# Translational Study of Blast mTBI Effects on Locus Ceruleus-Cerebellar Network Structure and Function

> **NIH VA I01** · VA PUGET SOUND HEALTHCARE SYSTEM · 2022 · —

## Abstract

Mild traumatic brain injuries (mTBIs or concussions) caused by blast overpressure from exploding
ordnance are the “signature injuries” of the wars in Iraq and Afghanistan. Postconcussive symptoms are
common and often persist for years after Veterans have returned from deployment(s); however, the
neuropathobiology underlying these symptoms is poorly understood. Our published and preliminary studies
demonstrate in a battlefield-relevant mouse model of blast mTBI, in living Veterans with repetitive blast
mTBIs, and in postmortem brain tissue from Veterans and Servicemembers with blast mTBIs that the
cerebellum is particularly vulnerable. The cerebellum is increasingly implicated in cognitive/behavioral
changes characteristic of persistent postconcussive symptoms. Our preliminary studies suggest that these
neuropathobiologic changes extend to the noradrenergic locus coeruleus (LC) and its projections to the
cerebellar dentate nucleus (CDN) via the superior cerebellar peduncles (SCP). To understand the nature and
implications of mTBI damage to the LC-cerebellar dentate nucleus network, the following conceptually
integrated translational Specific Aims are proposed:
 Specific Aim 1.1. To determine whether LC and cerebellar changes on initial DTI scan predict
longitudinal impairments in: a) cerebellar regional glucose uptake by FDG-PET, b) working memory, and c)
cognitive set-shifting in Iraq/Afghanistan Veterans with repetitive blast mTBI.
 Specific Aim 1.2. To determine in postmortem brain tissue from repetitive mTBI
Veteran/Servicemember and control cases whether mTBI is specifically associated with LC-cerebellar fiber
injury and/or loss as compared to LC-cortical and/or LC-hippocampal fibers injury and/or loss.
 Specific Aim 2. To determine, in our mouse blast model, whether LC-cerebellar projections are
specifically vulnerable to degeneration following repetitive blast mTBI. Cerebellum-projecting LC neurons will
be labeled using a canine adenovirus (CAV) red fluorescent reporter in mice expressing green fluorescent
protein in LC fibers. Single cell RNA sequencing will test whether dual-labeled LC neurons projecting to the
cerebellum exhibit a specific neurodegenerative and cell stress phenotype following repetitive blast mTBI.
 Specific Aim 3.1. To determine in non-blast mice whether working memory and cognitive set shifting
deficits are caused by nonspecific SCP WM injury or by specific injury to LC fibers projecting to the
cerebellum. SCP WM injury will be induced by bilateral injection of 1% lysolecithin. LC fiber injury will be
induced using bilateral viral transduction with CAV-Cre AAV-DO diphtheria toxin.
 Specific Aim 3.2. To determine in non-blast mice if loss of NA signaling by LC neurons projecting to
the posterior cerebellum is sufficient to cause working memory and cognitive set shifting deficits similar to
blast mTBI. A viral transgenic approach will be used to knock out TH expression bilaterally in LC neurons
passing through the SCP.

## Key facts

- **NIH application ID:** 10343746
- **Project number:** 5I01BX004896-02
- **Recipient organization:** VA PUGET SOUND HEALTHCARE SYSTEM
- **Principal Investigator:** James Stephan Meabon
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2020-10-01 → 2024-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10343746

## Citation

> US National Institutes of Health, RePORTER application 10343746, Translational Study of Blast mTBI Effects on Locus Ceruleus-Cerebellar Network Structure and Function (5I01BX004896-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10343746. Licensed CC0.

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