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

> **NIH NIH R01** · MCLEAN HOSPITAL · 2020 · $663,651

## 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 the amygdala to align with NIMH research priorities by cutting across many
of the RDoC 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 within the amygdala supporting fear inhibition
and fear extinction learning. It is known that the Basolateral Amygdala (BLA) modulates fear expression via
projections to the medial (CeM) and lateral division (CeL) of the central amygdala, in part through modulation
via the Intercalated Cell Nuclei of the Amygdala (ITC), which receive inputs from medial prefrontal cortex
(mPFC) and act as an inhibitory gate to the CeL. We will target the Thy1, FoxP2, and PKCsubpopulations
within the BLA, ITC, CeL, respectively, that are proposed to be associated with fear inhibition and extinction
within the amygdala – here termed the ‘Fear-Off’ populations.
 Through a variety of cell-type specific approaches, we will determine the events underlying the inhibition of
fear within three ‘Fear-Off’ cell types in the amygdala. Experiments will functionally and molecularly identify
populations of neurons within the BLA, ITC, and CeL that participate in these processes. Our central
hypothesis is that the Fear-Off pathway within the BLA-ITC-CeL circuit acts as an mPFC-regulated
inhibitory gate facilitating inhibition of fear during extinction training and retention, in part through
miRNA regulation of plasticity. Targeting multiple aspects of the Fear-Off pathway will expand our
understanding of fear inhibition.
 These hypotheses will be tested through the following Specific Aims: Aim 1) mPFC Regulation of
Amygdala Fear-Off Cells: To determine the differential afferent regulation from mPFC projections to BLA,
ITC, and CeA ‘Fear-Off’ neurons through direct manipulation of afferent neurons. Aim 2) Intra-Amygdala
Regulation of Fear-Off Cells: To determine the precise role of BLA, ITC, and CeA Fear-Off neurons in
regulating fear output circuitry of the amygdala; and Aim 3) miRNA Regulation of Fear-Off Cells: To determine
the role of miRNAs on behavior, neuronal function and plasticity within BLA, ITC, and CeA Fear-Off neurons
through direct manipulation of miRNA function. We use a combinatorial approach to functionally and
molecularly characterize specific target populations of amygdala neurons, which will elucidate important
microcircuitry within the amygdala governing fear extinction. The identification of novel targets will advance
our understanding of circuitry underlyin...

## Key facts

- **NIH application ID:** 9920213
- **Project number:** 5R01MH108665-05
- **Recipient organization:** MCLEAN HOSPITAL
- **Principal Investigator:** VADIM BOLSHAKOV
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $663,651
- **Award type:** 5
- **Project period:** 2016-07-01 → 2021-07-08

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9920213

## Citation

> US National Institutes of Health, RePORTER application 9920213, Cell Type Specific Genomic and Functional Dissection of Fear Off Amygdala Pathways (5R01MH108665-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9920213. Licensed CC0.

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