Regulatory role of BDNF on emotional and cognitive function

• Project/Area Number: 15H03123
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Basic / Social brain science
• Research Institution: Keio University
• Principal Investigator: Kenji Tanaka 慶應義塾大学, 医学部(信濃町), 准教授 (30329700)
• Research Collaborator: SUZUKI Toru
• Project Period (FY): 2015-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥18,330,000 (Direct Cost: ¥14,100,000、Indirect Cost: ¥4,230,000); Fiscal Year 2018: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2017: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2016: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2015: ¥6,890,000 (Direct Cost: ¥5,300,000、Indirect Cost: ¥1,590,000)
• Keywords: BDNF / うつ病 / 多機能遺伝子改変 / 肥満 / 大脳皮質 / 認知 / ストレス / 側坐核 / ノックダウン / 過剰発現

Outline of Final Research Achievements

It is well accepted that brain-derived neurotrophic factor (BDNF) is involved in the synaptic plasticity. Human studies demonstrated that serum BDNF amount can be used as a biomarker of neuropsychiatric conditions. However, how BDNF directly regulates brain higher functions is still unknown. Here we developed BDNF gene modifying mice in which BDNF gene expression was capable of time- and region-dependent manipulation. In the stress-free condition, up- or down-regulation of BDNF gene expression did not cause any anxiety-like and depression-like behaviors.In the stressful condition, down-regulation of BDNF gene expression impaired the autonomic function characterized with basal tear secretion. In particular, down-regulation of BDNF expression delayed a recovery from the stress. We conclude that levels of BDNF expression affect the stress resilience in stressful condition but not in stress free condition.

Academic Significance and Societal Importance of the Research Achievements

うつ病のバイオマーカーとして血液中のBDNF量が注目されている。これまでは、うつ病の診断基準を満たすかどうかで疾患群と健常群を分けて解析されてきた。今回の研究から、BDNFはうつ病の直接的な原因というよりも、ストレス応答にかかわる分子であることが示唆された。それにより、ヒトにおいて高ストレス状態・低ストレス状態の分類や、ストレスレジリエント・ストレス脆弱の分類を設けて、BDNF量を解析することを提案できる。うつ病のかかりやすさや初期症状をストレス応答で切り分ける研究へと展開することが期待できる。

