# Uncovering mechanisms of myelin formation and regeneration in the live brain

> **NIH NIH R00** · DARTMOUTH COLLEGE · 2020 · $248,919

## Abstract

Myelin formation and maintenance is vital for proper neuronal communication and its disruption is associated
with numerous diseases of the central nervous system. Oligodendrocytes make myelin and are the only cells in
the adult cerebral cortex that are continuously generated from a population of resident progenitors, called NG2
cells. Thus, protracted oligodendrocyte and myelin formation into adulthood constitutes a unique, understudied
system for adult neuroplasticity, with broad implications for human cognition and disease. Understanding the
process of oligodendrocyte generation is fundamental to dissect roles played by oligodendrocytes and
myelination in nervous system function, plasticity, and disease. We have a rudimentary understanding of how
new oligodendrocytes are generated in vivo. Reasons for this stem from inadequate tools for their dynamic
investigation in the live brain. In light of these challenges, my long-term goals are to develop and apply optical
and single cell molecular based approaches to dissect multicellular interactions in the intact developing and
diseased nervous system, with a primary focus on the interface between the axon and oligodendrocyte.
Realization of this goal has begun as we have now developed a range of novel complementary tools that allow
unprecedented detailed investigation into the transformation of single progenitor cells into gap junction-coupled,
mature myelinating oligodendrocytes in vivo. This proposal will implement and expand on these tools to ask
several fundamental questions basic to our understanding of adult nervous system plasticity and response to
injury. First, during the K99 phase, the in vivo dynamics of oligodendrocyte differentiation, gap junction coupling
and internode assembly during initial myelin formation and after a demyelinating event will be determined. Next,
a new method will be used to determine the developmental profile, longitudinal dynamics, and effects of
demyelination on internode and Node of Ranvier assembly and distribution along extensive stretches of single
axons. Finally, during the R00 phase, using a powerful combination of in vivo imaging and single cell molecular
manipulation techniques learned during the K99 training period, the effects of myelin deposition on dynamic
axonal structural plasticity will be tested. Overall the research portions of this proposal will uncover how functional
internodes initially form, restructure throughout life, respond to oligodendrocyte death, and interact with the axon
to influence its structural plasticity, all for the first time in the live brain. The aims set out in this proposal will
provide the foundation for implementing these in vivo optical tools during the R00 phase. Furthermore this
strategy will provide fundamental training in novel approaches for molecular design with unique intellectual,
professional and academic guidance during the K99 phase under the mentorship of Dr. Jaime Grutzendler in
collaboration with consultant...

## Key facts

- **NIH application ID:** 9952426
- **Project number:** 5R00NS099469-05
- **Recipient organization:** DARTMOUTH COLLEGE
- **Principal Investigator:** Robert Hill
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $248,919
- **Award type:** 5
- **Project period:** 2017-09-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9952426

## Citation

> US National Institutes of Health, RePORTER application 9952426, Uncovering mechanisms of myelin formation and regeneration in the live brain (5R00NS099469-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9952426. Licensed CC0.

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