Elucidating the autism pathogenesis through brain networks of "theory of mind" and modeling autism in non-human primates

• Project/Area Number: 26293261
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Psychiatric science
• Research Institution: Niigata University
• Principal Investigator: Someya Toshiyuki 新潟大学, 医歯学系, 教授 (50187902)
• Co-Investigator(Kenkyū-buntansha): 長谷川 功 新潟大学, 医歯学系, 教授 (60282620) ; 飯島 淳彦 新潟大学, 自然科学系, 教授 (00377186) ; 川嵜 圭祐 新潟大学, 医歯学系, 准教授 (60511178) ; 江川 純 新潟大学, 医歯学総合研究科, 特任准教授 (80648527) ; 北村 秀明 新潟大学, 医歯学総合研究科, 非常勤講師 (00361923)
• Project Period (FY): 2014-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥17,680,000 (Direct Cost: ¥13,600,000、Indirect Cost: ¥4,080,000); Fiscal Year 2017: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2016: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2015: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2014: ¥15,730,000 (Direct Cost: ¥12,100,000、Indirect Cost: ¥3,630,000)
• Keywords: 心の理論 / 非言語的誤信念課題 / DREADD / マカクザル / 自閉スペクトラム症(ASD) / 霊長類動物モデル / 自閉スペクトラム症 / 自閉スぺlクトラム症 / 脳磁図 / 皮質脳波 / 拡散テンソル画像 / 自閉スぺクトラム症 / 皮質脳波（ECoG） / 脳磁図（MEG） / 自閉症スペクトラム障害 / 視線計測

Outline of Final Research Achievements

Human neuroimaging studies using various false-belief (FB) attribution tasks have revealed relationships between theory of mind (ToM) and brain networks, including the medial prefrontal cortex (mPFC). In the present study, we examined whether there was causation between neuronal activity in the macaque mPFC and the spontaneous gaze bias to FB targets. We injected hM4Di, an inhibitory DREADD , into the mPFC. We chemogenetically inactivated the mPFC using clozapine N-oxide, a specific ligand to hM4Di. We found that chemogenetic deactivation of the mPFC with CNO injection in monkeys expressing hM4Di specifically altered the gaze bias to the FB target. Thus, our results indicate that neural activity in the macaque mPFC plays a causal role in ToM. These findings suggest the novel possibility that macaques implicitly attribute mental states to others via the operation of neural circuits that are shared with humans, in which the mPFC plays a pivotal role.

Academic Significance and Societal Importance of the Research Achievements

本研究により、マカクザルには心の理論がある可能性、及び内側前頭前野が心の理論の脳回路の一部である可能性が示唆された。本研究成果により妥当性の高いASDモデル動物を作成することが可能となり、分子遺伝的基盤や生物学的治療の研究が飛躍的に推進されると考えられる。

