# Characterizing the neural substrates of irritability in women: an experimental neuroendocrine model

> **NIH NIH R21** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $194,375

## Abstract

Irritability, defined as a predisposition to exhibit anger, is a prominent, defining symptom of perinatal
depression (PND) and many other neuropsychiatric disorders. Despite the near ubiquity of irritability across
disorders, the neural dysfunction underlying the vulnerability to, onset of, and exacerbation of irritability is
understudied and poorly understood. The proposed study involves experimentally manipulating reproductive
hormones in nonpregnant, euthymic women to create a scaled down version of the changes that occur during
pregnancy and the postpartum period. This endocrine manipulation paradigm, which we have shown provokes
irritability in past studies, will be used to examine the neurocircuitry underlying irritability under baseline and
hormone challenge conditions among women who are hormone sensitive (HS+; n=15) and non-hormone
sensitive (HS-; n=15). The long-term goal of this research is to advance our understanding of the neural
systems underlying both the triggering of and susceptibility to irritability in women. The objective of the current
project is to examine whether HS+ show differences in the behavioral activation system relative to HS- under
baseline and hormone challenge conditions using functional magnetic resonance imaging (fMRI) and
behavioral tests. Our central hypothesis is that reproductive hormone changes are associated with
dysregulated threat and reward processing and consequent irritability in HS+. The rationale for the proposed
study is that employing a scaled down model of puerperal hormonal events permits the identification of a group
of individuals homogeneous for hormone sensitivity (HS+), hence creating the best opportunity for
disentangling the specific changes in brain function due to reproductive hormones (i.e., HS-) from those
accompanying reproductive hormone-precipitated affective dysfunction (i.e., HS+). Because women will act as
their own controls across time, this study design also allows for a powerful evaluation of state and trait
variables that may contribute to irritability, including both threat and reward processing. Identifying both state
and trait markers of irritability, and disentangling them from the effects of reproductive hormones on brain and
behavior, will allow for the identification of neural substrates of irritability susceptibility that can be investigated
across neuropsychiatric disorders. We plan to accomplish the objectives of this application by pursuing the
following specific aims: to determine the extent to which irritability is characterized by 1) dysfunctional threat
processing and 2) dysfunctional reward processing during reproductive hormone challenge relative to baseline
in HS+ and HS-. We expect that, relative to baseline, HS+ women will show greater behavioral approach
during threat and frustration as well as dysregulation in brain regions responsible for threat and reward
processing during hormone challenge, relative to baseline, compared with HS-. The expected outc...

## Key facts

- **NIH application ID:** 9981834
- **Project number:** 5R21MH119615-02
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Crystal Edler Schiller
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $194,375
- **Award type:** 5
- **Project period:** 2019-08-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9981834

## Citation

> US National Institutes of Health, RePORTER application 9981834, Characterizing the neural substrates of irritability in women: an experimental neuroendocrine model (5R21MH119615-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9981834. Licensed CC0.

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