海馬歯状回の恒常性維持機能の理解とその神経細胞内メカニズムの解明
| Project Area | Brain Environment |
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| Project/Area Number |
24111546
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| Research Category |
Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
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| Allocation Type | Single-year Grants |
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| Review Section |
Biological Sciences
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| Research Institution | Fujita Health University |
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Principal Investigator |
宮川 剛 藤田保健衛生大学, 総合医科学研究所, 教授 (10301780)
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| Project Period (FY) |
2012-04-01 – 2014-03-31 (Estimated)
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| Project Status |
Completed (Fiscal Year 2013)
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| Budget Amount *help |
¥23,400,000 (Direct Cost: ¥18,000,000、Indirect Cost: ¥5,400,000)
Fiscal Year 2013: ¥11,700,000 (Direct Cost: ¥9,000,000、Indirect Cost: ¥2,700,000)
Fiscal Year 2012: ¥11,700,000 (Direct Cost: ¥9,000,000、Indirect Cost: ¥2,700,000)
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| Keywords | 脳・神経 / 神経科学 / 脳神経疾患 |
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| Research Abstract |
海馬歯状回の神経細胞の成熟度は各種の実験操作により双方向性に変化する。この細胞レベルでの成熟度変化は、ストレス下での脳のシステムの恒常性維持に重要な役割を果たしていると考えられるが、その機能的役割については未だ不明な点が多い。25年度は、非成熟歯状回を持つ遺伝子改変マウスを対象にデキサメタゾン（DEX）抑制テストを行い、海馬によるHPA系反応の抑制的な調節機能を評価した。これまでに調べた2系統のマウスでは、DEXを投与しても血中コルチコステロン濃度が高いままで低下しないことから、HPA系反応の抑制機能に障害があることが示唆された。この結果は、非成熟歯状回が恒常性維持機能の破綻に関連している可能性があることを示している。しかし、非成熟歯状回を引き起こす抗うつ薬の慢性投与が前頭皮質の特定の抑制性神経細胞も成熟前の状態に戻す作用があることが最近明らかとなり、歯状回以外の脳細胞の成熟度変化がHPA系反応の異常を引き起こしている可能性についても考慮する必要が出てきた。そこで、光遺伝学的手法を用いて歯状回神経細胞特異的に成熟度を操作する方法を確立するため、チャネルロドプシン2（ChR 2）を発現するfloxマウスを歯状回特異的Cre 発現マウスと交配し、歯状回神経細胞にのみChR 2を発現するマウスを作製した。このマウスの歯状回に複数回の光刺激を与えたところ、歯状回神経細胞が脱成熟したことを示唆する遺伝子発現変化が確認された。このように、歯状回神経細胞の成熟度と脳の恒常性維持機能との直接的な関係を明らかにするための解析系を確立した。また、本領域の他の班員との共同研究（10件）も実施し、複数の神経疾患モデルマウスの歯状回で成熟度変化を確認した。これは、歯状回の成熟度異常を伴う脳内環境の恒常性の維持機能の破綻が、様々な精神・神経疾患に関与している可能性があることを示唆している。
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| Current Status of Research Progress |
Reason
25年度が最終年度であるため、記入しない。
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| Strategy for Future Research Activity |
25年度が最終年度であるため、記入しない。
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Report
(2 results)
Research Products
(62 results)
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[Journal Article] Riccardo Fodde, Takao Senda. Targeted deletion of the C-terminus of the mouse adenomatous polyposis coli tumor suppressor results in neurologic phenotypes related to schizophrenia2014
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Takanori Onouchi, Katsunori Kobayashi, Kazuyoshi Sakai, Atsushi Shimomura, Ron Smits, Chiho Sumi-Ichinose, Masafumi Kurosumi Keizo Takao, Ryuji Nomura, Akiko Iizuka-Kogo, Hidenori Suzuki,Kazunao Kondo, Tetsu Akiyama Tsuyoshi Miyakawa Riccardo Fodde and Takao Senda, Riccardo Fodde, Takao
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Shiori Toba, Yasuhisa Tamura, Kanako Kumamoto, Masami Yamada, Keizo Takao, Satoko Hattori, Tsuyoshi Miyakawa, Yosky Kataoka, Mitsuyoshi Azuma, Kiyoshi Hayasaka, Masano Amamoto, Keiko Tominaga, Anthony Wynshaw-Boris, Mitsuhiro Kato and Shinji Hirotsune
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Sci Rep.