Research Products

• [Journal Article] Comparative Analyses of Copy-Number Variation in Autism Spectrum Disorder and Schizophrenia Reveal Etiological Overlap and Biological Insights. (2018)
  • Author(s): Kushima I, (27名中略）, Hashimoto R,(80名中29番目) , et al.
  • Journal Title: Cell Rep Volume: 24(11) Issue: 11 Pages: 2838-2856
  • DOI: 10.1016/j.celrep.2018.08.022
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Pathological alterations of chondroitin sulfate moiety in postmortem hippocampus of patients with schizophrenia (2018)
  • Author(s): Yukawa、Iwakura、Takei、Saito、Watanabe、Toyooka、Igarashi、Niizato、Oshima、Kunii、Yabe、Matsumoto、Wada、Hino、Iritanii、Niwa、Takeuchi、Takahashi、Kakita、Someya、Nawa
  • Journal Title: Psychiatry Research Volume: 270 Pages: 940-946
  • DOI: 10.1016/j.psychres.2018.10.062
  • Peer Reviewed / Open Access
• [Journal Article] Genome-Wide Association Study Detected Novel Susceptibility Genes for Schizophrenia and Shared Trans-Populations/Diseases Genetic Effect (2018)
  • Author(s): Ikeda M,Takahashi A,Kamatani Y,Momozawa Y,Saito T,Kondo K,Shimasaki A,Kawase K,Sakusabe T,Iwayama Y,Toyota T,Wakuda T,Kikuchi M,Kanahara N,Yamamori H,Yasuda Y,Watanabe Y,Hoya S,Aleksic B,Kushima I,Arai H,Takaki M,Hattori K,Kunugi H,Okahisa Y,Ohnuma T,Ozaki N,Someya T,Hashimoto R,Yoshikawa T,Kubo M,Iwata N
  • Journal Title: Schizophrenia Bulletin Volume: 印刷中 Issue: 4 Pages: 824-834
  • DOI: 10.1093/schbul/sby140
  • Peer Reviewed / Open Access
• [Journal Article] Longer telomeres in elderly schizophrenia are associated with long-term hospitalization in the Japanese population. (2018)
  • Author(s): Zhang Y, Hishimoto A, Otsuka I, Watanabe Y, Numata S, Yamamori H, Boku S, Horai T, Someya T, Ohmori T, Hashimoto R, Sora I.
  • Journal Title: J Psychiatr Res Volume: 103 Pages: 161-166
  • DOI: 10.1016/j.jpsychires.2018.05.014
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Effects of olanzapine on resting heart rate in Japanese patients with schizophrenia (2018)
  • Author(s): Tajiri M、Suzuki Y、Sugai T、Tsuneyama N、Someya T
  • Journal Title: PLOS ONE Volume: 13 Issue: 7 Pages: e0199922-e0199922
  • DOI: 10.1371/journal.pone.0199922
  • Peer Reviewed / Open Access
• [Journal Article] High-density lipoprotein-cholesterol and antipsychotic medication in overweight inpatients with schizophrenia: post-hoc analysis of a Japanese nationwide survey. (2018)
  • Author(s): Ono S, Sugai T, Suzuki Y, Yamazaki M, Shimoda K, Mori T, Ozeki Y, Matsuda H, Sugawara N, Yasui-Furukori N, Okamoto K, Sagae T, Someya T.
  • Journal Title: BMC Psychiatry Volume: 18 Issue: 1 Pages: 180-180
  • DOI: 10.1186/s12888-018-1764-1
  • Peer Reviewed / Open Access
• [Journal Article] Prevalence of underweight in patients with schizophrenia: A meta-analysis (2018)
  • Author(s): Sugawara N、Maruo K、Sugai T、Suzuki Y、Ozeki Y、Shimoda K、Someya T、Yasui-Furukori N
  • Journal Title: Schizophrenia Research Volume: 195 Pages: 67-73
  • DOI: 10.1016/j.schres.2017.10.017
  • Peer Reviewed
• [Journal Article] Heterogeneous Redistribution of Facial Subcategory Information Within and Outside the Face-Selective Domain in Primate Inferior Temporal Cortex (2018)
  • Author(s): Miyakawa Naohisa、Majima Kei、Sawahata Hirohito、Kawasaki Keisuke、Matsuo Takeshi、Kotake Naoki、Suzuki Takafumi、Kamitani Yukiyasu、Hasegawa Isao
  • Journal Title: Cerebral Cortex Volume: 28 Issue: 4 Pages: 1416-1431
  • DOI: 10.1093/cercor/bhx342
  • Peer Reviewed / Open Access
• [Journal Article] Locally induced neuronal synchrony precisely propagates to specific cortical areas without rhythm distortion. (2018)
  • Author(s): Toda H, Kawasaki K, Sato S, Horie M, Nakahara K, Bepari AK, Sawahata H, Suzuki T, Okado H, Takebayashi H, Hasegawa I.
  • Journal Title: Scientific Reports Volume: - Issue: 1 Pages: 7678-7678
  • DOI: 10.1038/s41598-018-26054-8
  • Peer Reviewed / Open Access
• [Journal Article] Rare loss of function mutations in N-methyl-d-aspartate glutamate receptors and their contributions to schizophrenia susceptibility (2018)
