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

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. https://doi.org/10.1016/j.biopsych.2021.04.010

Automated summary

Elevating glucocorticoid hormones induces generalized fear response after fear conditioning, while selective suppression of sparse DG cells prevents fear generalization and restores contextual memory specificity. These results implicate the sparse ensemble of DG engram cells as a critical cellular substrate underlying fear generalization induced by glucocorticoid stress hormones.