Elevated activity in the dorsal dentate gyrus reduces expression of fear memory after fear extinction training

Elevated activity in the dorsal dentate gyrus reduces expression of fear memory after fear extinction training

J Psychiatry Neurosci 2021;46(3):E390-E401 | PDF | Appendix

Yujie Zhang, PhD; Zongliang Wang, BS; Jun Ju, PhD; Jianxiang Liao, MD, PhD; Qiang Zhou, PhD

Background: Effectively reducing the expression of certain aversive memories (fear or trauma memories) with extinction training is generally viewed to be therapeutically important. A deeper understanding of the biological basis for a more effective extinction process is also of high scientific importance.

Methods: Our study involved intraventricular injection or local injection into the dorsal dentate gyrus of anti-neuregulin 1 antibodies (anti-NRG1) before fear extinction training, followed by testing the expression of fear memory 24 hours afterward or 9 days later. We used local injection of chemogenetic or optogenetic viruses into the dorsal dentate gyrus to manipulate the activity of the dorsal dentate gyrus and test the expression of fear memory. We also examined the effect of deep brain stimulation in the dorsal dentate gyrus on the expression of fear memory.

Results: Mice that received intraventricular injection with anti-NRG1 antibodies exhibited lower expression of fear memory and increased density of activated excitatory neurons in the dorsal dentate gyrus. Injection of anti-NRG1 antibodies directly into the dorsal dentate gyrus also led to lower expression of fear memory and more activated neurons in the dorsal dentate gyrus. Inhibiting the activity of dorsal dentate gyrus excitatory neurons using an inhibitory designer receptor exclusively activated by designer drugs (DREADD) eliminated the effects of the anti-NRG1 antibodies. Enhancing the activity of the dorsal dentate gyrus with an excitatory DREADD or optogenetic stimulation resulted in lower expression of fear memory in mice that did not receive infusion of anti-NRG1 antibodies. Deep brain stimulation in the dorsal dentate gyrus effectively suppressed expression of fear memory, both during and after fear extinction training.

Limitations: The mechanism for the contribution of the dorsal dentate gyrus to the expression of fear memory needs further exploration.

Conclusion: Activation of the dorsal dentate gyrus may play an important role in modulating the expression of fear memory; its potential use in fear memory extinction is worthy of further exploration.


Submitted Aug. 7, 2020; Revised Nov. 2, 2020; Revised Dec. 18, 2020; Accepted Jan. 23, 2021

Acknowledgements: We thank T. Li for the virus injection and Dr. Z. Gong for suggestions on immunohistochemistry methods. This work is supported by grants (2019SHIBS0004, SZBL2019062801003, KQTD2015032709315529, SZSM201812005).

Affiliations: From the Peking University, Shenzhen Graduate School, School of Chemical Biology and Biotechnology, State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Shenzhen 518055, Peoples R China (Zhang, Wang, Zhou); the Precision Medicine Centre, the Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, Guangdong, China (Ju); and the Pediatric Neurology, Shenzhen Children’s Hospital, Shenzhen, 518038, China (Zhang, Liao).

Competing interests: None declared.

Contributors: Y. Zhang and Q. Zhou designed the study. Y. Zhang, Z. Wang, J. Ju and J. Liao acquired the data, which Y. Zhang, Z. Wang, J. Ju and Q. Zhou analyzed. Y. Zhang and Q. Zhou wrote the article, which all authors reviewed. All authors approved the final version to be published and can certify that no other individuals not listed as authors have made substantial contributions to the paper.

Content licence: This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BYNC-ND 4.0) licence, which permits use, distribution and reproduction in any medium, provided that the original publication is properly cited, the use is non-commercial (i.e. research or educational use), and no modifications or adaptations are made. See: https://creativecommons.org/licenses/by-nc-nd/4.0/

DOI: 10.1503/jpn.200151

Correspondence to: Qiang Zhou, Peking University Shenzhen Graduate School, Shenzhen University Town, Lishui Road, Xili Town, Nanshan District, Shenzhen, China; zhouqiang.sz@pku.edu.cn