# Treatment of Sleep Disturbances in TBI with Orexin Receptor Antagonist

> **NIH VA I21** · VA BOSTON HEALTH CARE SYSTEM · 2022 · —

## Abstract

(1) PURPOSE- TBI in Veterans can often be a chronic condition and produce long-term sleep and behavioral
problems. Insomnia in the context of TBI is reported in 30–60% of individuals following TBI and produces
significant morbidity, daytime cognitive problems and impedes the quality of life. This proposal examines the
impact of sleep aberrations and cognitive and behavioral disturbances in a mouse model of chronic TBI (CCI).
Neural ORX dysregulation appears to be a mechanism for sleep and behavioral disturbances and provides an
opportunity to treat with orexinergic agents. We propose to examine the effects of a dual orexin receptor
antagonist treatment (DORA) on sleep, cognition, anxiety, and fearfulness in a mouse model of TBI. (2)
BACKGROUND- (a) Scientific Rationale- ORX activates neural circuits by regulating awake state and arousal,
anxiety, cognition, and other behaviors through widespread neural projections. Because ORX system
abnormalities in the LH develop after TBI, ORX sleep-wake disruptions are hypothesized to contribute to chronic
sleep and behavioral disturbances. Lemborexant (LEM) is a commercially available DORA that blocks orexin
OX1 and OX2 receptors and improves sleep latency and maintenance in primary insomnia in both humans and
animal models. LEM treatment is hypothesized to reverse sleep abnormalities and improve cognition and
daytime behaviors produced by TBI. (b) How This Research Will Advance Biomedical Knowledge- (c)
Significance of the Research and How it Relates to Priority Areas – This grant represents a potential high-
impact translational proposal for a mechanism-based treatment for insomnia and other behavioral disturbances
in chronic TBI. This proposal by experienced investigators (Kaplan and Zielinski) seeks to explore new research
in areas where they have not previously been funded. As such, it responds to RX-20-009 as a TBI Small Project
in Rehabilitation Research (SPiRE). (d) Direct Benefits and Quality of Services- If the utility of LEM on sleep
disturbances, anxiety, and cognition can be demonstrated in proposed SPiRE studies, then larger scale studies
using commercially available DORAs in animals and then Veterans with TBI can be pursued. (3) EXPECTED
OUTCOMES OR PRODUCTS– Chronic CCI is anticipated to produce sleep abnormalities including: increased
sleep latency and wake bouts, reduced total sleep time and sleeping bouts, disturbances of REM and NREM
sleep, and sleep fragmentation. LEM is hypothesized to reverse these sleep abnormalities compared to vehicle
treatment. CCI is expected to produce impaired memory in NOR test, greater anxiety as measured by decreased
exploration in LDTT task and increase aberrant FR after FC. It is expected that LEM reverses these behavioral
impairments in the CCI group. CCI is expected to produce reductions of ORX-A and -B levels in LH that are
inversely correlated with sleep and behavioral disturbances. (4) METHODS AND RESEARCH PLAN- We
examine a model of CCI vs. sham CCI i...

## Key facts

- **NIH application ID:** 10447665
- **Project number:** 5I21RX003722-02
- **Recipient organization:** VA BOSTON HEALTH CARE SYSTEM
- **Principal Investigator:** Mark Robert Zielinski
- **Activity code:** I21 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2021-07-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10447665

## Citation

> US National Institutes of Health, RePORTER application 10447665, Treatment of Sleep Disturbances in TBI with Orexin Receptor Antagonist (5I21RX003722-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10447665. Licensed CC0.

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