Identification of rule for expression and selection of engram cells

• Project/Area Number: 16H04653
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurophysiology / General neuroscience
• Research Institution: University of Toyama
• Principal Investigator: Ohkawa Noriaki 富山大学, 大学院医学薬学研究部(医学), 講師 (80416651)
• Research Collaborator: INOKUCHI kaoru ; FUKAI tomoki ; FUNG chi chung ; TAKEKAWA takashi
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥16,900,000 (Direct Cost: ¥13,000,000、Indirect Cost: ¥3,900,000); Fiscal Year 2018: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000); Fiscal Year 2017: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2016: ¥9,360,000 (Direct Cost: ¥7,200,000、Indirect Cost: ¥2,160,000)
• Keywords: 記憶 / エピソード / 学習 / 記憶痕跡 / カルシウムイメージング / 海馬 / 記憶痕跡細胞

Outline of Final Research Achievements

The brain stores and recalls memories through a set of neurons, termed engram cells. We established a unique imaging system that combines Ca2+ imaging and engram identification to extract the characteristics of engram activity by visualizing and discriminating between engram and non-engram cells. Here, we show that engram cells detected in the hippocampus display higher repetitive activity than non-engram cells during novel context learning. The total activity pattern of the engram cells during learning is stable across post-learning memory processing. Within a single engram population, we detected several sub-ensembles composed of neurons collectively activated during learning. Some sub-ensembles preferentially reappear during post-learning sleep, and these replayed sub-ensembles are more likely to be reactivated during retrieval. These results indicate that sub-ensembles represent distinct pieces of information, which are then orchestrated to constitute an entire memory.

Academic Significance and Societal Importance of the Research Achievements

本研究成果では、日々の生活で経験するエピソードの記憶について、脳内の神経細胞がどのような様式で集団で活動し記憶情報を符号化しているのかを明らかにしたとともに、経験に応じて形成された記憶が睡眠中に定着する様子を観察し明らかにした。これらの知見は、記憶の科学的かつ本質的な理解に貢献するものであり、脳内に表出した情報の解読法の提案や、効率の良い記憶学習法、認知症などの記憶障害の早期診断法への応用につながることが期待される。

