ABSTRACT Traumatic stress can cause long‐lasting changes in cognition and affect, sometimes leading to diagnoses such as posttraumatic stress disorder (PTSD). The stress‐enhanced fear learning (SEFL) model recapitulates understudied components of PTSD, such as trauma‐induced sensitization of fear learning. The SEFL procedure entails exposing mice to footshock stress followed later by fear conditioning in a different context. When tested later for recall of fear conditioning, previously stressed mice exhibit enhanced freezing compared to non‐stressed controls. Studies have shown that dorsal and ventral dentate gyrus (DG) generate neural ensemble representations of contextual fear, such that fear recall involves reactivation of a sparse set of “engram cells” that were active during fear memory acquisition. How stress affects these hippocampal ensemble representations is unknown. We used SEFL and activity‐dependent neuronal tagging with FosTRAP2 mice to investigate effects of stress on fear memory ensembles in rostral and caudal hippocampal DG. FosTRAP2/Ai6 mice received footshock stress or equivalent context exposure without shock in Context A on day 1. Five days later, mice received 1‐shock conditioning in Context B and immediately received an injection of 4‐hydroxytamoxifen (4‐OHT; 55 mg/kg) to tag fear acquisition neurons with the zsGreen reporter. One day later, mice were tested for fear recall in Context B and were perfused 90 min after testing. Confirming prior studies, stress potentiated 1‐shock conditioning in Context B, with stressed mice displaying higher freezing in the Context B test session than nonstressed mice. At the level of neural activity, results showed stress had no effect on the number of zsGreen+ fear ensemble cells or the number of cfos+ recall‐activated cells in rostral or caudal DG. However, stress increased reactivation (percentage of zsGreen+ cells expressing cfos) in the caudal but not rostral DG. The results suggest stress potentiates later fear learning by enhancing fear representations in caudal hippocampus, a region specialized for integrating emotional and motivational valence into memory.
Paredes et al. (Thu,) studied this question.