Research Products

• [Int'l Joint Research] University of Ottawa/University of British Columbia(カナダ)
• [Int'l Joint Research] Stanford University(米国)
• [Int'l Joint Research] University Texas, Austin/University of Pittsburgh/Columbia University(米国)
• [Int'l Joint Research] Universite Libre de Bruxelles(ベルギー)
• [Int'l Joint Research] Ottawa Hospital Research Institute(Canada)
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  • Author(s): Aida T, Chiyo K, Usami T, Ishikubo H, Imahashi R, Wada Y, Tanaka K, Sakuma T, Yamamoto T, Tanaka K
  • Journal Title: Genome Biol Volume: 16 Issue: 1 Pages: 87-87
  • DOI: 10.1186/s13059-015-0653-x
  • Peer Reviewed / Open Access
• [Journal Article] Unveiling astrocytic control of cerebral blood flow with optogenetics (2015)
  • Author(s): Masamoto K, Unekawa M, Watanabe T, Toriumi H, Takuwa H, Kawaguchi H, Kanno I, Matsui K, Tanaka K F, Tomita Y, Suzuki N
  • Journal Title: Scientific reports Volume: 5 Issue: 1 Pages: 11455-11455
  • DOI: 10.1038/srep11455
  • Peer Reviewed / Open Access
• [Journal Article] Observation and manipulation of glial cell function by virtue of sufficient probe expression (2015)
  • Author(s): Akiyo Natsubori, Norio Takata, Kenji F Tanaka
  • Journal Title: Frontiers in Cellular Neuroscience Volume: 176 Pages: 1-7
  • DOI: 10.3389/fncel.2015.00176
  • Peer Reviewed / Open Access
• [Journal Article] Adult Hippocampal Neurogenesis Modulates Fear Learning through Associative and Nonassociative Mechanisms. (2015)
  • Author(s): Seo DO, Carillo MA, Chih-Hsiung Lim S, Tanaka KF, Drew MR
  • Journal Title: J Neurosci. Volume: 35 Issue: 32 Pages: 11330-11345
  • DOI: 10.1523/jneurosci.0483-15.2015
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Neuronal heterotopias affect the activities of distant brain areas and lead to behavioral deficits (2015)
  • Author(s): Kazuhiro Ishii, Ken-ichiro Kubo, Toshihiro Endo, Keitaro Yoshida, Seico Benner, Yukiko Ito, Hidenori Aizawa, Michihiko Aramaki, Akihiro Yamanaka, Kohichi Tanaka, Norio Takata, Kenji Tanaka, Masaru Mimura, Chiahru Tohyama, Masaki Kakeyama, and Kazunori Nakajima
  • Journal Title: Journal of Neuroscience Volume: 35 Issue: 36 Pages: 12432-45
  • DOI: 10.1523/jneurosci.3648-14.2015
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 5-HT1A Receptors on Mature Dentate Gyrus Granule Cells are Critical for the Antidepressant Response (2015)
  • Author(s): Samuels BA, Anacker C, Hu A, Levinstein MR, Pickenhagen A, Tsetsenis T, Madro .A Nqal N, Donaldson ZR, Drew LJ, Dranovsky A, Gross CT, Tanaka KF, Hen R
  • Journal Title: Nat Neurosci Volume: 18 Issue: 11 Pages: 1606-1616
  • DOI: 10.1038/nn.4116
  • Peer Reviewed / Int'l Joint Research
• [Presentation] 光観察と光操作を融合させた神経回路研究 (2018)
  • Author(s): 田中謙二
  • Organizer: 第114回 日本精神神経科学会学術総会
• [Presentation] 意欲行動 (2018)
  • Author(s): 田中謙二
  • Organizer: 第2回三融会
  • Invited
• [Presentation] 強迫症モデルマウス研究が提唱する強迫症の病態生理 (2018)
  • Author(s): 田中謙二
  • Organizer: 第59回 日本児童青年精神医学会
  • Invited
• [Presentation] 意欲の開始と維持の神経基盤. (2018)
  • Author(s): 田中謙二
  • Organizer: 第3回ルミノジェネティクス研究会
  • Invited
• [Presentation] Optogenetics-combined diffusion tensor imaging: tool for analyzing axon-glia interaction (2018)
  • Author(s): 田中謙二
  • Organizer: 第23回グリア研究会
  • Invited
• [Presentation] Motivated behavior regulated by the ventral striatum (2018)
  • Author(s): 田中謙二
  • Organizer: The 7th Annual IIIS Symposium
  • Int'l Joint Research / Invited
• [Presentation] 光観察と光操作を組み合わせた意欲行動研究 (2017)
  • Author(s): 田中謙二
  • Organizer: 第2回 ルミノジェネティクス研究会
  • Invited
• [Presentation] Oligodendrocyte is a dynamic modulator of conduction velocity (2017)
  • Author(s): 田中謙二、山崎良彦
  • Organizer: 第60回 日本神経化学会
• [Presentation] 島皮質-線条体回路と意欲行動 (2017)
  • Author(s): 田中謙二
  • Organizer: 第5回 心身医学のニューロサイエンス研究会
  • Invited
