# Cell Type Specific Genomic and Functional Dissection of Fear-Off Amygdala Pathways

> **NIH NIH R01** · MCLEAN HOSPITAL · 2024 · $776,261

## Abstract

Fear-related disorders such as Post-Traumatic Stress Disorder (PTSD) are often characterized by an
inability to inhibit and extinguish fear memories leading to pathological expression of fear-related behaviors.
For progress to occur with targeted rationally-designed therapeutic approaches, a greater understanding of
the neural circuitry mediating fear inhibition and extinction is needed. This proposal utilizes cutting-edge, cell-
type specific approaches targeting circuits that control amygdala fear inhibition and extinction, via medial
prefrontal cortex (mPFC) and ventral hippocampus (vHPC) cell-type specific neural pathways, to align with
NIMH research priorities by cutting across RDoC domains in the NIH strategic plan for identifying the
pathophysiology of fear-related disorders.
 It is critical that we understand the role of specific cell types projecting to the amygdala supporting fear
inhibition and fear extinction learning. This Competitive Renewal expands our prior work dissecting function of
cell-type-specific mechanisms in the amygdala that differentially mediate fear and extinction. In addition to
other neuronal subtypes, our prior work dissected roles of the CRF and Thy1-specific neuronal populations
within the mouse Basolateral Amygdala (BLA) nuclei, demonstrating distinct molecular and physiological
functions underlying fear and extinction pathways. Here we aim to extend this work using a variety of
currently available intersectional circuit dissection tools, to understand the role of medial prefrontal cortex
(mPFC) and ventral hippocampus (vHPC) projections in regulating amygdala CRF and Thy1 populations.
 We predict that this approach will identify novel pharmacological targets for fear inhibition and
extinction, pursuing new pathways for fear-related anxiety disorders. Our central hypothesis is that the
specific pathways within the mPFC and vHPC to BLA circuits, involving projections to fear-controlling
amygdala CRF- and Thy1-positive cells, contribute to the mechanisms of fear retention. Targeting
these specific pathways will provide greater understanding of fear inhibitory control. This hypothesis will be
tested through the following Specific Aims: 1) Explore the role of mPFC and vHPC projections to CRF and
Thy1 cells in amygdala in control of fear and extinction. 2) Identify activity patterns in mPFC and vHPC
neurons projecting to fear-controlling cells in amygdala using GCaMP miniscope and fiber photometry. 3)
Explore synaptic and network-level mechanisms of repeated stress-triggered fear renewal, focusing on mPFC
and vHPC projections to amygdala CRF and Thy1 positive neurons, respectively. 4) Perform cell type
specific RNA profiling of amygdala-projecting mPFC and vHPC neurons (both CRH/Thy1 targeted cells and
engram activity dependent cells) with and without chronic stress. The identification of novel targets will
advance our understanding of circuitry underlying fear behaviors and will provide unique avenues for
therapeuti...

## Key facts

- **NIH application ID:** 10841031
- **Project number:** 5R01MH108665-09
- **Recipient organization:** MCLEAN HOSPITAL
- **Principal Investigator:** VADIM BOLSHAKOV
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $776,261
- **Award type:** 5
- **Project period:** 2016-07-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10841031

## Citation

> US National Institutes of Health, RePORTER application 10841031, Cell Type Specific Genomic and Functional Dissection of Fear-Off Amygdala Pathways (5R01MH108665-09). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10841031. Licensed CC0.

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