Stress-Enhanced Fear Learning in Rodents: A Systematic Review and Meta-Analysis of Fear-Learning Sensitization After...

Background/Objectives: Stress-enhanced fear learning (SEFL) tests whether severe stress amplifies a later, separate fear-learning episode. Although SEFL studies commonly report increased freezing, its overall effect size, robustness, protocol-level variation, and translational interpretation have not been systematically quantified. This review evaluated SEFL as a focused paradigm of stress-induced fear-learning sensitization rather than as a comprehensive model of posttraumatic stress disorder (PTSD). Methods: Web of Science Core Collection, PubMed, Embase, and Scopus were searched from inception to June 2026. Eligible studies used an SEFL-related procedure, included independent stress-exposed and control groups, and reported extractable freezing outcomes during later fear testing. Hedges' g values were pooled using restricted maximum-likelihood random-effects models. We also examined exploratory subgroup analyses, sensitivity analyses, and small-study-effect assessments. Results: Twenty-five studies comprising 49 comparisons were included. Stress-exposed animals showed higher freezing than controls during later fear testing (Hedges' g = 1.71, 95% CI [1.38, 2.04], p < 0.001). Heterogeneity was substantial (I² = 81.91%, τ² = 1.07), and the 95% prediction interval crossed zero (-0.40 to 3.82), indicating that SEFL is not protocol-invariant. Exploratory subgroup analyses suggested protocol- and sample-level variation, particularly by species, strain, stress method, testing interval, and stress type. Contextual-fear-conditioning-only, study-level, non-footshock-exclusion, and leave-one-out sensitivity analyses supported the overall positive effect, although possible small-study effects should be considered when interpreting the pooled estimate. Conclusions: SEFL is best interpreted as a protocol-sensitive behavioral neuroscience paradigm for studying stress-enhanced later fear learning after severe stress rather than as a broad PTSD model. The current evidence supports a large average freezing-defined SEFL effect, but the marked heterogeneity and limited intervention-related evidence indicate that the paradigm should be interpreted with attention to protocol conditions and translational scope.