# Neural Substrates of Contextual Memory in Fear Extinction

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN · 2024 · $600,208

## Abstract

PROJECT SUMMARY
Therapeutic interventions, such as exposure therapy, reduce pathological fear in patients with anxiety
disorders. Extinction is a fundamental form of learning that underlies these therapies. A major challenge to
extinction-based therapies is that the fear reduction is often transient and bound to the place or context in
which therapy occurs. For example, when patients confront phobic objects or reminders of trauma outside of
the clinic, their fear often relapses. This reveals that extinction learning does not erase fear memory, but yields
a context-dependent “safety” memory that inhibits the expression of fear in the place where it is learned.
Accordingly, the long-term goal of this project is to understand the neural substrates of fear extinction and
relapse, particularly the specific brain circuits involved in the contextual control of extinction. Work in the
current funding period of this project has focused on renewal, a relapse of extinguished fear outside the
extinction context. Importantly, it was found that the hippocampus (HPC) mediates renewal by inhibiting
retrieval of extinction memories encoded by the infralimbic (IL) cortex. In the extinction context, the
suppression of conditioned fear is thought to involve IL inhibition of amygdala neurons encoding fear memory.
However, recent data challenge this notion—silencing prefrontal-amygdala projections does not impair
extinction retrieval. Hence, the precise mechanism for suppressing fear after extinction is still unknown.
Recent work on this project suggests a novel alternative: the mPFC may suppress the reactivation of
hippocampus-dependent fear memories to facilitate context-dependent extinction memory retrieval. The
mPFC projects to the HPC via the thalamic nucleus reuniens (RE), and RE inactivation or chemogenetic
silencing of mPFCgRE projections impairs the expression of extinction. Based on this work, it is hypothesized
that the RE mediates mPFC-HPC interactions required for context-dependent retrieval of extinction
memories. This hypothesis will be tested in three specific aims. The first aim explores whether the mPFC,
particularly IL, suppresses the retrieval of extinguished fear memories via RE projections to the HPC. The
second aim examines whether the activity of HPC ensembles representing fear and extinction memories are
regulated by the RE. The third aim determines whether the RE coordinates oscillatory synchrony in HPC and
mPFC during extinction retrieval. The proposed work will elucidate the specific neural circuits mediating the
expression of extinction and has important clinical implications for developing therapeutic interventions that
target these neural circuits to promote fear suppression and oppose relapse.

## Key facts

- **NIH application ID:** 11136115
- **Project number:** 7R01MH065961-21
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
- **Principal Investigator:** Stephen Maren
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $600,208
- **Award type:** 7
- **Project period:** 2024-08-16 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11136115

## Citation

> US National Institutes of Health, RePORTER application 11136115, Neural Substrates of Contextual Memory in Fear Extinction (7R01MH065961-21). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11136115. Licensed CC0.

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