• [Presentation] 光操作・光計測 (2017)
  • Author(s): 田中謙二
  • Organizer: 第４９回藤田学園医学会・研究最前線セミナー
  • Invited
• [Presentation] Fiberphotometry (2017)
  • Author(s): 田中謙二
  • Organizer: 第28回 マイクロダイアリシス研究会
  • Invited
• [Presentation] 意欲行動の開始を支配する島皮質-線条体回路 (2017)
  • Author(s): 田中謙二
  • Organizer: 次世代脳 新学術領域合同シンポジウム
  • Invited
• [Presentation] Tetracycline-controllable gene expression system in glial cell biology. (2016)
  • Author(s): Tanaka KF
  • Organizer: Glia Heterogeneity SPP 1757
  • Place of Presentation: Homburg, German
  • Year and Date: 2016-10-08
  • Int'l Joint Research / Invited
• [Presentation] KENGE-tet system: promising strategy to achieve sufficient probe expression in glial cells. (2016)
  • Author(s): Tanaka KF
  • Organizer: XII European Meeting on Glial Cells in Health and Disease
  • Place of Presentation: Bilbao, Spain
  • Year and Date: 2016-07-15
  • Int'l Joint Research / Invited
• [Presentation] 単分子研究から行動研究へ (2016)
  • Author(s): 田中謙二
  • Organizer: 第2回 バイオ単分子研究会
  • Place of Presentation: いわき湯本温泉 新つた（福島県いわき市）
  • Year and Date: 2016-03-30
  • Invited
• [Presentation] アパシーの神経基盤 (2016)
  • Author(s): 田中謙二
  • Organizer: 第121回 日本解剖学会総会
  • Place of Presentation: ビッグパレット福島（福島県郡山市）
  • Year and Date: 2016-03-29
  • Invited
• [Presentation] グリアアセンブリ活動の観察と操作 (2016)
  • Author(s): 田中謙二
  • Organizer: 第89回日本薬理学会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-03-11
  • Invited
• [Presentation] Optogenetics for neurotrauma research (2016)
  • Author(s): Tanaka KF
  • Organizer: Japan-US Forum on Blast Injury 2016
  • Place of Presentation: 山王ホテル、港区、東京
  • Int'l Joint Research / Invited
• [Presentation] Recent advances in emotional and motivational circuits. (2016)
  • Author(s): Tanaka KF
  • Organizer: The 14th Pacific Rim International Conference on Artificial Intelligence (PRICAI 2016)
  • Place of Presentation: Phuket, Thailand
  • Int'l Joint Research / Invited
• [Presentation] Dysfunction of ventrolateral striatal dopamine receptor type 2-expressing medium spiny neurons impairs instrumental motivation: possible relevance to apathy pathogenesis. (2016)
  • Author(s): Tanaka KF
  • Organizer: 2nd UK-Japan Frontier of Science
  • Place of Presentation: Milton Keynes, UK
  • Int'l Joint Research / Invited
• [Presentation] Optogenetics (2016)
  • Author(s): 田中謙二
  • Organizer: 第10回ドライアイ研究会
  • Place of Presentation: ヒルトン小田原、小田原、神奈川
  • Invited
• [Presentation] 階層をつなぎ種を越える脳科学研究 (2016)
  • Author(s): 田中謙二
  • Organizer: 第46回日本神経精神薬理学会年会
  • Place of Presentation: ソウル、韓国
  • Invited
• [Presentation] Ventral striatopallidal neurons govern motivated behaviors (2016)
  • Author(s): 田中謙二
  • Organizer: 第39回日本神経科学大会
  • Place of Presentation: パシフィコ横浜、横浜市、神奈川
  • Invited
• [Presentation] ミクロスコピックからメゾスコピックのカルシウムイメージング・計測 (2016)
  • Author(s): 田中謙二
  • Organizer: 第38回日本生物学的精神医学会・第59回日本神経化学会大会合同年会
  • Place of Presentation: 福岡国際会議場、福岡市、福岡
  • Invited
• [Presentation] 遺伝子改変を駆使したGliopsychiatry研究 (2016)
  • Author(s): 田中謙二
  • Organizer: 第38回日本生物学的精神医学会・第59回日本神経化学会大会合同年会
  • Place of Presentation: 福岡国際会議場、福岡市、福岡
  • Invited
• [Presentation] 神経科学・神経化学におけるレジリエンス研究 (2016)
  • Author(s): 田中謙二
  • Organizer: 第32回日本ストレス学会学術総会
  • Place of Presentation: 杏林大学、三鷹市、東京
  • Invited
• [Presentation] 無神経なオプトジェネティクス (2016)
  • Author(s): 田中謙二
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜、横浜市、神奈川
  • Invited
• [Presentation] Promotion of glial cell research by virtue of transgenic approach. (2015)
  • Author(s): 田中謙二
  • Organizer: 第58回日本神経化学会
  • Place of Presentation: 大宮ソニックシティ（埼玉県さいたま市)
  • Year and Date: 2015-09-11
  • Invited
• [Remarks] 脳内にある、やる気のスイッチを発見－意欲障害の治療法探索が可能に－
  • URL: https://www.keio.ac.jp/ja/press-releases/2017/2/2/28-19536/
• [Remarks] 動物の意欲を司る2種類の線条体神経の活動と役割分担について解明
  • URL: http://www.igakuken.or.jp/topics/2017/0206.html