Multiple-context extinction strengthens fear suppression through hippocampal dopamine D2R-dependent memory updating.
- 1Psychology Department, Neuroscience Program, Williams College, Williamstown, MA, USA.
- 2Psychology Department, Neuroscience Program, Williams College, Williamstown, MA, USA. [email protected].
Abstract
Extinction learning, which underlies exposure therapy, generates safety memories that are often context-dependent, limiting their persistence and generalization. Although varying contextual cues during extinction has been proposed to strengthen safety learning, the neural mechanisms remain unknown. Here, we compared fear extinction conducted in a single context (SCFE) or multiple contexts (MCFE) in 129S1 and C57BL/6J mice. MCFE enhanced extinction learning and generalized extinction recall in novel contexts at 2-d, with this advantage persisting at 30-d when intervening testing occurred in the trained extinction context. This enhancement required exposure to distinct, but not novel, contexts and did not prevent spontaneous recovery or US-induced reinstatement. Dual Fos-TRAP activity mapping revealed differential recruitment of the fear conditioning-tagged cells following MCFE and identified the hippocampus as a key node supporting MCFE. Consistent with this, chemogenetic silencing of dorsal, but not ventral, hippocampus selectively impaired extinction acquisition during MCFE and abolished its behavioral advantage. Likewise, local blockade of dopamine D2-, but not D1-like, receptors in the dorsal hippocampus eliminated the enhancement in extinction acquisition produced by MCFE. Together, these findings demonstrate that contextual variation strengthens and generalizes extinction learning through dorsal hippocampal dopamine D2-like receptor-dependent memory updating, identifying a neural mechanism through which behavioral modifications of exposure therapy can improve fear suppression.
Related
- On the mapping between evolutionary scenarios and governing rules in state-dependent speciation-extinction models
- Juvenile behavioral alterations and sex-dependent deficits in hippocampal neurogenesis following early-life stress in rats
- Inflammatory signaling drives SQSTM1-dependent suppression of interferon-γ-induced MHC class I
- Activity dependent regulation of Angiomotin modulates dendritic complexity in hippocampal neurons
- Age‐Dependent Regulation of Hippocampal Inflammation by the Mitochondrial Translocator Protein in Mice
BibTeX
@article{hammerman2026multiplecontext,
title = {{Multiple-context extinction strengthens fear suppression through hippocampal dopamine D2R-dependent memory updating.}},
author = {Eve A Hammerman and Suzanne R Penna and Shania E Gonzalez and Shiv Patel and Carter Roebuck and Emily K Lock and Cooper Desmond and Yuichi Fukunaga and Gwyneth C Maloy and Victor A Cazares},
journal = {Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology},
year = {2026},
month = oct,
doi = {10.1038/s41386-026-02577-x},
url = {https://europepmc.org/article/MED/42839033},
note = {CC BY},
}
RIS
TY - JOUR
TI - Multiple-context extinction strengthens fear suppression through hippocampal dopamine D2R-dependent memory updating.
AU - Eve A Hammerman
AU - Suzanne R Penna
AU - Shania E Gonzalez
AU - Shiv Patel
AU - Carter Roebuck
AU - Emily K Lock
AU - Cooper Desmond
AU - Yuichi Fukunaga
AU - Gwyneth C Maloy
AU - Victor A Cazares
PY - 2026
DA - 2026/10/06
JO - Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
DO - 10.1038/s41386-026-02577-x
UR - https://europepmc.org/article/MED/42839033
AB - Extinction learning, which underlies exposure therapy, generates safety memories that are often context-dependent, limiting their persistence and generalization. Although varying contextual cues during extinction has been proposed to strengthen safety learning, the neural mechanisms remain unknown. Here, we compared fear extinction conducted in a single context (SCFE) or multiple contexts (MCFE) in 129S1 and C57BL/6J mice. MCFE enhanced extinction learning and generalized extinction recall in novel contexts at 2-d, with this advantage persisting at 30-d when intervening testing occurred in the trained extinction context. This enhancement required exposure to distinct, but not novel, contexts and did not prevent spontaneous recovery or US-induced reinstatement. Dual Fos-TRAP activity mapping revealed differential recruitment of the fear conditioning-tagged cells following MCFE and identified the hippocampus as a key node supporting MCFE. Consistent with this, chemogenetic silencing of dorsal, but not ventral, hippocampus selectively impaired extinction acquisition during MCFE and abolished its behavioral advantage. Likewise, local blockade of dopamine D2-, but not D1-like, receptors in the dorsal hippocampus eliminated the enhancement in extinction acquisition produced by MCFE. Together, these findings demonstrate that contextual variation strengthens and generalizes extinction learning through dorsal hippocampal dopamine D2-like receptor-dependent memory updating, identifying a neural mechanism through which behavioral modifications of exposure therapy can improve fear suppression.
SN - 0893-133X
SN - 1740-634X
ER -