# Microcircuits governing conflicting memories of threat and safety

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2024 · $612,404

## Abstract

Fear learning allows animals to detect and defend themselves from dangerous situations by forming a memory
that links stimuli encountered during trauma with the experience of physical or psychological harm. Conversely,
the primary mechanism through which these behaviors are constrained is through extinction, in which repeated
re-exposure to conditioned stimuli without aversive consequences attenuates fear. Research suggests that
extinction forms a new memory of safety that competes with the original fear association during memory recall.
However, while deficits at the recall stage are a major factor in pathological fear, the circuit mechanisms
underlying extinction recall and how they might differentiate between competing fear and extinction memories
remain largely enigmatic. This is a fundamental knowledge gap that limits insight into extinction and the potential
reasons for its failure in psychiatric disorders. In this project we hypothesize that an important mechanism in
context fear extinction is recruitment of somatostatin interneurons in the ventral hippocampus, and that these
cells control switching between competing context representations, one signaling threat and the other safety. In
support of this hypothesis, we find that somatostatin interneurons are preferentially activated by an extinguished
context and their manipulation modulates fear expression in this context but not others. Using a combination of
intersectional genetics, electrophysiology, optogenetics and calcium imaging, we will investigate the properties
and function of discrete populations of somatostatin interneurons underlying context-dependent behavior. In
particular, we will examine whether these cells control transitions between high and low fear states and elucidate
the mechanisms underlying this switch at the level of excitatory neuronal populations involved in fear and
extinction memory. Successful completion of these aims will shed light on how the brain governs conflicting
internal models of an ambiguous environment as well as provide a detailed account of circuit dynamics that
promote the loss of fear and prevent it from reemerging.

## Key facts

- **NIH application ID:** 10841609
- **Project number:** 5R01MH132224-02
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Roger L Clem
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $612,404
- **Award type:** 5
- **Project period:** 2023-05-15 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10841609

## Citation

> US National Institutes of Health, RePORTER application 10841609, Microcircuits governing conflicting memories of threat and safety (5R01MH132224-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10841609. Licensed CC0.

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