Study on the neuronal circuit and molecular mechanis underlying decision-making and its application for drug development

• Project/Area Number: 26293053
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: General pharmacology
• Research Institution: Nagoya University
• Principal Investigator: Yamada Kiyofumi 名古屋大学, 医学部附属病院, 教授 (30303639)
• Co-Investigator(Kenkyū-buntansha): 溝口 博之 名古屋大学, 環境医学研究所, 助教 (70402568)
• Co-Investigator(Renkei-kenkyūsha): NAGAI Taku 名古屋大学, 医学部附属病院, 准教授 (10377426)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥16,120,000 (Direct Cost: ¥12,400,000、Indirect Cost: ¥3,720,000); Fiscal Year 2016: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2015: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2014: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000)
• Keywords: 神経科学 / 脳神経疾患 / 意思決定 / 薬理学 / 覚せい剤 / メタンフェタミン / 島皮質 / 大脳基底核 / 神経回路 / DREADDシステム

Outline of Final Research Achievements

Patients suffering from neuropsychiatric disorders such as substance-related and addictive disorders have impairments in decision-making, which may be associated with their behavioral abnormalities. However, the neuronal mechanisms underlying such impairments are largely unknown. Using a gambling test, we demonstrated that methamphetamine (METH)-dependent rats choose a high-risk/high-reward option more frequently, and assign higher subjective value to high returns, than control rats, suggesting that decision-making is impaired in the drug-dependent animals. Immunohistochemical analysis following the gambling test revealed aberrant activation of the insular cortex (INS) and nucleus accumbens in METH-dependent animals. Pharmacological studies together with in vivo microdialysis showed that GABAergic neurotransmission in INS played a crucial role in decision-making. Moreover, manipulation of INS activation using DREADD technology resulted in alterations to decision-making.

