Development of an anorexia animal model using an arterially perfused decorticated mouse preparation

• Project/Area Number: 19K22726
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 57:Oral science and related fields
• Research Institution: Showa University
• Principal Investigator: Inoue Tomio 昭和大学, 歯学部, 教授 (70184760)
• Co-Investigator(Kenkyū-buntansha): 中村 史朗 昭和大学, 歯学部, 准教授 (60384187) ; 中山 希世美 昭和大学, 歯学部, 講師 (00433798) ; 望月 文子 昭和大学, 歯学部, 講師 (10453648) ; 壇辻 昌典 昭和大学, 歯学部, 助教 (60826634)
• Project Period (FY): 2019-06-28 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000); Fiscal Year 2020: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000); Fiscal Year 2019: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
• Keywords: 食欲 / 動脈灌流標本 / 嚥下 / 食欲不振 / 大脳除去ラット動脈灌流標本 / グレリン / 咀嚼 / 腕傍核

Outline of Research at the Start

高齢者の食欲不振は、要介護状態にいたる重大なリスク要因となる。食欲不振の真の原因の解明は、動物の摂食量の減少を指標にする従来の研究手法では難しかった。最近私たちは、標本の全身状態に関係なく中枢神経系や頭部組織の活性を保つことができる大脳除去動物の動脈灌流標本を開発した。そこで本研究は、摂食行動を制御する基本的な神経回路が存在するとされる視床下部から脳幹に着目し、視床下部や脳幹が“食欲不振の状態”になると動脈灌流標本の咀嚼様運動や嚥下様運動が起こりにくくなると仮定し、これらの運動の誘発を指標に食欲不振を起こす条件とその背景にある神経メカニズムを探り、新規の食欲不振動物実験モデルの確立を目指す。

Outline of Final Research Achievements

Anorexia is caused by physical and emotional diseases, as well as aging. It is not clear that neural mechanisms underlying appetite control because the amount of food intake which is used for the the analysis in conventional animal models, is often affected by health condition of the subjects. In this study, we analyzed the effects of several physiologically active substances that have been ascribed to affect the amount of food intake on swallowing-like movement induced in an arterially perfused decerebrated rat preparation to establish a new experimental model to analyze neural mechanisms underlying appetite control. Application of ghrelin increased swallowing-like movement by 31%. Thus, it is possible that the arterially perfused decerebrated rat preparation may be used for analyze neural mechanisms underlying appetite control.

Academic Significance and Societal Importance of the Research Achievements

摂食行動を司る神経機構を解明するために、従来の動物の摂食量を指標にした解析方法では、覚醒レベルや体調などの変動要因が数多く存在する。本研究は、除脳によって精神的、心理的な食欲不振の要因を取り除き、口腔内への蒸留水注入によって誘発された嚥下様運動を指標とすることで、変動要因を極力減らし、食欲不振に関わるニューロン機構を解析できる。さらに、食欲不振と摂食行動の実行システム（嚥下）との関連も解析できる。本実験によって食欲不振だけでなく過食の神経メカニズムについても新たな発想の画期的な研究手法の開発につながる可能性があり、がん患者や高齢者の食欲不振の治療法の開発につながる可能性がある。

