# Prefrontal circuit mechanisms of threat conditioning

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $421,237

## Abstract

Psychiatric conditions such as phobia, panic and post-traumatic stress disorder (PTSD) are associated with
heightened fear-related behavior. This has been attributed in part to increased acquisition and expression of
threat memory, which occurs when an innocuous stimulus encountered under threatening circumstances
becomes a potent trigger for defensive emotional reactions. Research indicates that this form of memory
engages the prelimbic cortex, a rodent brain region that is analogous to an area of pathological hyperactivity in
the human medial prefrontal cortex (mPFC). Prelimbic excitatory neurons are thought to mediate memory
expression by signaling to key downstream brain regions. However, the circuit and synaptic mechanisms
underlying memory-specific recruitment of these cells remain poorly understood. The purpose of this project is
to identify prelimbic synaptic changes associated with threat memory formation in mice, to elucidate the role of
neural circuits where these modifications occur, and to define specific prelimbic output connections that
mediate threat-related behaviors. Based on preliminary experiments, this work will focus sparse populations of
inhibitory interneurons that express the peptide marker somatostatin and exhibit increased excitatory synaptic
activity after threat learning. Our central hypothesis is that these cells undergo an increase in stimulus-related
activity after learning and that they function to suppress parvalbumin-containing interneurons and thereby
relieve a major brake on excitatory neuronal firing. In Aim 1, we will use brain slice electrophysiology to
examine synapses mediating elevated activity of somatostatin interneurons as well as their interaction with
parvalbumin interneurons. In Aim 2, we will use optogenetics and calcium-based imaging in freely behaving
animals to test the role of somatostatin and parvalbumin interneurons in threat memory expression. Finally, in
Aim 3, we will identify specific excitatory populations mediating behavioral outcomes of somatostatin
interneuron manipulations as well as establish downstream brain regions to which these neurons provide
synaptic input. This project represents the first attempt to establish how emotional learning alters complex
inhibitory stimulus processing to support mPFC memory functions, and will identify potential targets for
attenuating pathological activity and associated behaviors.

## Key facts

- **NIH application ID:** 9839681
- **Project number:** 5R01MH116445-03
- **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:** 2020
- **Award amount:** $421,237
- **Award type:** 5
- **Project period:** 2018-04-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9839681

## Citation

> US National Institutes of Health, RePORTER application 9839681, Prefrontal circuit mechanisms of threat conditioning (5R01MH116445-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9839681. Licensed CC0.

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