Exposure to Novelty Promotes Long-Term Contextual Fear Memory Formation in Juvenile Mice: Evidence for a Behavioral Tagging


Episodic memories acquired early in life are fragile and rapidly forgotten in both humans and nonhuman animals. However, early life experiences have been documented to profoundly affect brain function and physiology throughout life, suggesting that in certain circumstances, the developing brain is capable of producing long-term memory (LTM). In this study, we asked whether exposure to a novel environment, a process named “behavioral tagging,” may promote the persistence of weak memories in male juvenile mice. Using a contextual fear conditioning (CFC) paradigm, we found that a weak training protocol, which typically induces a transient form of memory, results in LTM when paired with an exploration to a novel but not a familiar environment that occurs close in time to the training session. The promoting effect of the novel context exploration (NCE) on CFC-LTM formation is dependent on the activation of dopamine D1/D5 receptors and requires novel protein synthesis in the dorsal hippocampus. Moreover, NCE increases the size of overlapping CA1 neuronal ensembles engaged by CFC and NCE. These results provide direct support for the existence of a behavioral tagging process, in which exposure to novelty provides newly synthesized proteins to stabilize the contextual fear memory trace in juvenile mice.

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We thank Drs. Hsueh-Cheng Chiang and Wei-Li Wu for their helpful discussion and suggestions. We also thank the technical services provided by the Bio-image Core Facility of the National Core Facility Program for Biotechnology, Ministry of Science and Technology, Taiwan.


This work was supported by research grants from the Ministry of Science and Technology (106-2320-B-006-026-MY3; 107-2320-B-006-037-MY3; 108-2331-B-006-025-MY2) and the National Health Research Institute (NHRI-EX109-10912NI), Taiwan.

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N.C., T.C.T. and K.S.H. designed the study; N.C. and T.C.T. performed the experiments and data analysis; K.S.H. supervised the entire study and wrote the manuscript with N.C. and T.C.T.

Corresponding author

Correspondence to Kuei-Sen Hsu.

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All procedures involving the use of animals were conducted in compliance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and were approved by the National Cheng Kung University Animal Care and Use Committee (authorization no. 106048).

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The authors declare that they have no conflict of interest.

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Chen, N., Tsai, TC. & Hsu, KS. Exposure to Novelty Promotes Long-Term Contextual Fear Memory Formation in Juvenile Mice: Evidence for a Behavioral Tagging. Mol Neurobiol 57, 3956–3968 (2020). https://doi.org/10.1007/s12035-020-02005-1

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  • Behavioral tagging
  • Cellular tagging
  • Dopamine
  • CREB
  • Contextual fear memory
  • Hippocampus