Glucocorticoids Promote Fear Generalization by Increasing the Size of a Dentate Gyrus Engram Cell Population

Sylvie L. Lesuis*, Niek Brosens, Nathalie Immerzeel, Rolinka J. van der Loo, Miodrag Mitrić, Pascal Bielefeld, Carlos P. Fitzsimons, Paul J. Lucassen, Steven A. Kushner, Michel C. van den Oever, Harm J. Krugers

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

35 Citations (Scopus)
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BACKGROUND: Traumatic experiences, such as conditioned threat, are coded as enduring memories that are frequently subject to generalization, which is characterized by (re-) expression of fear in safe environments. However, the neurobiological mechanisms underlying threat generalization after a traumatic experience and the role of stress hormones in this process remain poorly understood. METHODS: We examined the influence of glucocorticoid hormones on the strength and specificity of conditioned fear memory at the level of sparsely distributed dentate gyrus (DG) engram cells in male mice. RESULTS: We found that elevating glucocorticoid hormones after fear conditioning induces a generalized contextual fear response. This was accompanied by a selective and persistent increase in the excitability and number of activated DG granule cells. Selective chemogenetic suppression of these sparse cells in the DG prevented glucocorticoid-induced fear generalization and restored contextual memory specificity, while leaving expression of auditory fear memory unaffected. CONCLUSIONS: These results implicate the sparse ensemble of DG engram cells as a critical cellular substrate underlying fear generalization induced by glucocorticoid stress hormones.

Original languageEnglish
Pages (from-to)494-504
Number of pages11
JournalBiological Psychiatry
Issue number7
Publication statusPublished - 1 Oct 2021

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Copyright © 2021 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.


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