Research Products

• [Journal Article] Postnatal Maturation of Glutamatergic Inputs onto Rat Jaw-closing and Jaw-opening Motoneurons (2022)
  • Author(s): Nakamura Shiro、Kajiwara Risa、Noguchi Tsuyoshi、Nakayama Kiyomi、Mochizuki Ayako、Dantsuji Masanori、Sarkar Avijite Kumer、Inoue Tomio
  • Journal Title: Neuroscience Volume: 480 Pages: 42-55
  • DOI: 10.1016/j.neuroscience.2021.11.016
  • Peer Reviewed
• [Journal Article] Developmental changes in GABAergic and glycinergic synaptic transmission to rat motoneurons innervating jaw-closing and jaw-opening muscles (2022)
  • Author(s): Noguchi Tsuyoshi、Nakamura Shiro、Nakayama Kiyomi、Mochizuki Ayako、Dantsuji Masanori、Ihara Yoshiaki、Takahashi Koji、Inoue Tomio
  • Journal Title: Brain Research Volume: 1777 Pages: 147753-147753
  • DOI: 10.1016/j.brainres.2021.147753
  • Peer Reviewed
• [Journal Article] Increased excitability of human iPSC-derived neurons in HTR2A variant-related sleep bruxism (2022)
  • Author(s): Sarkar Avijite Kumer、Nakamura Shiro、Nakai Kento、Sato Taro、Shiga Takahiro、Abe Yuka、Hoashi Yurie、Inoue Tomio、Akamatsu Wado、Baba Kazuyoshi
  • Journal Title: Stem Cell Research Volume: 59 Pages: 102658-102658
  • DOI: 10.1016/j.scr.2022.102658
  • Peer Reviewed / Open Access
• [Journal Article] In vitro monitoring of HTR2A-positive neurons derived from human-induced pluripotent stem cells (2021)
  • Author(s): Nakai Kento、Shiga Takahiro、Yasuhara Rika、Sarkar Avijite Kumer、Abe Yuka、Nakamura Shiro、Hoashi Yurie、Kotani Keisuke、Tatsumoto Shoji、Ishikawa Hiroe、Go Yasuhiro、Inoue Tomio、Mishima Kenji、Akamatsu Wado、Baba Kazuyoshi
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 15437-15437
  • DOI: 10.1038/s41598-021-95041-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Responses evoked by electrical stimulation of the brainstem reticular formation in the jaw-opening and hypoglossal motor nerves of an arterially perfused rat preparation (2020)
  • Author(s): Ofuji Takuo、Nakayama Kiyomi、Nakamura Shiro、Mochizuki Ayako、Dantsuji Masanori、Ishiguro Mitsunori、Yamamoto Matsuo、Inoue Tomio
  • Journal Title: Neuroscience Letters Volume: 738 Pages: 135400-135400
  • DOI: 10.1016/j.neulet.2020.135400
  • Peer Reviewed
• [Journal Article] Involvement of the basal nucleus of Meynert on regional cerebral cortical vasodilation associated with masticatory muscle activity in rats. (2019)
  • Author(s): Hotta H, Suzuki H, Inoue T, Stewart M.
  • Journal Title: J Cereb Blood Flow Metab Volume: in press Issue: 12 Pages: 2416-2428
  • DOI: 10.1177/0271678x19895244
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] 5-HT2A receptor activation enhances NMDA receptor-mediated glutamate responses therough Src kinase in the dendrites of rat jaw-closing motoneurons. (2019)
  • Author(s): Dantsuji M, Nakamura S, Nakayam, K, Mochizuki A, Park SK, Bae YC, Ozeki M, Inoue T.
  • Journal Title: J. Physiol. Volume: 印刷中 Issue: 9 Pages: 2565-2589
  • DOI: 10.1113/jp275440
