# Orexin regulation of responses to brain injury

> **NIH NIH R21** · CHILDREN'S HOSP OF PHILADELPHIA · 2024 · $220,000

## Abstract

PROJECT SUMMARY
Traumatic brain injuries (TBI) have devastating consequences for the quality of life of affected individuals.
Mild TBI (mTBI) is extremely common affecting approximately 42 million individuals worldwide (NINDS.gov;
2015). Key symptoms include excessive daytime sleepiness, poor memory and attention and psychiatric
symptoms including anxiety [1, 2]. Recovery from mTBI can be uneven with some individuals developing
long-term symptoms [3]. One factor that could underlie variations between individuals in mTBI severity of
symptoms is stress exposure. Stress exposure is common in environments that lead to TBI [4], stress can
exacerbate mTBI outcomes and result in protracted mTBI outcomes While psychological stress resulting
from mTBI can exacerbate symptoms and lead to psychiatric problems [7], the role of prior stress in
increasing vulnerability to subsequent mTBI is less clear [5]. These results suggest that mitigating the impact
of stress could improve clinical outcomes after mTBI. The objective of this proposal is to determine whether
the neuropeptides orexins are neural substrates through which stress exerts its effects. Orexins have
primarily been studied for their role in regulating behavioral outcomes after injury. However, whether orexins
act during prior stress exposure to regulate outcomes of subsequent mTBI is poorly studied. Based on our
preliminary data, the central hypothesis of this proposal is that orexin neuron activity underlies the
effects of chronic stress on mild lateral fluid percussion injury (LFPI)-induced anxiety-related
behaviors and these actions of orexins are sex-dependent. Two Aims are designed to test this
hypothesis. Experiments in Specific Aim 1 will test the hypothesis that mice susceptible to CSDS will
exhibit sex-specific alterations in glutamatergic regulation of orexin neurons after LFPI. Experiments
in Specific Aim 2 will test the hypothesis that reducing orexin activity during stress will promote
resilience and reduce the effects of LFPI on anxiety outcomes. The proposed experiments will provide
important new information on orexin cell activity as a mechanism to reduce the impact of stress on mTBI-
induced anxiety. The experiments bring together the expertise of the PIs in stress neurobiology and mTBI.
The tools and paradigms proposed for use are well-validated in our labs.

## Key facts

- **NIH application ID:** 10798292
- **Project number:** 5R21NS128745-02
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** SEEMA BHATNAGAR
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $220,000
- **Award type:** 5
- **Project period:** 2023-04-01 → 2025-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10798292

## Citation

> US National Institutes of Health, RePORTER application 10798292, Orexin regulation of responses to brain injury (5R21NS128745-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10798292. Licensed CC0.

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