# Targeted neuromodulation strategies to delay hypoglossal motoneuron death and preserve tongue strength, function, and structure in a mouse model of ALS

> **NIH NIH R21** · UNIVERSITY OF MISSOURI-COLUMBIA · 2022 · $426,985

## Abstract

Project Summary
One of the most debilitating consequences of amyotrophic lateral sclerosis (ALS) is swallowing impairment
(dysphagia), which is associated with significant morbidity, depression/social isolation, and early mortality. From
a neurological perspective, dysphagia in ALS has been attributed to progressive tongue weakness caused by
degeneration of brainstem hypoglossal neurons and their axons (hypoglossal nerve) innervating the tongue
muscles. Progressive tongue weakness and atrophy ultimately render nearly all ALS patients unable to eat and
drink naturally; instead, they must depend on a feeding tube for survival. Despite the multiple life-threatening
consequences of dysphagia in ALS, current therapies, including the FDA-approved drugs riluzole and
edaravone, have no beneficial effect on swallowing function. Therefore, there is an urgent clinical need to identify
effective therapeutic solutions targeting the underlying pathophysiology of dysphagia to preserve swallowing
function, and by proxy, significantly extend survival and improve the quality of life for ALS patients.
 In this project, to address this clinical need, we will leverage a translational mouse model of ALS with
dysphagia to explore optogenetic stimulation (opto-stim) as a therapeutic strategy targeting the tongue. The
opto-stim treatment is a gene therapy-based approach that has been shown to promote neuronal survival, nerve
growth, and muscle reinnervation in nervous system injury. In our approach, we will use opto-stim to selectively
“excite” hypoglossal neurons to cause tongue muscle contraction/resistance that mice must overcome to
sufficiently protrude the tongue while voluntarily drinking from a waterspout. We hypothesize that this regime,
synergistically integrating the benefits of optogenetics and tongue exercise training, has the potential to prevent
or slow down the progression of hypoglossal degeneration and associated tongue weakness.
 To explore the effects of opto-stim treatment, our project is divided into two aims. In Aim 1, we will apply
high- and low-frequency opto-stim treatments three times per week in ALS mice, initiated at clinical disease
onset (i.e., start of body weight decline), and assess the treatment effect on tongue motility and swallowing
function (via fluoroscopy) and lick force (via force-lickometer) from disease onset to end-stage (i.e., 20% weight
loss). In Aim 2, we will employ a variety of histological assessments to quantify the corresponding neuroplastic
changes in the hypoglossal nucleus neurons, hypoglossal nerve, and the tongue muscles in response to each
neuromodulation strategy to establish clinico-pathological correlations. Our results will provide insight into
therapeutic effects and mechanisms of optogenetic-based treatment strategies in ALS. Optogenetics has been
gaining increasingly significant translational potential and may be particularly beneficial for advanced-stage ALS
patients who cannot participate in alternative t...

## Key facts

- **NIH application ID:** 10527999
- **Project number:** 1R21NS123761-01A1
- **Recipient organization:** UNIVERSITY OF MISSOURI-COLUMBIA
- **Principal Investigator:** TERESA E LEVER
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $426,985
- **Award type:** 1
- **Project period:** 2022-06-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10527999

## Citation

> US National Institutes of Health, RePORTER application 10527999, Targeted neuromodulation strategies to delay hypoglossal motoneuron death and preserve tongue strength, function, and structure in a mouse model of ALS (1R21NS123761-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10527999. Licensed CC0.

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