Research Products

• [Journal Article] Artificial association of memory events by optogenetic stimulation of hippocampal CA3 cell ensembles (2019)
  • Author(s): Oishi Naoya、Nomoto Masanori、Ohkawa Noriaki、Saitoh Yoshito、Sano Yoshitake、Tsujimura Shuhei、Nishizono Hirofumi、Matsuo Mina、Muramatsu Shin-ichi、Inokuchi Kaoru
  • Journal Title: Molecular Brain Volume: 12 Issue: 1 Pages: 111111-111111
  • DOI: 10.1186/s13041-018-0424-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Adult neurogenesis conserves hippocampal learning capacity (2018)
  • Author(s): Alam J, Kitamura T, Saitoh Y, Ohkawa N, Kondo T, Inokuchi K
  • Journal Title: J Neuroscinece Volume: 38 Issue: 31 Pages: 6854-6863
  • DOI: 10.1523/jneurosci.2976-17.2018
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Overlapping memory trace indispensable for linking, but not recalling, individual memories. (2017)
  • Author(s): Yokose, J., Okubo-Suzuki, R., Nomoto, M., Ohkawa, N., Nishizono, H., Suzuki, A., Matsuo, M., Tsujimura, S., Takahashi, Y., Nagase, M.,Watabe, A.M., Sasahara, M., Kato, F., Inokuchi, K.
  • Journal Title: Science Volume: 355 Issue: 6323 Pages: 398-403
  • DOI: 10.1126/science.aal2690
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Cellular tagging as a neural network mechanism for behavioral tagging. (2016)
  • Author(s): Nomoto, M., Ohkawa, N., Nishizono, H., Yokose, J., Suzuki, A., Matuo, M., Tsujimura, S., Takahashi, Y., Nagase, M., Watabe, A.M., Kato, F., Inokuchi, K.
  • Journal Title: Nature Communications Volume: 7:12319 Issue: 1 Pages: 1-11
  • DOI: 10.1038/ncomms12319
  • Peer Reviewed / Open Access
• [Presentation] Ensemble representation of contextual memory in hippocampal engram cells (2018)
  • Author(s): Ohkawa N., and Inokuchi K.
  • Organizer: The 41st Annual Meeting of the Japan Neuroscience Society. 2018. 7. 27, Kobe, Japan.
  • Invited
• [Presentation] Integrating Neuronal Ensembles Constitute and Replay Hippocampal Engram (2018)
  • Author(s): Ghandour K., Ohkawa N., Fung C.C.A., Asai H., Saitoh Y., Takekawa T., Okubo-Suzuki R., Soya S., Nishizono H., Matsuo M., Sato M., Ohkura M., Nakai J., Hayashi Y., Sakurai T., Osanai M., Kitamura T.,Fukai T, and Inokuchi K.
  • Organizer: The 41st Annual Meeting of the Japan Neuroscience Society. 2018. 7. 27, Kobe, Japan.
• [Presentation] Establishment of in vivo field excitatory post synaptic potential (fEPSP) recording system at hippocampal CA3-CA3 synapses (2018)
  • Author(s): Oishi N., Koga K., Nomoto M., Ohkawa N., Tsujimura S., Sano Y., Saitoh Y., Nishizono H., Matsuo M., Muramatsu S, and Inokuchi K.
  • Organizer: The 41st Annual Meeting of the Japan Neuroscience Society. 2018. 7. 27, Kobe, Japan.
• [Presentation] Impairment of memory consolidation by anesthesia immediately after conditioning (2018)
  • Author(s): Kameyama A., Asai H., Saitoh Y., Ghandour K., Okubo-Suzuki R., Nomoto M., Tsujimura S., Ohkawa N, and Inokuchi K.
  • Organizer: The 41st Annual Meeting of the Japan Neuroscience Society. 2018. 7. 27, Kobe, Japan.
• [Presentation] Hippocampal CA3 is involved in associative memory processing via learning-induced high frequent activity (2018)
  • Author(s): Nomoto M., Murayama E., Ohkawa N., Nishizono H., Matsuo M., Muramatsu S, and Inokuchi K.
  • Organizer: The 41st Annual Meeting of the Japan Neuroscience Society. 2018. 7. 27, Kobe, Japan.
• [Presentation] Orchestrated ensembles activity constitute hippocampal memory engram (2018)
  • Author(s): Ghandour K., Ohkawa N., Fung C. A., Asai H, Saitoh Y., Takekawa T., Okubo-Suzuki R., Soya S., Nishizono H., Matsuo M. , Osanai M., Sato M., Ohkura M., Nakai J., Hayashi Y., Sakurai T., Kitamura T., Fukai T., and Inokuchi K.
  • Organizer: The 17th Annual MCCS meeting, 2018. 11. 1, San Diego, CA, USA.
  • Int'l Joint Research
• [Presentation] Manipulation of fear memory association by posterior parietal cortex (2018)
  • Author(s): Suzuki A., Kosugi S., Murayama E., Ohkawa N., Matsuo M., Nishizono H., and Inokuchi K.
  • Organizer: The 17th Annual MCCS meeting, 2018. 11. 1, San Diego, CA, USA.
  • Int'l Joint Research
• [Presentation] Orchestrated ensembles activity constitute hippocampal memory engram (2018)
  • Author(s): Ghandour K., Ohkawa N., Fung C. A., Asai H, Saitoh Y., Takekawa T., Okubo-Suzuki R., Soya S., Nishizono H., Matsuo M. , Osanai M., Sato M., Ohkura M., Nakai J., Hayashi Y., Sakurai T., Kitamura T., Fukai T., and Inokuchi K.
  • Organizer: Neuroscience 2018, Annual Meeting of Society for Neuroscience, 2018. 11. 4, San Diego, CA, USA.
  • Int'l Joint Research
• [Presentation] Manipulation of fear memory association by posterior parietal cortex (2018)
  • Author(s): Suzuki A., Kosugi S., Murayama E., Ohkawa N., Matsuo M., Nishizono H., and Inokuchi K.
  • Organizer: Neuroscience 2018, Annual Meeting of Society for Neuroscience, 2018. 11. 4, San Diego, CA, USA.
  • Int'l Joint Research
• [Presentation] Identification of characteristic dynamism of engram cells during learning (2017)
