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Dynamic tripartite construct of interregional engram circuits underlies forgetting of extinction memory

Molecular Psychiatry volume 27, pages 4077–4091 (2022)Cite this article

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Abstract

Fear extinction allows for adaptive control of learned fear responses but often fails, resulting in a renewal or spontaneous recovery of the extinguished fear, i.e., forgetting of the extinction memory readily occurs. Using an activity-dependent neuronal labeling strategy, we demonstrate that engram neurons for fear extinction memory are dynamically positioned in the medial prefrontal cortex (mPFC), basolateral amygdala (BLA), and ventral hippocampus (vHPC), which constitute an engram construct in the term of directional engram synaptic connectivity from the BLA or vHPC to mPFC, but not that in the opposite direction, for retrieval of extinction memory. Fear renewal or spontaneous recovery switches the extinction engram construct from an accessible to inaccessible state, whereas additional extinction learning or optogenetic induction of long-term potentiation restores the directional engram connectivity and prevents the return of fear. Thus, the plasticity of engram construct underlies forgetting of extinction memory.

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Fig. 1: Retrieval of extinction memory recruits a subset of neurons as extinction engram.
Fig. 2: Bidirectional manipulation of extinction engram neurons correspondingly dictates retrieval of extinction memory.
Fig. 3: Optogenetic stimulation of BLA or vHPC extinction engram neurons induces mPFC extinction engram neuronal activation, while inhibition of BLA or vHPC extinction engram neurons suppresses the activation of mPFC extinction engram neurons induced by extinction retrieval.
Fig. 4: BLA and vHPC→mPFC engram circuits but not the opposite routes are required for extinction retrieval.
Fig. 5: Dynamics of engram connectivity correlate instability of extinction memory.
Fig. 6: Engram-specific optical LTP enables retrieval of extinction memory.

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Data availability

All data needed to evaluate the conclusions of the present study are present in the main paper and/or the Supplementary Materials. Additional data are available from the authors upon request.

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Acknowledgements

We thank Prof. Miao He at Fudan University for kindly providing the H2B-GFPflox mice used in the current study. This study was supported by grants from the Ministry of Science and Technology China Brain Initiative Project (2021ZD0202802), the National Natural Science Foundation of China (31930050, 32071023, 31900701, and 81903583), the Shanghai Municipal Science and Technology Major Project (2018SHZDZX05), the Science and Technology Commission of Shanghai Municipality (18JC1420302), the Shanghai Jiao Tong University College of Basic Medical Sciences (YCTSQN2021002), and innovative research team of high-level local universities in Shanghai. Dr. Yan-Jiao Wu is awarded the fellowship of China Postdoctoral Science Foundation (2021T140456).

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  1. These authors contributed equally: Xue Gu, Yan-Jiao Wu.

Authors and Affiliations

  1. Center for Brain Science, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China

    Xue Gu, Yan-Jiao Wu, Zichen Zhang, Qi Wang, Xin Yi, Ze-Jie Lin, Zhi-Han Jiao, Qin Jiang, Ying Li, Fan Jiang, Tian-Le Xu & Wei-Guang Li

  2. Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China

    Xue Gu, Yan-Jiao Wu, Zichen Zhang, Jia-Jie Zhu, Xin-Rong Wu, Qi Wang, Xin Yi, Ze-Jie Lin, Zhi-Han Jiao, Qin Jiang, Ying Li, Nan-Jie Xu, Tian-Le Xu & Wei-Guang Li

  3. Department of Developmental and Behavioral Pediatrics, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China

    Zichen Zhang & Fan Jiang

  4. Department of Rehabilitation Medicine, Huashan Hospital, Institute for Translational Brain Research, State Key Laboratory of Medical Neurobiology and Ministry of Education Frontiers Center for Brain Science, Fudan University, Shanghai, 200032, China

    Xin Yi, Miao Xu & Wei-Guang Li

  5. Department of Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, 77030, USA

    Michael X. Zhu

  6. Program in Neuroscience and Mental Health, SickKids Research Institute, Toronto, M5G 1X8, Canada

    Lu-Yang Wang

  7. Department of Physiology, University of Toronto, Toronto, M5S 1A1, Canada

    Lu-Yang Wang

  8. Shanghai Research Center for Brain Science and Brain-Inspired Intelligence, Shanghai, 201210, China

    Fan Jiang, Tian-Le Xu & Wei-Guang Li

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  1. Xue Gu
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Contributions

XG, T-LX, and W-GL conceived the project, designed the experiments, and interpreted the results. XG performed the majority of behavioral experiments, animal surgery, immunohistochemistry, and data analysis. Y-JW, ZZ, J-JZ, QW, XY, Z-JL, Z-HJ, MX, QJ, and YL assisted with some of the behavioral experiments and conducted viral injections. XG, Y-JW, X-RW, and W-GL performed slice recording and data analysis. N-JX, M-XZ, L-YW, and FJ contributed to data interpretation and experimental design. XG, M-XZ, L-YW, T-LX, and W-GL wrote the manuscript with contributions from all authors. All authors read and approved the final manuscript.

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Correspondence to Fan Jiang, Tian-Le Xu or Wei-Guang Li.

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Gu, X., Wu, YJ., Zhang, Z. et al. Dynamic tripartite construct of interregional engram circuits underlies forgetting of extinction memory. Mol Psychiatry 27, 4077–4091 (2022). https://doi.org/10.1038/s41380-022-01684-7

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