# Axonal Varicosity Dynamics in Central Neuron Mechanosensation and Injury

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2024 · $348,508

## Abstract

PROJECT SUMMARY
Little is known about the role of micromechanical stress in regulating morphology and function of
neurons in the central nervous system (CNS). Axonal varicosities (swelling or beading) are enlarged,
heterogeneous structures along axonal shafts, profoundly affecting axonal conduction and synaptic
transmission. They are a key pathological feature believed to represent slow accumulation of axonal damage
that occurs during irreversible degeneration, for example in mild traumatic brain injury (mTBI), Alzheimer’s
disease (AD), and multiple sclerosis. In the first funding period of this R01, we discovered that fluid mechanical
stress immediately and reversibly induced varicosities in unmyelinated axons of cultured CNS neurons, and we
further visualized varicosity induction in vivo. Most brain regions including the corpus callosum in healthy adults
contain both myelinated and unmyelinated axons, while myelin appears to protect the axon from initial
mechanical injury. Using a mouse model mimicking concussion, our new studies have found immediate
varicosity formation in unmyelinated axons of cortical neurons and delayed demyelination in the cortex after
mechanical impact. Our new results have also indicated that microtubule (MT)-associated protein 6 (MAP6)
regulates axonal varicosity formation through its properties of MT stabilization and Ca2+/calmodulin binding.
Based on our new findings, we hypothesize that mechanical impact immediately induces varicosity
formation in unmyelinated axons, which is restrained by MAP6-mediated MT stabilization and
subsequently promotes adjacent demyelination that increases axon vulnerability to second impact,
leading to a vicious cycle in repeated mTBI and hence worsened behavioral impairment. To test this
original hypothesis, we will use a multidisciplinary approach including mTBI and demyelination mouse models,
cell-type-specific overexpression, knockout and rescue, confocal and electron microscopy, behavioral testing,
electrophysiological recording, a versatile biomechanical assay, myelin coculture and state-of-the-art imaging
techniques. We will determine (Aim 1) whether mTBI-induced axonal varicosity formation and behavioral
impairment can be aggravated by MAP6 deletion and ameliorated by MAP6-mediated MT stabilization, (Aim 2)
how MAP6 regulates axonal varicosity initiation, recovery, location, heterogeneity and long-term fate through
distinct signaling pathways in partially myelinated axons, and (Aim 3) how MAP6 regulates oligodendrocyte
mechanosensation, and whether preexisting demyelination and/or preexisting axonal varicosities increase the
risk of injury from repeated mechanical impact. This project represents an underexplored research field with
many open questions. This research is significant because it will provide novel mechanistic insights into central
neuron mechanosensation and mTBI primary injury.

## Key facts

- **NIH application ID:** 10841531
- **Project number:** 5R01NS093073-08
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** CHEN GU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $348,508
- **Award type:** 5
- **Project period:** 2016-06-15 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10841531

## Citation

> US National Institutes of Health, RePORTER application 10841531, Axonal Varicosity Dynamics in Central Neuron Mechanosensation and Injury (5R01NS093073-08). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10841531. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*