Multiple-Context Training Enhances Generalization of Cued Fear Extinction and Requires the Dorsal Hippocampus

Multiple-session fear extinction (FE) models exposure therapy, which also occurs over many sessions. In humans, conducting extinction training across multiple contexts improves fear suppression as compared to a single context, but rodent work delineating boundary conditions and neural mechanisms remains sparse.

We compared single-context FE (SCFE) versus multiple-context FE (MCFE) in 129S1 and C57BL/6J mice, manipulating context familiarity (familiar vs novel FE contexts). Outcomes included FE acquisition and tests for fear relapse such as recent (2 d) and remote (30 d) recall in trained, extinction, and novel contexts, as well as reinstatement tests. We mapped extinction-related neural activity with dual Fos labeling (TRAP×Fos immunofluorescence) and graph analyses of regional co-activation, and used chemogenetic inhibition to selectively silence dorsal (dHP) or ventral hippocampus (vHP) during extinction.

MCFE produced greater across-session reduction in freezing than SCFE. The MCFE advantage did not require contextual novelty. MCFE also enhanced short- (2 d) and long-term (30 d) recall in a novel context, but did not prevent recovery over time or US-induced reinstatement. Dual-labeling revealed that MCFE strengthened hippocampal-prefrontal co-activation (with relatively weaker prefrontal-amygdala coupling than SCFE). Chemogenetic silencing of dHP, but not vHP, selectively impaired between-session extinction under MCFE and abolished the MCFE benefit; hippocampal silencing did not improve SCFE.

Conducting extinction across multiple contexts enhances acquisition and recall relative to SCFE, without requiring novelty, and engages distinct hippocampal-prefrontal circuit dynamics. dHP activity is necessary for the MCFE-specific improvement, highlighting a circuit mechanism in which distributing extinction across contexts augments fear reduction.