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Serotonin1B receptor-mediated presynaptic inhibition of proprioceptive sensory inputs to jaw-closing motoneurons. (2019)
  • Author(s): Nagata A, Nakayama K, Nakamura S, Mochizuki A, Gemba C, Aoki R, Dantsuji M, Maki K, Inoue T.
  • Journal Title: Brain Res Bull. Volume: 149 Pages: 260-267
  • DOI: 10.1016/j.brainresbull.2019.05.001
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] High molecular weight amyloid β1‐42 oligomers induce neurotoxicity via plasma membrane damage (2019)
  • Author(s): Yasumoto Taro、Takamura Yusaku、Tsuji Mayumi、Watanabe‐Nakayama Takahiro、Imamura Keiko、Inoue Haruhisa、Nakamura Shiro、Inoue Tomio、Kimura Atsushi、Yano Satoshi、Nishijo Hisao、Kiuchi Yuji、Teplow David B.、Ono Kenjiro
  • Journal Title: The FASEB Journal Volume: 33 Issue: 8 Pages: 9220-9234
  • DOI: 10.1096/fj.201900604r
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Enhancement of swallowing motor activity by the ACE inhibitor imidapril in an arterially perfused rat preparation. (2019)
  • Author(s): Moriya T, Nakayama K, Nakamura S, Mochizuki A, Ofuji T, Shirota T, Inoue T.
  • Journal Title: Eur J Pharmacol. Volume: 861 Pages: 172601-172601
  • DOI: 10.1016/j.ejphar.2019.172601
  • Peer Reviewed / Int'l Joint Research
• [Presentation] ラット小細胞性網様体に存在するPhox2b発現細胞の生理学的・形態学的特性解析 (2022)
  • Author(s): 梶原里紗，中村史朗，池田啓子，鬼丸洋，吉田篤，堤友美，中山希世美，望月文子，壇辻昌典，飯島毅彦，井上富雄
  • Organizer: 第99回日本生理学会大会
• [Presentation] Optogenetic activation of serotonergic neurons in the dorsal raphe nucleus changes masticatory movements in mice (2021)
  • Author(s): Dantsuji M, Mochizuki A, Nakayama K, Nakamura S, Kanamaru M, Izumizaki M, Tanaka KF, Inoue T
  • Organizer: 第44回日本神経科学大会
• [Presentation] 加齢に伴う口腔機能低下と大脳皮質機能 (2021)
  • Author(s): 井上富雄
  • Organizer: 日本老年歯科医学会第32回学術大会 「口腔機能の生理的老化と病的老化」シンポジウム
  • Invited
• [Presentation] 閉口筋および開口筋運動ニューロンにおける抑制性シナプス伝達様式の生後変化 (2021)
  • Author(s): 野口毅，中村史朗，中山希世美，望月文子，壇辻昌典，伊原良明, 髙橋浩二, 井上 富雄
  • Organizer: 第98回日本生理学会大会
• [Presentation] Electrophysiological maturation and characteristics of human stem cells in sleep bruxism. (2021)
  • Author(s): Avijite KS, Nakamura S, Abe Y, Nakai K, Yasuhara R, Shiga T, Hoashi Y, Kotani K, Inoue T, Mishima K, Akamatsu W, Baba K.
  • Organizer: The 7th Biennial Joint Congress of JPS-CPS-KAP
  • Int'l Joint Research
• [Presentation] Electrophysiological characterization of sleep bruxism patient-specific induced pluripotent stem cell-derived neurons. (2020)
  • Author(s): Avijite KS, Nakai K, Nakamura S, Yasuhara R, Shiga T, Abe Y, Hoashi Y, Kotani K, Inoue T, Mishima K, Akamatsu W, Baba K.
  • Organizer: 日本顎口腔機能学会第64回学術大会
• [Presentation] 睡眠時ブラキシズム患者特異的iPS細胞由来ニューロンの電気生理学的基本特性 (2020)
  • Author(s): Avijite Kumer Sarkar，中村史朗，中井健人，小渓啓介，安原理佳，安部友佳，美島健二，井上富雄，馬場一美
  • Organizer: 第67回昭和大学学士会総会
• [Presentation] ミリセチンは抗酸化作用を介し、ミトコンドリア・細胞膜でアミロイドβオリゴマーによる神経毒性を抑制する (2020)
  • Author(s): 木村篤史，森友起子，小口達敬，海野真一，海野麻未，宇高結子，中村史朗，井上富雄，辻まゆみ，小野賢二郎，木内祐二
  • Organizer: 第39回日本認知症学会学術集会