  • Author(s): Ghandour K., Ohkawa N., Fung C.C.A., Saitoh Y., Takekawa T., Asai H., Okubo-Suzuki R., Nomoto M., Tsujimura S., Nishizono H., Matsuo M., Tsujimura M., Ohkura M., Nakai J., Hayashi Y., Fukai T., and Inokuchi K.
  • Organizer: 第40回日本神経科学大会
• [Presentation] Ultra-thin fluorescence endoscope imaging system for functional brain imaging (2017)
  • Author(s): Osanai M., Ohkawa N., Sakamoto K., Miwa H., Kikuta S., Tamura A., Sato A., Ohkura M., Kojima T., Kohmura Y., Nakai J., Hayashi Y., Yanagawa Y., Inokuchi K., Homma N., Mushiake H.
  • Organizer: 第40回日本神経科学大会
• [Presentation] Specific regulation of CS-US association in fear memory by manipulating the activity of parietal association cortex (2017)
  • Author(s): Suzuki A., Kosugi-Ushijima S., Murayama E., Ohkawa N., Matsuo M., Nishizono H., and Inokuchi K.
  • Organizer: 第40回日本神経科学大会
• [Presentation] Optogenetic approaches to reveal association and consolidation of memories in engram cell ensembles (2017)
  • Author(s): Ohkawa N.
  • Organizer: The 9th Optogenetics Research Society Japan International Symposium
  • Int'l Joint Research / Invited
• [Presentation] Unraveling the dynamism of engram cells during contextual memory processing (2017)
  • Author(s): Ghandour K., Ohkawa N., Fung C.C.A., Saitoh Y., Takekawa T., Asai H., Okubo-Suzuki R., Nomoto M., Soya S., Tsujimura S., Nishizono H., Matsuo M., Sato M., Ohkura M., Nakai J., Hayashi Y., Sakurai T., Osanai M., Fukai T., and Inokuchi K.
  • Organizer: The 16th Annual MCCS meeting
  • Int'l Joint Research
• [Presentation] Unraveling the dynamism of engram cells during contextual memory processing (2017)
  • Author(s): Ghandour K., Ohkawa N., Fung C.C.A., Saitoh Y., Takekawa T., Asai H., Okubo-Suzuki R., Nomoto M., Soya S., Tsujimura S., Nishizono H., Matsuo M., Sato M., Ohkura M., Nakai J., Hayashi Y., Sakurai T., Osanai M., Fukai T., and Inokuchi K.
  • Organizer: Neuroscience 2017, Annual Meeting of Society for Neuroscience
  • Int'l Joint Research
• [Presentation] 記憶痕跡セル・アンサンブルによる記憶情報処理 (2017)
  • Author(s): 大川宜昭，井ノ口馨
  • Organizer: 第36回日本認知症学会学術集会・シンポジウム：記憶のメカニズムとシナプスイメージング
  • Invited
• [Presentation] Optical manipulation of parietal association cortex regulates contextual fear memory (2016)
  • Author(s): Suzuki A., Kosugi-Ushijima S., Ohkawa N., Matsuo M., Nishizono H., and Inokuchi K.
  • Organizer: Neuroscience 2016, Annual Meeting of Society for Neuroscience
  • Place of Presentation: San Diego, USA
  • Year and Date: 2016-11-12
  • Int'l Joint Research
• [Presentation] Neuronal ensemble orchestrated intersection of two distinct emotional memory traces (2016)
  • Author(s): Yokose J., Okubo-Suzuki R., Nomoto M., Ohkawa N., Nishizono H., Matsuo M., Suzuki A., Takahashi Y., Nagase M., Watabe A.M., Sasahara M., Kato F., and Inokuchi K.
  • Organizer: Neuroscience 2016, Annual Meeting of Society for Neuroscience
  • Place of Presentation: San Diego, USA
  • Year and Date: 2016-11-12
  • Int'l Joint Research
• [Presentation] Adult neurogenesis in maintenance of the hippocampal learning capacity (2016)
  • Author(s): Alam M., Kitamura T., Saitoh Y., Ohkawa N., Kondo T., and Inokuchi K.
  • Organizer: Neuroscience 2016, Annual Meeting of Society for Neuroscience
  • Place of Presentation: San Diego, USA
  • Year and Date: 2016-11-12
  • Int'l Joint Research
• [Presentation] Artificial regulation of contextual fear memory by manipulating the parietal association cortex (2016)
  • Author(s): Suzuki A., Kosugi-Ushijima S., Ohkawa N., Matsuo M., Nishizono H., Inokuchi K.
  • Organizer: 第39回日本神経科学大会
  • Place of Presentation: 横浜
  • Year and Date: 2016-07-20
• [Presentation] The functional role of neuronal ensemble activated in intersection of two distinct memories (2016)
  • Author(s): Yokose J., Nomoto M., Okubo-Suzuki R., Takahashi Y., Suzuki A., Ohkawa N., Nishizono H., Matsuo M., Watabe A.M., Kato F., Inokuchi K.
  • Organizer: 第39回日本神経科学大会
  • Place of Presentation: 横浜
  • Year and Date: 2016-07-20
• [Presentation] Adult neurogenesis conserves the hippocampal learning capacity (2016)
  • Author(s): Alam M.J., Kitamura T., Saitoh Y., Ohkawa N., Kondo T., Inokuchi K.
  • Organizer: 第39回日本神経科学大会
  • Place of Presentation: 横浜
  • Year and Date: 2016-07-20
• [Presentation] Enhancing memory destabilization through protein degradation induction (2016)
  • Author(s): Takekawa T., Nemoto T., Fujii A., Tanaka T., Ohkawa N., Sato M., Hayashi Y., Inokuchi K., Fukai T.
  • Organizer: 第39回日本神経科学大会
  • Place of Presentation: 横浜
  • Year and Date: 2016-07-20
• [Book] 記憶の操作 (2018)
  • Author(s): 大川 宜昭、横瀬 淳、井ノ口 馨
  • Total Pages: 5
  • Publisher: 中外医学社, Clinical Neuroscience・特集：光が開く神経科学の未来－オプトジェネティクスと光イメージング, Vol. 36, No. 8: 916-920
• [Book] 記憶痕跡セル・アンサンブルを利用した人工連合記憶の創出 (2018)
  • Author(s): 大川 宜昭、井ノ口 馨
  • Total Pages: 8
  • Publisher: 日本認知症学会紙, Dementia Japan, Vol. 33, No. 1: 2-9
• [Book] 脳科学辞典, 記憶固定化 (2017)
  • Author(s): 大川 宜昭、野本 真順、井ノ口 馨
  • Publisher: 脳科学辞典編集委員会
• [Remarks] 富山大学大学院医学薬学研究部（医学）生化学講座ホームページ
  • URL: http://www.med.u-toyama.ac.jp/bmb/index-j.html