# Investigating the mechanism by which orexins contribute to sex differences in cognitive flexibility after stress

> **NIH NIH R15** · BRYN MAWR COLLEGE · 2024 · $344,589

## Abstract

Project Summary and Abstract
 Stress-related psychiatric disorders, such as post-traumatic stress disorder (PTSD) and
depression, are serious mental illnesses that occur twice as frequently in women compared to men.
Despite this disparity, we do not understand the biological basis of these sex differences. A key
feature of stress-related disorders such as PTSD is hyperarousal, which contributes to cognitive
flexibility deficits. The neuropeptides orexins, known to promote arousal and the stress response, are
altered in PTSD patients; increased orexin expression has been reported in women compared to men
in postmortem clinical populations. My previous research demonstrates that female rats exhibit higher
levels of orexins compared with male rats, contributing to impaired habituation to repeated stress and
subsequent cognitive flexibility deficits. However, the brain areas and specific receptors that orexins
target to cause sex-specific cognitive deficits after stress are unclear. Importantly, the orbitofrontal
cortex (OFC) is known to play a role in cognitive flexibility, and both the orexin 1 and 2 receptors
(Ox1R and Ox2R) are present in this brain area. Another important question that remains unanswered
is the mechanism by which orexins are upregulated in females compared with males. The gonadal
hormone estrogen is a likely candidate, as our previous data indicate that estrogen and orexin levels
are positively correlated and females in proestrus (when estrogen levels peak) show higher orexin
system activity and cognitive deficits after stress. Thus, the proposed research aims to understand
how orexins contribute to sex-specific cognitive deficits after stress and the mechanism behind sex
differences in the orexin system. Specifically, Aim 1 of this proposal will use a newly developed orexin
sensor paired with fiber photometry to examine real time orexin binding in the OFC to understand how
orexins lead to sex-specific cognitive deficits after stress. Aim 2 will examine the mechanism behind
sex differences in the orexin system by manipulating estrogen levels and assaying orexin measures
and cognitively flexibility after stress. We will also test whether estrogen exerts its actions via the G
protein coupled estrogen receptor (GPER), which is highly expressed in orexin neurons. These
findings will have immediate implications for treatment, as orexin antagonists are currently used to
treat insomnia, so it is crucial we understand how this neuropeptide system differs between males and
females, as there may be a future need to develop sex-specific guidelines in dosing. Moreover,
orexins regulate stress responses, food intake, autonomic responses, and emotional memory and
thereby contribute to a variety of psychiatric symptoms. In this way, targeting orexins may treat a
broad range of psychiatric symptoms in a sex-specific manner.

## Key facts

- **NIH application ID:** 10954498
- **Project number:** 1R15MH137506-01
- **Recipient organization:** BRYN MAWR COLLEGE
- **Principal Investigator:** Laura Grafe
- **Activity code:** R15 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $344,589
- **Award type:** 1
- **Project period:** 2024-08-15 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10954498

## Citation

> US National Institutes of Health, RePORTER application 10954498, Investigating the mechanism by which orexins contribute to sex differences in cognitive flexibility after stress (1R15MH137506-01). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10954498. Licensed CC0.

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