• [Presentation] 高分子Aβオリゴマーは細胞膜完全性を崩壊し細胞毒性を発揮する (2020)
  • Author(s): 安本太郎，高村雄策，辻まゆみ，中山隆宏，今村恵子，井上治久，中村史朗，井上富雄，木村篤史，矢野怜，西条寿夫，木内祐二，デービッドテプロフ，小野賢 二郎
  • Organizer: 第39回日本認知症学会学術集会
• [Presentation] 咬筋運動ニューロン樹状突起における5-HT2A受容体の活性化はSrcを介してGluN2Aを含むNMDA受容体の機能を亢進する (2020)
  • Author(s): 壇辻昌典，中村史朗，中山希世美，望月文子，井上富雄
  • Organizer: 第62回歯科基礎医学会学術大会
• [Presentation] 小細胞性網様体に存在するPhox2陽性ニューロンの電気生理学的・形態学的解析 (2020)
  • Author(s): 梶原里紗，中村史朗，中山希世美，望月文子，壇辻昌典，立川哲史, 飯島毅彦，井上富雄
  • Organizer: 第62回歯科基礎医学会学術大会
• [Presentation] 咀嚼運動制御に関わる神経基盤：脳幹に存在する顎運動制御回路について (2020)
  • Author(s): 中村史朗
  • Organizer: 第62回歯科基礎医学会学術大会
• [Presentation] 閉口筋運動ニューロンにおける抑制性シナプス伝達の生後変化 (2020)
  • Author(s): 野口毅，中村史朗，中山希世美，望月文子，壇辻昌典，井上富雄
  • Organizer: 第62回歯科基礎医学会学術大会
• [Presentation] High molecular weight Amyloid b oligomer induces disruption and structural change of cell membrane (2020)
  • Author(s): 安本太郎，高村雄策，辻まゆみ，中山隆宏，今村恵子，井上治久，中村史朗，井上富雄，木村篤史，矢野怜，西条寿夫，木内祐二，デービッドテプ ロフ，小野賢二郎
  • Organizer: 第61回日本神経学会学術大会
• [Presentation] Responses evoked by electrical stimulation of the brainstem reticular formation in the mylohyoid and hypoglossal motor nerves of an arterially perfused rat preparation. (2020)
  • Author(s): Ofuji T, Nakayama K, Nakamura S, Mochizuki A, Dantsuji M, Ishiguro M, Yamamoto M, Inoue T
  • Organizer: 第61回日本神経学会学術大会
• [Presentation] High molecular weight amyloid β1-42 oligomers induce neurotoxicity via plasma membrane damage (2020)
  • Author(s): Yasumoto T, Takamura Y, Tsuji M, Nakayama T, Imamura K, Inoue H, Nakamura S, Inoue T, Kimura AM, Yano S, Nishijo H, Kiuchi Y, Teplow DP, Ono K
  • Organizer: Alzheimer's Association International Conference
  • Int'l Joint Research
• [Presentation] Vitamin B12 may prevent Aβ oligomer-induced neurotoxicity in Alzheimer's Disease. (2020)
  • Author(s): Kimura AM, Tsuji M, Yasumoto T, Oguchi T, Mori Y, Yano S, Kinnno R, Nakamura S, Inoue T, Teplow DP, Kiuchi Y, Ono K
  • Organizer: Alzheimer's Association International Conference
  • Int'l Joint Research
• [Presentation] 除脳動脈ラット標本を用いた嚥下改善薬の効果の検討 (2020)
  • Author(s): 守谷崇, 中山希世美, 中村史朗, 望月文子, 壇辻昌典, 井上富雄
  • Organizer: 第43回日本嚥下医学会学術講演会
• [Presentation] ミリセチンは抗酸化作用を介し、ミトコンドリア・細胞膜でアミロイドβオリゴマーによる神経毒性を抑制する (2020)
  • Author(s): 木村篤史，安本太郎，森友起子，小口達敬，海野真一，海野麻未，宇高結子，中村史朗，井上富雄，辻まゆみ，小野賢二郎，木内祐二
  • Organizer: 第363回昭和大学学士会例会
• [Presentation] Myricetin prevents Aβ oligomer-induced neurotoxicity via cell membrane damage. (2020)
  • Author(s): Kimura A, Yasumoto T, Mori Y, Oguchi T, Nakamura S, Inoue T, Yamada M, Teplow D, Ono K, Kiuchi Y, Tsuji M
  • Organizer: Advances in Alzheimer’s and Parkinson’s therapies, an AAT-AD/PDTM focus meeting
  • Int'l Joint Research
• [Presentation] 除脳ラット動脈灌流標本を用いた咀嚼様リズム神経活動の誘発. (2019)
  • Author(s): 大藤拓生, 中山希世美, 中村史朗, 望月文子, 壇辻昌典, 井上富雄.
  • Organizer: 日本顎口腔機能学会第63回学術大会
• [Presentation] Serotonin1b receptor mediated presynaptic inhibition of jaw closing motoneurons. (2019)
  • Author(s): Nakayama K, Nagata A, Nakamura S, Mochizuki A, Dantsuji M, Maki K, Inoue T.
