Myelin Plasticity

Open Scientific Question

Does activity-dependent oligodendrocyte and oligodendrocyte progenitor cell function shape adult cortical and hippocampal circuits on behavioral timescales, and what mechanisms link neural activity to myelin remodeling? The classical view, that myelin is laid down developmentally and is largely static in adult cortex, has been overturned by the last decade of imaging and genetic work in the field. The lab's contribution is to use chronic device implantation and parametric stimulation as the controlled in vivo perturbation context that reveals which aspects of activity-dependent myelin biology are reversible, which are protective, and which fail under pathological conditions.

Anchor Papers from the Lab

•         Wellman SM, Guzman K, Suematsu N, Thai T, Tung TH, Garcia Padilla C, Sridhar S, Chen K, Cambi F, Kozai TDY. Oligodendrocyte-specific fus depletion preserves CA1 single-unit fidelity and stabilizes network dynamics during chronic recording. Journal of Neural Engineering, 2026, 23(2), 026009. The first in vivo demonstration that genetic perturbation of oligodendrocyte cholesterol biosynthesis improves CA1 single-unit detectability and network stability over 16 weeks, with cortical recordings unchanged.

•         Wellman SM, Guzman K, Stieger KC, Brink LE, Sridhar S, Dubaniewicz M, Li L, Cambi F, Kozai TDY. Cuprizone-induced oligodendrocyte loss and demyelination impairs recording performance of chronically implanted neural interfaces. Biomaterials, 2020, 239, 119842. Demonstrated the converse direction, demyelination impairs chronic recording performance, establishing the causal role of myelin biology in device function.

•         Chen K, Cambi F, Kozai TDY. Pro-myelinating clemastine administration improves recording performance of chronically implanted microelectrodes. Biomaterials, 2023, 301, 122210. Pharmacological repositioning of clemastine, an FDA-approved antihistamine in MS clinical trials, as an oligodendrocyte-targeted intervention for chronic recording stability.

•         Wellman SM, Cambi F, Kozai TDY. The role of oligodendrocytes and their progenitors on neural interface technology, a novel perspective on tissue regeneration and repair. Biomaterials, 2018, 164, 121-133. The framing review establishing OL and OPC biology as a rate-limiting determinant of chronic neural interface performance.

•         Chen K, Wellman SM, Yaxiaer Y, Eles JR, Kozai TDY. In vivo spatiotemporal patterns of oligodendrocyte and myelin damage at the neural electrode interface. Biomaterials, 2021, 268, 120526. Longitudinal characterization of OL and myelin damage dynamics around chronic implants.

Disease and Translational Connections

•         Multiple sclerosis. Direct mechanistic continuity with MS, where myelin loss and repair are the central question. Collaboration with Dr. Franca Cambi (Pitt), an MS researcher and co-author on the lab's recent oligodendrocyte papers. Clemastine, the lab's pharmacological repositioning candidate, is in MS clinical trials for remyelination.

•         Alzheimer's disease. Recent single-cell transcriptomic atlases (Mathys et al., Nature 2019, Cell 2023, Nature 2024) identify oligodendrocytes among the most transcriptionally altered cell types in AD, with myelin maintenance genes contributing to cognitive resilience. The lab's Fus-depleted oligodendrocyte work in the AppNL-G-F AD model (Tung et al., bioRxiv 2025) provides mechanism for these transcriptomic observations.

•         Traumatic brain injury and stroke. White matter injury is increasingly recognized as a primary determinant of long-term outcome in both TBI and stroke. The lab's framework for activity-dependent myelin plasticity informs hypotheses about white matter recovery in both conditions.

Skills Developed by Trainees on This Thrust

•         Conditional knockout and transgenic mouse models, including FusOLcKO and oligodendrocyte progenitor reporters

•         Longitudinal in vivo two-photon imaging of OL and OPC populations across weeks to months

•         Chronic single-unit and multi-unit electrophysiology with cross-session unit tracking

•         Biophysical modeling of action potential conduction in partially myelinated axons

•         Quantitative immunohistochemistry for myelin markers, OL and OPC populations, and metabolic infrastructure

•         Pharmacological intervention studies, including FDA-approved drug repositioning