  • Author(s): Yu Yanjie、Lin Yingni、Takasaki Yuto、Wang Chenyao、Kimura Hiroki、Xing Jingrui、Ishizuka Kanako、Toyama Miho、Kushima Itaru、Mori Daisuke、Arioka Yuko、Uno Yota、Shiino Tomoko、Nakamura Yukako、Okada Takashi、Morikawa Mako、Ikeda Masashi、Iwata Nakao、Okahisa Yuko、Takaki Manabu、Sakamoto Shinji、et al.
  • Journal Title: Translational Psychiatry Volume: 8 Issue: 1 Pages: 12-20
  • DOI: 10.1038/s41398-017-0061-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Rare genetic variants in CX3CR1 and their contribution to the increased risk of schizophrenia and autism spectrum disorders (2017)
  • Author(s): Ishizuka K、Fujita Y、Kawabata T、Kimura H、Iwayama Y、Inada T、Okahisa Y、Egawa J、Usami M、Kushima I、Uno Y、Okada T、Ikeda M、Aleksic B、Mori D、Someya To、Yoshikawa T、Iwata N、Nakamura H、Yamashita T、Ozaki N
  • Journal Title: Translational Psychiatry Volume: 7 Issue: 8 Pages: e1184-e1184
  • DOI: 10.1038/tp.2017.173
  • Peer Reviewed / Open Access
• [Journal Article] Associative-memory representations emerge as shared spatial patterns of theta activity spanning the primate temporal cortex (2016)
  • Author(s): Kiyoshi Nakahara, Ken Adachi, Keisuke Kawasaki, Takeshi Matsuo, Hirohito Sawahata, Kei Majima, Masaki Takeda, Sayaka Sugiyama, Ryota Nakata, Atsuhiko Iijima, Hisashi Tanigawa, Takafumi Suzuki, Yukiyasu Kamitani, Isao Hasegawa
  • Journal Title: Nature Communications Volume: 未定 Issue: 1 Pages: 11827-11827
  • DOI: 10.1038/ncomms11827
  • NAID: 120005822769
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 皮質脳波（ECoG）信号を用いた脳内イメージ情報のデコーディング. (2016)
  • Author(s): 長谷川功
  • Journal Title: Clinical Neuroscience Volume: 34(2) Pages: 193-196
• [Journal Article] 皮質脳波（ECoG）信号を用いた脳内イメージ情報のデコーディング (2016)
  • Author(s): 長谷川功
  • Journal Title: Clinical Neuroscience Volume: 34(2) Pages: 193-196
• [Journal Article] Alternating zones selective to faces and written words in the human ventral occipitotemporal cortex (2013)
  • Author(s): Matsuo T, Kawasaki K, Kawai K, Majima K, Masuda H, Murakami H, Kunii N, Kamitani Y, Kameyama S, Saito N, Hasegawa I
  • Journal Title: Cereb Cortex Volume: (in press) Issue: 5 Pages: 1265-77
  • DOI: 10.1093/cercor/bht319
  • Peer Reviewed
• [Presentation] マカクザルにおける心の理論の検討および内側前頭前野の不活性化によるその関連性について (2019)
  • Author(s): 林剛丞, 江川純, 秋川諒太, 川嵜圭祐, 長谷川功, 飯島淳彦, 染矢俊幸
  • Organizer: 第115回日本精神神経学会
• [Presentation] 拡散テンソル画像を用いた脳機能結合と自閉スペクトラム症との関連解析 (2019)
  • Author(s): 江川純, 杉本篤言, 吉永清宏, 林剛丞, 染矢俊幸
  • Organizer: 第115回日本精神神経学会
• [Presentation] Anticipating of other's behavior on the basis of understanding other's false beliefs in rhesus monkeys (Macaca fuscata) (2018)
  • Author(s): Hayashi T, Kawasaki K, Akikawa R, Hasegawa I, Egawa J, Someya T, Iijima A
  • Organizer: 第41回日本神経科学大会
• [Presentation] Relationship between prefrontal cortex activity during task execution and ADHD symptoms of adult patients, and their changes by atomoxetine. (2018)
  • Author(s): Sugimoto A, Suzuki Y, Yoshinaga K, Orime N, Hayashi T, Egawa J, Ono S, Sugai T, Someya T
  • Organizer: WFSBP Asia Pacific Regional Congress of Biological Psychiatry
  • Int'l Joint Research
• [Presentation] Resequencing of the SETD1A gene in Japanese patients with schizophrenia. (2018)
  • Author(s): Hoya S, Igeta H, Watanabe Y, Nunokawa A, Inoue E, Shibuya M, Egawa J, Someya T
  • Organizer: WFSBP Asia Pacific Regional Congress of Biological Psychiatry
  • Int'l Joint Research
• [Presentation] Rare FBXO18 variations and risk of schizophrenia. (2018)
  • Author(s): Watanabe Y, Hoya S, Hishimoto A, Nunokawa A, Inoue E, Igeta H, Otsuka I, Shibuya M, Sora I, Someya T
  • Organizer: WFSBP Asia Pacific Regional Congress of Biological Psychiatry
  • Int'l Joint Research
• [Presentation] Whole-exome sequencing in a consanguineous multiplex family with schizophrenia and a case-control study. (2018)
  • Author(s): Igeta H, Watanabe Y, Hoya S, Ikeda M, Hishimoto A, Nunokawa A, Inoue E, Sora I, Iwata N, Someya T
