Rescuing impaired learning in a mouse model for autism

• Project/Area Number: 19H03553
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 51030:Pathophysiologic neuroscience-related
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: Middleton Steven 国立研究開発法人理化学研究所, 脳神経科学研究センター, 研究員 (60526797)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000); Fiscal Year 2021: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2020: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2019: ¥9,230,000 (Direct Cost: ¥7,100,000、Indirect Cost: ¥2,130,000)
• Keywords: Hippocampus / Prefrontal cortex / Memory / Autism / Sharp-wave ripples / SCN2A / hippocampus / memory / autism / disease / rescue / learning / Sharp- wave ripples

Outline of Research at the Start

The key purpose of this research is to understand the neural basis of learning and how this is altered in autism. We will study two brain regions that are key for the learning (prefrontal cortex and hippocampus) and how they differ in a transgenic mouse model of autism.

Outline of Final Research Achievements

This project aims to reverse the impaired learning in a mouse model of autism. To address this I first aimed to characterize in detail the differences between normal and the autism model mice, in two specific brain areas (hippocampus and prefrontal cortex) that are important in working memory tasks. Here, I found in line with the original first hypothesis, that in normal healthy mice, a specific type of activity that occurs in the brain called sharp-wave ripples have a dual role with respect to learning. When animals make a correct vs an incorrect decision, activity within the brain networks that connect these two areas change in a systematic way, dependent on the trial outcome. However, in line with hypothesis 2, when the same experiments are done in the autism model mice the networks appear to be overly rigid, meaning that sharp-wave ripples cannot reconfigure the connections between the neurons appropriately, explaining why learning is impaired. The remaining data is being analysed

Academic Significance and Societal Importance of the Research Achievements

This project demonstrates that by using large scale recording of neural activity and using the appropriate analytical techniques to understand the interaction of multiple brain regions, we can better understand disease states. Moreover, the results and follow up work aim to explore better treatments

Research Products

• [Journal Article] A hypothalamic novelty signal modulates hippocampal memory (2020)
  • Author(s): Chen Shuo、He Linmeng、Huang Arthur J. Y.、Boehringer Roman、Robert Vincent、Wintzer Marie E.、Polygalov Denis、Weitemier Adam Z.、Tao Yanqiu、Gu Mingxiao、Middleton Steven J.、Namiki Kana、Hama Hiroshi、Therreau Ludivine、Chevaleyre Vivien、Hioki Hiroyuki、Miyawaki Atsushi、Piskorowski Rebecca A.、McHugh Thomas J.
  • Journal Title: Nature Volume: 586 Issue: 7828 Pages: 270-274
  • DOI: 10.1038/s41586-020-2771-1
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] CA2: A Highly Connected Intrahippocampal Relay (2020)
  • Author(s): Middleton Steven J.、McHugh Thomas J.
  • Journal Title: Annual Review of Neuroscience Volume: 43 Issue: 1 Pages: 55-72
  • DOI: 10.1146/annurev-neuro-080719-100343
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Gamma Entrainment Binds Higher-Order Brain Regions and Offers Neuroprotection (2019)
  • Author(s): Adaikkan Chinnakkaruppan, Middleton Steven J, Marco Asaf, Pao Ping-Chieh, Mathys Hansruedi, Kim David Nam-Woo, Gao Fan, Young Jennie Z, Suk Ho-Jun, Boyden Edward S, McHugh Thomas J, Tsai Li-Huei
  • Journal Title: Neuron Volume: 102 Issue: 5 Pages: 929-943
  • DOI: 10.1016/j.neuron.2019.04.011
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Memory: Sequences Take Time (2019)
  • Author(s): Middleton Steven J.、McHugh Thomas J.
  • Journal Title: Current Biology Volume: 29 Issue: 5 Pages: R158-R160
  • DOI: 10.1016/j.cub.2019.01.024