# CRCNS: Biophysical modeling of axonal morphology and function

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2024 · $375,835

## Abstract

PROJECT SUMMARY (See instructions):
Intricate cellular morphology is essential for neuron function. Axons in particular form thin and extremely
long cables with synaptic contacts along their length to communicate with their target neurons. This cable
property of the axons allows rapid conduction of electrical signals, or action potentials, to activate synaptic
communication. Traditionally, axon diameter is thought to be relatively uniform. However, recent studies
suggest that axon diameter is highly dynamic and can be controlled by neuronal firing. Our preliminary
data further the view of dynamic axon morphology by revealing that axons are not simple cylindrical tubes,
but rather exhibit peals-on-a-string morphology between synaptic varicosities. This structure is
reminiscent of lipid bilayer pearling, generated through a tension-driven instability. In support of this, in
silico modeling suggests that axon pearling depends on membrane mechanics such as bending modulus
and tension. In fact, axon pearling is lost when hyperosmotic solution is applied, while it is exacerbated in
hypoosmotic conditions. Thus, pearled axon morphology is tightly coupled to the biophysical properties of
membranes. Two of the major determinants of membrane mechanics are lipid composition and
cytoskeletal structure. Importantly, lipid composition and cytoskeletal structure also control the localization
of transmembrane proteins such as voltage-gated sodium and potassium channels, essential for action
potential firing. Therefore, membrane properties likely regulate both axon morphology and function. In this
proposal, we will test this hypothesis by 1) determining the contribution of lipid composition and
cytoskeletal structure to the axon morphology, channel localization, and action potential firing, and 2)
determining how these factors change with plasticity induced by repetitive neuronal firing. Since many
factors controlling membrane mechanics are implicated in neurological disorders such as epilepsy and
depression, this study will potentially reveal the underling mechanisms by which misregulation of
biophysical factors leads to pathophysiological conditions. We will achieve these goals with the expertise
in theoretical modeling by Pl Rangamani and the expertise in ultrastructural analysis of neurons by co-Pl
Watanabe. Together, we will elucidate the fundamental biophysical principles governing axon morphology
and function.

## Key facts

- **NIH application ID:** 11083186
- **Project number:** 1R01MH139350-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Padmini Rangamani
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $375,835
- **Award type:** 1
- **Project period:** 2024-09-01 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11083186

## Citation

> US National Institutes of Health, RePORTER application 11083186, CRCNS: Biophysical modeling of axonal morphology and function (1R01MH139350-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11083186. Licensed CC0.

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