Volume: 3
Pages: 1224-1224
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[Journal Article] Deficiency of Schnurri-2, an MHC Enhancer Binding Protein, Induces Mild Chronic Inflammation in the Brain and Confers Molecular, Neuronal, and Behavioral Phenotypes Related to Schizophrenia.2013
Author(s)
Takao K, Kobayashi K, Hagihara H, Ohira K, Shoji H, Hattori S, Koshimizu H, Umemori J, Toyama K, Nakamura HK, Kuroiwa M, Maeda J, Atsuzawa K, Esaki K, Yamaguchi S, Furuya S, Takagi T, Walton NM, Hayashi N, Suzuki H, Higuchi M, Usuda N, Suhara T, Nishi A, Matsumoto M, Ishii S, Miyakawa T.
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Journal Title
Neuropsychopharmacology.
Volume: 38(8)
Pages: 1409-1425
DOI
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Peer Reviewed / Open Access
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[Journal Article] PRICKLE1 interaction with SYNAPSIN I reveals a role in autism spectrum disorders2013
Author(s)
Paemka L, Mahajan VB, Skeie JM, Sowers LP, Ehaideb SN, Gonzalez-Alegre P, Sasaoka T, Tao H, Miyagi A, Ueno N, Takao K, Miyakawa T, Wu S, Darbro BW, Ferguson PJ, Pieper AA, Britt JK, Wemmie JA, Rudd DS, Wassink T, El-Shanti H, Mefford HC, Carvill GL, Manak JR, Bassuk AG
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DOI
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[Journal Article] DRPLA transgenic mouse substrains carrying single copy of full-length mutant human DRPLA gene with variable sizes of expanded CAG repeats exhibit CAG repeat length- and age-dependent changes in behavioral abnormalities and gene expression profiles.2012
Author(s)
Suzuki K, Zhou J, Sato T, Takao K, Miyakawa T, Oyake M, Yamada M, Takahashi H, Takahashi Y, Goto J, Tsuji S.
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Journal Title
Neurobiol Dis
Volume: 46(2)
Pages: 336-50
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[Journal Article] Detection of an immature dentate gyrus feature in human schizophrenia/bipolar patients.2012
Author(s)
Walton NM, Zhou Y, Kogan JH, Shin R, Webster M, Gross AK, Heusner CL, Chen Q, Miyake S, Tajinda K, Tamura K, Miyakawa T, Matsumoto M
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Journal Title
Transl Psychiatry
Volume: 2
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[Journal Article] Impaired synaptic clustering of postsynaptic density proteins and altered signal transmission in hippocampal neurons, and disrupted learning behavior in PDZ1 andPDZ2 ligand binding-deficient PSD-95 knockin mice2012
Author(s)
Nagura H, Ishikawa Y, Kobayashi K, Takao K, Tanaka T, Nishikawa K, Tamura H, Shiosaka S, Suzuki H, Miyakawa T, Fujiyoshi Y, Doi T.
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Journal Title
Mol Brain.
