Activation of astrocytes in hippocampus decreases fear memory through adenosine A1 receptors

  1. Yulan Li
  2. Lixuan Li
  3. Jintao Wu
  4. Zhenggang Zhu
  5. Xiang Feng
  6. Liming Qin
  7. Yuwei Zhu
  8. Zilong Qiu
  9. Shumin Duan  Is a corresponding author
  10. Yan-Qin Yu  Is a corresponding author
  1. Zhejiang University School of Medicine, China
  2. Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, China

Abstract

Astrocytes respond to and regulate neuronal activity, yet their role in mammalian behavior remains incompletely understood. Especially unclear is whether, and if so how, astrocyte activity regulates contextual fear memory, the dysregulation of which leads to pathological fear-related disorders. We generated GFAP-ChR2-EYFP rats to allow the specific activation of astrocytes in vivo by optogenetics. We found that after memory acquisition within a temporal window, astrocyte activation disrupted memory consolidation and persistently decreased contextual but not cued fear memory accompanied by reduced fear-related anxiety behavior. In vivo microdialysis experiments showed astrocyte photoactivation increased extracellular ATP and adenosine concentrations. Intracerebral blockade of adenosine A1 receptors (A1Rs) reversed the attenuation of fear memory. Furthermore, intracerebral or intraperitoneal injection of A1R agonist mimicked the effects of astrocyte activation. Therefore, our findings provide a deeper understanding of the astrocyte-mediated regulation of fear memory, and suggest a new and important therapeutic strategy against pathological fear-related disorders.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for all manuscript figures.Source data has been provided online at datadryad.org https://doi.org/10.5061/dryad.p8cz8w9mc

The following data sets were generated

Article and author information

Author details

  1. Yulan Li

    Department of Neurobiology and Department of Neurology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  2. Lixuan Li

    Department of Neurobiology and Department of Neurology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Jintao Wu

    Department of Neurobiology and Department of Neurology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Zhenggang Zhu

    Department of Neurobiology and Department of Neurology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Xiang Feng

    Department of Neurobiology and Department of Neurology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Liming Qin

    Department of Neurobiology, Key Laboratory of Medical Neurobiology of Ministry of Health of China, Key Laboratory of Neurobiology, Zhejiang University School of Medicine, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Yuwei Zhu

    Department of Neurobiology and Department of Neurology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  8. Zilong Qiu

    Institute of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  9. Shumin Duan

    Department of Neurobiology, Key Laboratory of Medical Neurobiology of Ministry of Health of China, Key Laboratory of Neurobiology, Zhejiang University School of Medicine, Hangzhou, China
    For correspondence
    duanshumin@zju.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
  10. Yan-Qin Yu

    Department of Neurobiology and Department of Neurology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
    For correspondence
    yanqinyu@zju.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4378-5931

Funding

The National Key Research and Development Program (2016YFC1306700)

  • Yan-Qin Yu

The National Key Research and Development Program (2016YFA0501000)

  • Shumin Duan

The National Natural Science Fundation of China (31970939,31771167,31571090)

  • Yan-Qin Yu

The National Natural Science Fundation of China (81527901,81821091,31490592)

  • Shumin Duan

The Non-profit Central Research Institute Fund of the Chinese Academy of Medical Sciences (2018PT31041)

  • Shumin Duan

Science and technology Planning Project of Guangdong Province (2018B030331001)

  • Shumin Duan

Science and technology Planning Project of Guangdong Province (2018B030331001)

  • Yan-Qin Yu

Fundamental Research Funds for the Central Universitues (2019FZA7009)

  • Shumin Duan
  • Yan-Qin Yu

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Margaret M McCarthy, University of Maryland School of Medicine, United States

Ethics

Animal experimentation: All experimental procedures were approved by the Animal Advisory Committee at Zhejiang University (2019-2#) and were performed in strict accordance with the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals (2006-398#). All surgery was performed under sodium pentobarbital anesthesia, and every effort was made to minimize suffering.

Version history

  1. Received: March 23, 2020
  2. Accepted: August 31, 2020
  3. Accepted Manuscript published: September 1, 2020 (version 1)
  4. Version of Record published: September 21, 2020 (version 2)

Copyright

© 2020, Li et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Yulan Li
  2. Lixuan Li
  3. Jintao Wu
  4. Zhenggang Zhu
  5. Xiang Feng
  6. Liming Qin
  7. Yuwei Zhu
  8. Zilong Qiu
  9. Shumin Duan
  10. Yan-Qin Yu
(2020)
Activation of astrocytes in hippocampus decreases fear memory through adenosine A1 receptors
eLife 9:e57155.
https://doi.org/10.7554/eLife.57155

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https://doi.org/10.7554/eLife.57155

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