# Synaptic and circuit mechanisms of fear suppression

> **NIH NIH R01** · TUFTS UNIVERSITY BOSTON · 2021 · $412,500

## Abstract

PROJECT SUMMARY
Exposure therapy is the most widely used treatment for excessive fear caused by post-traumatic stress disorder
and phobias. During exposure therapy the patient repeatedly confronts the fear-inducing situation or the
memory of a traumatic event in a safe environment, which over time results in decreased fear in most patients.
However, exposure therapy in its current form rarely leads to a permanent suppression of fear. A better
understanding of how exposure therapy, also known as fear extinction, works is therefore needed. A brain
region called the basolateral amygdala (BLA) can cause increased fear in both humans and other mammals. We
found that the BLA of mice undergoes changes during fear extinction that might help to suppress fear.
Specifically, fear extinction silenced BLA fear neurons, while changing the inhibitory synapses that are located
around these fear neurons. To test if these changes in perisomatic inhibitory synapses contribute to fear
suppression, we silenced the parvalbumin-positive (PV+) interneurons that make these perisomatic inhibitory
synapses. This increased the activation of BLA fear neurons and the expression of fear. Furthermore, it
changed the activation of neurons in a brain region outside of the BLA called the medial prefrontal cortex
(mPFC). Finally, silencing PV+ interneurons in the BLA altered the frequency distribution of local field
potential (LFP) oscillations in both the BLA and mPFC, indicating broad changes in the activation of neuronal
circuits that connect these two brain regions. Based on these results, we formulated a model in which
extinction decreases fear by increasing the ability of PV+ perisomatic synapses to inhibit BLA fear neurons,
thereby giving fear-suppressing circuits a competitive advantage over fear-promoting circuits. The three aims
of this proposal will test if this model is correct. Aim 1 is to determine the contribution of PV+ perisomatic
synapse remodeling in the BLA to extinction-induced fear suppression. To achieve this, we will monitor the
strength of PV+ perisomatic synapses under conditions when fear suppression stops working, and by
manipulating brain-derived neurotrophic factor signaling during fear extinction, which is predicted to
interfere with extinction-induced perisomatic synapse remodeling. Aim 2 is to localize and manipulate
functionally opposed LFP oscillations in the BLA during extinction-induced fear suppression. To achieve this,
we will manipulate the activation state of three types of BLA neurons (PV+ interneurons, fear neurons,
extinction neurons), while measuring both LFP oscillations and fear behavior. Aim 3 is to identify downstream
neural circuits that mediate the contribution of BLA PV+ interneurons to extinction-induced fear suppression.
This will be achieved by analyzing and manipulating BLA projection pathways to two subdivisions of the mPFC.
Completion of this proposal can identify a critical role for BLA PV+ interneurons in tuning the balanc...

## Key facts

- **NIH application ID:** 10196952
- **Project number:** 5R01MH104589-05
- **Recipient organization:** TUFTS UNIVERSITY BOSTON
- **Principal Investigator:** Leon Reijmers
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $412,500
- **Award type:** 5
- **Project period:** 2017-08-05 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10196952

## Citation

> US National Institutes of Health, RePORTER application 10196952, Synaptic and circuit mechanisms of fear suppression (5R01MH104589-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10196952. Licensed CC0.

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