Incomplete remyelination via therapeutically enhanced oligodendrogenesis is sufficient to recover visual cortical function

Gustavo Della-Flora Nunes, Lindsay A. Osso, Johana A. Haynes, Lauren Conant, Michael A. Thornton, Michael E. Stockton, Katherine A. Brassell, Amanda Morris, Yessenia I. Mancha Corchado, John A. Gaynes, Anthony R. Chavez, Michaelanne B. Woerner, Deidre A. MacKenna, Aryan Alavi, Anne Danks, Alon Poleg-Polsky, Rohan Gandhi, Jeffrey A. Vivian, Daniel J. Denman () and Ethan G. Hughes ()
Additional contact information
Gustavo Della-Flora Nunes: University of Colorado School of Medicine
Lindsay A. Osso: University of Colorado School of Medicine
Johana A. Haynes: University of Colorado School of Medicine
Lauren Conant: University of Colorado School of Medicine
Michael A. Thornton: University of Colorado School of Medicine
Michael E. Stockton: University of Colorado School of Medicine
Katherine A. Brassell: University of Colorado School of Medicine
Amanda Morris: University of Colorado School of Medicine
Yessenia I. Mancha Corchado: University of Colorado School of Medicine
John A. Gaynes: University of Colorado School of Medicine
Anthony R. Chavez: University of Colorado School of Medicine
Michaelanne B. Woerner: Autobahn Therapeutics Inc
Deidre A. MacKenna: Autobahn Therapeutics Inc
Aryan Alavi: Autobahn Therapeutics Inc
Anne Danks: Autobahn Therapeutics Inc
Alon Poleg-Polsky: University of Colorado School of Medicine
Rohan Gandhi: Autobahn Therapeutics Inc
Jeffrey A. Vivian: Autobahn Therapeutics Inc
Daniel J. Denman: University of Colorado School of Medicine
Ethan G. Hughes: University of Colorado School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-22

Abstract: Abstract Myelin loss induces neural dysfunction and contributes to the pathophysiology of neurodegenerative diseases, injury conditions, and aging. Because remyelination is often incomplete, better understanding endogenous remyelination and developing remyelination therapies that restore neural function are clinical imperatives. Here, we use in vivo two-photon microscopy and electrophysiology to study the dynamics of endogenous and therapeutic-induced cortical remyelination and functional recovery after cuprizone-mediated demyelination in mice. We focus on the visual pathway, which is uniquely positioned to provide insights into structure-function relationships during de/remyelination. We show endogenous remyelination is driven by recent oligodendrocyte loss and is highly efficacious following mild demyelination, but fails to restore the oligodendrocyte population when high rates of oligodendrocyte loss occur quickly. Testing a thyromimetic (LL-341070) compared to clemastine, we find it better enhances oligodendrocyte gain and hastens recovery of neuronal function. The therapeutic benefit of the thyromimetic is temporally restricted, and it acts exclusively following moderate to severe demyelination, eliminating the endogenous remyelination deficit. However, we find regeneration of oligodendrocytes and myelin to healthy levels is not necessary for recovery of visual neuronal function. These findings advance our understanding of remyelination and its impact on functional recovery to inform future therapeutic strategies.

Date: 2025
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DOI: 10.1038/s41467-025-56092-6

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