Volume: 5
Pages: 1-19
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Peer Reviewed
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[Presentation] “Immature dentate gyrus”, a candidate endophenotype for psychotic disorders, emerges after adolescence in Schnurri-2 KO mice.2013
Author(s)
Keizo Takao, Hideo Hagihara, Koji Ohira, Hirotaka Shoji, Satoko Hattori, Hisatsugu Koshimizu, Juzoh Umemori, Tsuyoshi Takagi, Shunsuke Ishii, Tsuyoshi Miyakawa
Organizer
Neuroscience 2013
Place of Presentation
San Diego
Related Report
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[Presentation] Deficiency of Schnurri-2, an MHC enhancer binding protein, induces mild chronic inflammation in the brain and confers molecular, neuronal, and behavioral phenotypes related to schizophrenia2012
Author(s)
Takao K, Kobayashi K, Hagihara H, Ohira K, Toyama K, Shoji H, Nakamura HK, Esaki K, Furuya S, Takagi T, Walton N, Hayashi N, Suzuki H, Matsumoto M, Ishii S, Miyakawa T
Organizer
14th Annual Meeting of the International Behavioural and Neural Genetics Society
Place of Presentation
Colorado, USA
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[Presentation] Deficiency of Schnurri-2, an MHC enhancer binding protein, induces mild chronic inflammation in the brain and confers molecular, neuronal, and behavioral phenotypes related to schizophrenia2012
Author(s)
Takao K, Kobayashi K, Esaki K, Furuya S, Takagi T, Hayashi N, Walton N, Suzuki H, Matsumoto M, Ishii S, Miyakawa T
Organizer
28th CINP World Congress of Neuropsychopharmacology
Place of Presentation
Stockholm, Sweden
Related Report
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[Presentation] Deficiency of Schnurri-2, an MHC enhancer binding protein, induces mild chronic inflammation in the brain and confers molecular, neuronal, and behavioral phenotypes related to schizophrenia2012
Author(s)
Takao K, Kobayashi K, Hagihara H, Ohira K, Toyama K, Shoji H, Nakamura HK, Esaki K, Furuya S, Takagi T, Walton N, Yamaguchi S, Hayashi N, Suzuki H, Matsumoto M, Ishii S, Miyakawa T.
Organizer
Neuroscience 2012
Place of Presentation
New Orleans, USA
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[Presentation] Behavioral state of model mice of bipolar disorder can be retrospectively predicted by gene expression in dentate gyrus and plasma metabolites2012
Author(s)
Umemori J, Hagihara H, Nakamura HK, Horikawa T, Shoji H, Toyama K, Irino Y, Yoshida M, Kamitani Y, Miyakawa T.
Organizer
Neuroscience 2012
Place of Presentation
New Orleans, USA
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[Presentation] Upregulation of mature form brain-derived neurotrophic factor and carboxypeptidase E, and ectopic expression of tyrosine kinase receptor B in the hippocampus of mice with maturation failure in dentate gyrus neurons2012
Author(s)
Koshimizu H, Ohira K, Hagihara H, Takao K, Takagi T, Kataoka M, Ishii S, Takahashi M, Miyakawa T.
Organizer
Neuroscience 2012
Place of Presentation
New Orleans, USA
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[Presentation] Deficiency of Schnurri-2, an MHC enhancer binding protein, induces mild chronic inflammation in the brain and confers molecular, neuronal, and behavioral phenotypes related to schizophrenia.2012
Author(s)
Tsuyoshi Miyakawa, Keizo Takao, Katsunori Kobayashi, Hideo Hagihara, Koji Ohira, Hirotaka Shoji, Satoko Hattori, Hisatsugu Koshimizu, Juzoh Umemori, Shun Yamaguchi, Tsuyoshi Takagi, Noah Walton, Hidenori Suzuki, Mitsuyuki Matsumoto, Shunsuke, Ishii
Organizer
ACNP 51st Annual Meeting
Place of Presentation
Hollywood, Florida USA
Related Report
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[Presentation] Deficiency of Schnurri-2, an MHC enhancer binding protein, induces mild chronic inflammation in the brain and confers molecular, neuronal, and behavioral phenotypes related to schizophrenia.2012
Author(s)
Tsuyoshi Miyakawa, Keizo Takao, Hideo Hagihara, Koji Ohira, Hirotaka Shoji, Satoko Hattori, Hisatsugu Koshimizu, Juzoh Umemori, Tsuyoshi Takagi, Shunsuke Ishii.
Organizer
第35回日本分子生物学会年会
Place of Presentation
福岡国際会議場、マリンメッセ福岡
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