# Characterizing Sleep Disruption as a Post-Injury Immune Stressor

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2020 · $332,221

## Abstract

Project Summary/Abstract
Accumulating evidence shows that traumatic brain injury (TBI) impairs the ability to restore homeostasis in
response to a stressor, reflecting dysregulation of the hypothalamic-pituitary-adrenal (HPA)-axis. As a result,
normal everyday stressors elicit intense “wear and tear” or “allostatic load” on the body and substantially
influence outcome after brain injury. The overall hypothesis is that daily sleep disruption is a physiologically
relevant stressor that directly engages the HPA-axis after TBI, and upon a dysregulated stress response
promotes increased neuroinflammation, neuropathology, and behavioral impairment. Published data show that
microglia are “primed” after TBI and become hyper-reactive in response to secondary immune challenge
resulting in increased neuropathology and behavioral impairment. Since reactive microglia can drive neuronal
injury and the spreading of progressive neurodegeneration through the brain, preliminary data suggest that
they are the primary effector cells that exacerbate neuroinflammation and pathology after post-injury sleep
disruption. Three specific aims will test the following hypotheses: (Aim 1) TBI reduces the corticosterone
(CORT)-mediated neuroendocrine response to sleep disruption resulting in worsened neuropathology and
recovery; (Aim 2) TBI mice demonstrate increased glucocorticoid negative-feedback sensitivity and restoration
of the CORT response to sleep disruption will reduce neuroinflammation and neuropathology; (Aim 3) Post-TBI
sleep disruption will enhance tau pathology and behavioral impairments caused by TBI, which will both be
improved upon pharmacological removal of microglia. Upon conclusion, sleep disruption can be considered a
post-injury stressor that challenges the HPA-axis and mediates increased post-injury neuroinflammation
through glucocorticoid receptors. The therapeutic potential of removing microglia to improve outcome following
post-injury sleep disruption will also be confirmed. The proposed research is innovative because, for the first
time data are provided to show that sleep disruption can serve as a pathological stressor that exacerbates
neuroinflammation, neuropathology, and behavioral impairment after TBI. These studies can prompt the
development of therapeutic interventions that do not require drug development. For example, specific
guidelines can be implemented to reduce nighttime awakenings in hospitals and care facilities. The ultimate
goal of this proposal is to highlight the neuroendocrine effects of post-injury sleep disruption and identify key
molecular pathways that promote chronic neuroinflammation and neurodegeneration after TBI.

## Key facts

- **NIH application ID:** 9896863
- **Project number:** 5R01NS109585-02
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Olga N. Kokiko-Cochran
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $332,221
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9896863

## Citation

> US National Institutes of Health, RePORTER application 9896863, Characterizing Sleep Disruption as a Post-Injury Immune Stressor (5R01NS109585-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9896863. Licensed CC0.

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