  • Organizer: WFSBP Asia Pacific Regional Congress of Biological Psychiatry
  • Int'l Joint Research
• [Presentation] Increased serum levels and promoter polymorphisms of macrophage migration inhibitory factor in schizophrenia. (2018)
  • Author(s): Okazaki S, Otsuka I, Watanabe Y, Numata S, Boku S, Shimmyo N, Ohmori T, Someya T, Sora I, Hishimoto A.
  • Organizer: WFSBP Asia Pacific Regional Congress of Biological Psychiatry
  • Int'l Joint Research
• [Presentation] Anticipating of other's behavior on the basis of understanding other's false beliefs in rhesus monkeys (Macaca fuscata) (2018)
  • Author(s): 川嵜圭祐、長谷川功、江川純、染矢俊幸、飯島淳彦
  • Organizer: 第41回日本神経科学会
• [Presentation] 視線・矢印による注意喚起が眼球運動に及ぼす影響 (2017)
  • Author(s): 染矢俊幸
  • Organizer: 日本視覚学会2017年冬季大会
  • Place of Presentation: NHK放送技術研究所（東京都世田谷区）
  • Year and Date: 2017-01-19
• [Presentation] Spatial and temporal distribution of value-related and visual information in the macaque lateral prefrontal cortex. (2017)
  • Author(s): 川嵜圭祐、長谷川功
  • Organizer: Society of Neuroscience 2017
  • Int'l Joint Research
• [Presentation] Relationships between the internal representations of convolutional neural network and the space, time and frequency domains of ECoG signals on macaque inferior temporal cortex. (2016)
  • Author(s): 川嵜圭祐、長谷川功
  • Organizer: Neuroscience2016
  • Place of Presentation: San Diego (U.S.A)
  • Year and Date: 2016-11-16
  • Int'l Joint Research
• [Presentation] Modulation of value information coded in the lateral prefrontal cortex by decode neurofeedback with electrocorticographic (ECoG) signals. (2016)
  • Author(s): 川嵜圭祐、長谷川功
  • Organizer: Neuroscience2016
  • Place of Presentation: San Diego (U.S.A)
  • Year and Date: 2016-11-12
  • Int'l Joint Research
• [Presentation] Decoding recalled color imagery using ECoG signals in macaque inferior temporal and prefrontal cortices. (2016)
  • Author(s): 川嵜圭祐、長谷川功
  • Organizer: Neuroscience2016
  • Place of Presentation: San Diego (U.S.A)
  • Year and Date: 2016-11-12
  • Int'l Joint Research
• [Presentation] Information flow dynamics in inferior temporal cortex involving visual object processing. (2015)
  • Author(s): 川嵜圭祐
  • Organizer: Society for Neuroscience 2015
  • Place of Presentation: Chicago, U.S.A
  • Year and Date: 2015-10-17
  • Int'l Joint Research
• [Presentation] 自閉症の分子遺伝研究から橋渡し研究へ (2014)
  • Author(s): 江川純
  • Organizer: 第3回金沢大学子どものこころサミット
  • Place of Presentation: 北國新聞 赤羽ホール（石川県金沢市）
  • Year and Date: 2014-11-27 – 2014-11-29
  • Invited
• [Presentation] Spatial pattern similarity of ECoG responses represents associative memory in the primate medial temporal lobe. (2014)
  • Author(s): Adachi K, Kawasaki K, Sawahata H, Matsuo T, Suzuki T, Majima K, Tanigawa H, Iijima A, Kamitani Y, Hasegawa I
  • Organizer: Neuro2014
  • Place of Presentation: PACIFICO YOKOHAMA, Yokohama, Japan
  • Year and Date: 2014-09-11 – 2014-09-13
• [Presentation] Decoding of material categories from ECoG signals in the macaque inferior temporal cortex. (2014)
  • Author(s): Teramoto T, Kawasaki K, Okatani T, Sawahata H, Suzuki T, Hasegawa I
  • Organizer: Neuro2014
  • Place of Presentation: PACIFICO YOKOHAMA, Yokohama, Japan
  • Year and Date: 2014-09-11 – 2014-09-13
• [Presentation] Hierarchical propagation of visual response through the inferior temporal cortex. (2014)
  • Author(s): Kawasaki K, Haruna T, Fujiki Y, Sawahata H, Tanigawa H, Iijima A, Suzuki T, Hasegawa I
  • Organizer: Neuro2014
  • Place of Presentation: PACIFICO YOKOHAMA, Yokohama, Japan
  • Year and Date: 2014-09-11 – 2014-09-13
• [Presentation] Super multi-channel recording systems with UWB wireless transmitter for BMI. (2014)
  • Author(s): Suzuki T, Ando H, Yoshida T, Sawahata H, Kawasaki K, Hasegawa I, Matsushita K, Hirata M, Yoshimine T, Takizawa K
  • Organizer: 36th Annual international conference of the IEEE engineering in medicine and biology society (EMBC’14)
  • Place of Presentation: Sheraton Hotel & Towers, Chicago, U.S.A.
  • Year and Date: 2014-08-26 – 2014-08-30