューロン群を活性化する行動実験の選定を前倒しで開始しているので,データをまとめて,今後使用する実験系を決定する.

  2. Analysis of stress neural circuits using oxytocin neuron-selective activity manipulation

    Grant number:16H05128  2016.4 - 2019.3

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

    Nakamura Kazuhiro, NAKAMURA Yoshiko, KATAOKA Naoya, FUKUSHIMA Akihiro

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    Authorship:Principal investigator 

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

    I studied how oxytocin, a neuropeptide often called the “love hormone”, acts in the brain to affect autonomic physiological functions, such as body temperature regulation and stress-coping responses. By employing in vivo optogenetic techniques to selectively stimulate a group of oxytocin neurons in the hypothalamus together with other anatomical and physiological techniques, I identified an oxytocinergic neuronal pathway that stimulates brown adipose tissue thermogenesis and tachycardia.