  • Organizer: Society for Neuroscience 49th annual meeting
  • Int'l Joint Research
• [Presentation] Orexin modulates electrophysiological properties of Phox2b neurons located around trigeminal motor nucleus. (2019)
  • Author(s): Nagoya K, Nakamura S, Tsujimura T, Inoue M, Inoue T.
  • Organizer: Society for Neuroscience 49th annual meeting
  • Int'l Joint Research
• [Presentation] ?Phox2b-expressing neurons located around trigeminal motor nucleus have specific properties for jaw-movements. (2019)
  • Author(s): Nagoya K, Nakamura S, Tsujimura T, Inoue M, Inoue T.
  • Organizer: Society for Neuroscience 49th annual meeting
  • Int'l Joint Research
• [Presentation] マウス咬筋の筋活動に対するSSRIの影響． (2019)
  • Author(s): 望月文子，池田美菜子，中村史朗，中山希世美，壇辻昌典，加藤隆史，馬場一美，井上富雄．
  • Organizer: 第61回歯科基礎医学会学術大会
• [Presentation] 嚥下関連筋支配神経の活動に対するイミダプリルの効果． (2019)
  • Author(s): 守谷崇, 中山希世美, 中村史朗, 望月文子, 壇辻昌典, 井上富雄.
  • Organizer: 第61回歯科基礎医学会学術大会
• [Presentation] Serotonin1B receptors are involved in presynaptic inhibition of proprioceptive afferent transmission to jaw-closing motoneurons. (2019)
  • Author(s): Inoue T, Nagata A, Nakayama K, Dantsuji M, Nakamura S, Mochizuki A, Maki K.
  • Organizer: IBRO2019 (The 10th IBRO World Congress of Neuroscience)
  • Int'l Joint Research
• [Presentation] Presynaptic Activation of 5-HT1B Receptors Inhibits Proprioceptive Sensory Inputs to Jaw-Closing Motoneurons. (2019)
  • Author(s): Inoue T, Nagata A, Nakayama K, Dantsuji M, Nakamura S, Mochizuki A, Maki K.
  • Organizer: FENS Regional Meeting 2019
  • Int'l Joint Research
• [Presentation] Electrophysiological recordings of neurons derived from sleep bruxism patient-specific iPSCs. (2019)
  • Author(s): Nakai K, Shiga T, Abe Y, Hoashi Y, Nakamura S, Yasuhara R, Matsumoto T, Avijite KS, Kotani K, Mishima K, Inoue T, Akamatsu W, Baba K.
  • Organizer: ISSCR Annual Meeting
  • Int'l Joint Research
• [Presentation] Patch-clamp recordings of neurons induced from sleep bruxism patient specific iPSCs. (2019)
  • Author(s): Nakai K, Hoashi Y, Abe Y, Nakamura S, Siga T, Avijite KS, Yasuhara R, Matsumoto T, Kotani K, Inoue T, Mishima K, Akamatsu W, Baba K.
  • Organizer: 97th general session & exhibition of the IADR
  • Int'l Joint Research
• [Presentation] 睡眠時ブラキシズム特異的iPS細胞由来GABA作動性神経細胞の電気生理学的評価 (2019)
  • Author(s): 中井健人，小溪啓介，帆足有理恵，松本貴志，安部友佳，安原理佳，美島健二，中村史朗，井上富雄，志賀孝宏，赤 松和士，馬場一美
  • Organizer: 日本補綴歯科学会128回学術大会
• [Presentation] 嚥下関連筋支配神経への嚥下改善薬の効果． (2019)
  • Author(s): 守谷崇, 中山希世美, 中村史朗, 望月文子, 壇辻昌典, 代田達夫, 井上富雄
  • Organizer: 日本顎口腔機能学会第62回学術大会
• [Book] 口腔・顎顔面の機能；有床義歯補綴学 (2021)
  • Author(s): 井上富雄
  • Total Pages: 344
  • Publisher: 永末書店
  • ISBN: 9784816013836
• [Book] 口腔生理学総論；基礎歯科生理学 第７版 (2019)
  • Author(s): 井上富雄
  • Total Pages: 475
  • Publisher: 医歯薬出版
  • ISBN: 9784263458464
• [Book] 咀嚼；基礎歯科生理学 第７版 (2019)
  • Author(s): 井上富雄、中村史朗
  • Total Pages: 475
  • Publisher: 医歯薬出版
  • ISBN: 9784263458464
• [Remarks] 昭和大学歯学部口腔生理学講座について
  • URL: http://www10.showa-u.ac.jp/~oralphys/index.html