# Prefrontal modulation of vulnerability to stress-induced emotional dysregulation

> **NIH NIH R21** · OHIO STATE UNIVERSITY · 2020 · $191,316

## Abstract

Women are at increased risk to develop a stress-related psychopathology, including depression and anxiety. Unfortunately,
the molecular mechanisms underlying this sex-specific vulnerability to stress remain unclear. The prefrontal cortex (PFC)
is particularly sensitive to stress. Rodent-based research indicates that changes in prefrontal activity during exposure to
chronic stress could underlie individual susceptibility to dysregulated emotional behaviors in male populations. However,
this idea was never tested in females, and the molecular regulators to these stress-induced changes in prefrontal activity are
yet to be identified. This information would not only advance the basic stress field, but could also have broad implications
for treating stress-related mood disorders. Here, we will use interactions between sex-specific vulnerabilities and chronic
stress paradigms to characterize a novel molecular mechanism underlying vulnerability to stress-induced dysregulation in
emotional behaviors. Specifically, we will test the overall hypothesis that sex-specific plasticity of the prefrontal
parvalbumin (PV) system determines the extent to which chronic stress leads to aberrant emotional behaviors in a sex-
specific manner. Our recent work showed that 4-weeks of unpredictable chronic mild stress (UCMS) increases anxiety-like
behaviors and PV interneurons (PV-I) activity in the PFC of female, but not male, mice. These findings suggest that chronic
stress-induced changes in the prefrontal PV system could determine sex-specific stress-induced emotional dysregulation. It
also suggests that females have a more sensitive prefrontal PV system, which could directly modulate their heightened
vulnerability to stress-induced emotional disturbances. In this proposal, we will aim at testing these two ideas. First, we will
use naturalistic interactions between sex and two different UCMS protocols that vary in length to verify that plasticity of
prefrontal PV-I in response to stress correlates with the susceptibility of mice to display dysregulated emotional behaviors.
Exposure to a short period (4 weeks) of UCMS has been reported to induce anxiety-like behaviors in female mice but not
males, while a longer exposure (8 weeks) is necessary to induce a similar anxious phenotype in males. Molecular and ex
vivo electrophysiology approaches will be used to correlate stress-induced changes in prefrontal PV-I activity with changes
in emotional behaviors after exposure to UCMS. We will then use a chemogenetics approach (Designer Receptors
Exclusively Activated by Designer Drugs – DREADD) to decrease or increase the activity of prefrontal PV-I during
exposure to UCMS, and demonstrate a causal relationship between the level of activity of PV-I during stress and the
development of stress-induced emotional dysregulations. At completion of these experiments, we will have provided
evidence that the plasticity of the prefrontal PV system during stress is a major mechanism underly...

## Key facts

- **NIH application ID:** 10018935
- **Project number:** 5R21MH119090-02
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Laurence D Coutellier
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $191,316
- **Award type:** 5
- **Project period:** 2019-09-16 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10018935

## Citation

> US National Institutes of Health, RePORTER application 10018935, Prefrontal modulation of vulnerability to stress-induced emotional dysregulation (5R21MH119090-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10018935. Licensed CC0.

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