Research Products

• [Journal Article] Current understanding of methamphetamine-associated dopaminergic neurodegeneration and psychotoxic behaviors. (2017)
  • Author(s): Shin EJ, Dang DK, Tran TV, Tran HQ, Jeong JH, Nah SY, Jang CG, Yamada K, Nabeshima T, Kim HC.
  • Journal Title: Arch. Pharm. Res. Volume: - Issue: 4 Pages: 403-428
  • DOI: 10.1007/s12272-017-0897-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Protective potential of the glutathione peroxidase-1 gene in abnormal behaviors induced by phencyclidine in mice. (2016)
  • Author(s): Tran TV, Shin EJ, Jeong JH, Lee JW, Lee Y, Jang CG, Nah SY, Lei XG, Toriumi K, Yamada K, Nabeshima T, Kim HC.
  • Journal Title: Mol Neurobiol. Volume: - Issue: 9 Pages: 7042-7062
  • DOI: 10.1007/s12035-016-0239-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Prenatal Nicotine Exposure Impairs the Proliferation of Neuronal Progenitors, Leading to Fewer Glutamatergic Neurons in the Medial Prefrontal Cortex. (2016)
  • Author(s): Aoyama Y, Toriumi K, Mouri A, Hattori T, Ueda E, Shimato A, Sakakibara N, Soh Y, Mamiya T, Nagai T, Kim HC, Hiramatsu M, Nabeshima T, Yamada K.
  • Journal Title: Neuropsychopharmacology Volume: 41(2) Issue: 2 Pages: 578-89
  • DOI: 10.1038/npp.2015.186
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Molecular mechanism linking BDNF/TrkB signaling with the NMDA receptor in memory: The role of Girdin in the CNS. (2016)
  • Author(s): Itoh N, Enomoto A, Nagai T, Takahashi M, Yamada K
  • Journal Title: Rev Neurosci Volume: - Issue: 5 Pages: 481-490
  • DOI: 10.1515/revneuro-2015-0072
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Insular neural system controls decision-making in healthy and methamphetamine-treated rats (2015)
  • Author(s): Mizoguchi H, Katahira K, Inutsuka A, Fukumoto K, Nakamura A, Wang T, Nagai T, Sato J, Sawada M, Ohira H,Yamanaka A, Yamada K
  • Journal Title: Proc Natl Acad Sci U S A Volume: 112 (29) Issue: 29 Pages: 3930-3939
  • DOI: 10.1073/pnas.1418014112
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Therapeutic targets for neurodevelopmental disorders emerging from animal models with perinatal immune activation. (2015)
  • Author(s): Ibi D and Yamada K
  • Journal Title: Int J Mol Sci Volume: 16 Issue: 12 Pages: 1-12
  • DOI: 10.3390/ijms161226092
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Alterations of GABAergic and dopaminergic system in mutant mice with disruption of exons 2 and 3 of the Disc1 gene. (2014)
  • Author(s): Nakai T, Nagai T, Wang R, Yamada S, Kuroda K, Kaibuchi K, Yamada K
  • Journal Title: Neurochem. Int. Volume: 74 Pages: 74-83
  • DOI: 10.1016/j.neuint.2014.06.009
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Induction of interferone-induced transmembrane protein 3 gene expression by lipopolysaccharide in astrocytes. (2014)
  • Author(s): Nakajima A, Ibi D, Nagai T, Yamada S, Nabeshima T, Yamada K
  • Journal Title: Eur. J. Pharmacol. Volume: 745 Pages: 166-175
  • DOI: 10.1016/j.ejphar.2014.08.034
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Girdin phosphorylation is crucial for synaptic plasticity and memory: A potential role in the interaction of BDNF/TrkB/Akt signaling with NMDA receptor (2014)
  • Author(s): Tsuyoshi Nakai, Taku Nagai, Motoki Tanaka, Norimichi Itoh, Naoya Asai, Atsushi Enomoto, Masato Asai, Shinnnosuke Yamada, Ali Bin Saifullah, Masahiro Sokabe, Masahide Takahashi, Kiyofumi Yamada
  • Journal Title: The Journal of Neuroscience Volume: 34 Issue: 45 Pages: 14995-15008
  • DOI: 10.1523/jneurosci.2228-14.2014
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Nicotinic acetylcholine receptor as a target of harm reduction and treatment in addiction. (2016)
  • Author(s): 溝口博之、山田清文
  • Organizer: 第５１回日本アルコール・アディクション医学会学術総会
  • Place of Presentation: タワーホール船堀（東京都江戸川区）
  • Year and Date: 2016-10-07
• [Presentation] 意思決定障害と創薬標的としてのニコチン受容体 (2016)
  • Author(s): 溝口博之、山田清文
  • Organizer: 第18回応用薬理シンポジウム
  • Place of Presentation: 名古屋大学（愛知県名古屋市）
  • Year and Date: 2016-08-05
• [Presentation] 島皮質GABA神経は薬物依存ラットの意思決定に関与する (2016)
  • Author(s): 溝口博之、山田清文
  • Organizer: 第39回日本神経科学会
  • Place of Presentation: パシフィコ横浜（横浜市西区）
  • Year and Date: 2016-07-20
• [Presentation] 薬物依存症における意思決定異常 (2016)
  • Author(s): 溝口博之、山田清文.
  • Organizer: 第46回日本神経精神薬理学会
  • Place of Presentation: ソウル（韓国）
  • Year and Date: 2016-07-02
  • Int'l Joint Research
• [Presentation] Nicotine receptor as a potential target for treatment of pathological decision-making in addiction (2015)
  • Author(s): Hiroyuki Mizoguchi, Kiyofumi Yamada.
  • Organizer: WPAIC 2015, 4th Asian Congress of Schizophrenia Research, 4th Congress of Asian College of Neuropsychopharmacology
  • Place of Presentation: Taipei、Taiwan
  • Year and Date: 2015-11-18
  • Int'l Joint Research
• [Presentation] 基礎研究から探る薬物依存者の意思決定：リスク回避より目先の利益を優先する近視眼的意思決定 (2015)
  • Author(s): 溝口博之、山田清文
  • Organizer: 平成27年度アルコール・薬物依存関連学会合同学術総会
  • Place of Presentation: 神戸国際会議場（神戸市中央区）
  • Year and Date: 2015-10-11
• [Presentation] The insular GABAergic system controls decision-making in healthy and drug-dependent animals (2015)
  • Author(s): Hiroyuki Mizoguchi, Kiyofumi Yamada
  • Organizer: IBNS 24th Annual Meeting
  • Place of Presentation: Victoria, Canada
  • Year and Date: 2015-06-02
  • Int'l Joint Research
• [Presentation] Dysfunction of gabaergic system in the insular cortex contributes to impairments of decision-making in methamphetamine-depandent rats. (2014)
  • Author(s): Yamada K, Mizoguchi H
  • Organizer: ISAM2014
  • Place of Presentation: 神奈川県横浜市 パシフィコ横浜
  • Year and Date: 2014-10-02 – 2014-10-06
• [Presentation] Dysfunction of GABA ergic system in the insular cortex is associated with impaired decision-making in methamphetamine-treated rats. (2014)
  • Author(s): Yamada K, Fukumoto K, Wang T, Mizoguchi H
  • Organizer: 29th CINP World Congress of Neuropsychopharmacology
  • Place of Presentation: バンクーバー（カナダ）
  • Year and Date: 2014-06-22 – 2014-06-26
• [Remarks] 名古屋大学大学院医学系研究科 医療薬学・医学部附属病院薬剤部
  • URL: http://www.med.nagoya-u.ac.jp/pharmacy/