# Neural Circuits for Stress-Impaired Extinction Learning

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN · 2024 · $722,519

## Abstract

PROJECT SUMMARY
Clinical disorders of fear and anxiety, including trauma- and stressor-related disorders, represent an enormous
public health burden. Unfortunately, cognitive-behavioral therapies, such as exposure therapy, that are aimed
at reducing pathological fear are vulnerable to relapse. This is particularly problematic for patients under high
levels of stress, which undermines exposure-based therapies by impairing extinction learning and promoting
fear relapse. Despite years of work elucidating the neural circuitry for extinction, the neural mechanisms
responsible for stress-induced extinction impairments remain poorly understood. In previous work on this
project, we established that stress recruits bottom-up neuromodulatory circuits that inhibit the medial
prefrontal cortex (mPFC), a brain area that is critical for extinction learning. We have now shown that that
noradrenergic neurons in the locus coeruleus (LC) are critical for stress-induced extinction impairments, such
as the immediate shock deficit. Critically, chemogenetic activation of noradrenergic LC neurons induces
basolateral amygdala (BLA) hyperexcitability, which in turn drives feed-forward inhibition of the mPFC.
Preliminary data indicate that stress-sensitive corticotropin-releasing factor (CRF) neurons in the central
nucleus of the amygdala (CEA) drive extinction learning deficits. Based on this, we propose a novel hypothesis
that CEA-CRF+ neurons drive LC-NE projections to the BLA, which results in both BLA hyperexcitability and
impaired extinction learning. We propose three specific aims to test this hypothesis using a combination of in
vivo electrophysiology, calcium imaging, and intersectional opt0genetic manipulations in male and female rats.
The first specific aim examines whether CEA-CRF+ projections to the LC are necessary and sufficient for stress-
induced increases in BLA hyperexcitability and extinction learning deficits. The second specific aim examines
explores whether noradrenergic modulation of parvalbumin (PV) interneurons in the BLA regulates stress-
induced hyperexcitability and extinction deficits. Lastly, the third specific aim examines whether the BLA is
critical for transducing stress-induced activation of CEA-CRF+ and LC➙BLA circuits to undermine mPFC
activity and extinction learning. The outcomes of these aims will advance a novel circuit mechanism for stress-
induced extinction impairments. Understanding this mechanism will facilitate the development of novel
pharmacotherapeutic approaches that optimally engage mPFC circuits to promote extinction learning under
stress.

## Key facts

- **NIH application ID:** 11133358
- **Project number:** 7R01MH117852-07
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
- **Principal Investigator:** Stephen Maren
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $722,519
- **Award type:** 7
- **Project period:** 2024-08-16 → 2029-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11133358

## Citation

> US National Institutes of Health, RePORTER application 11133358, Neural Circuits for Stress-Impaired Extinction Learning (7R01MH117852-07). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/11133358. Licensed CC0.

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