Incomplete remyelination via therapeutically enhanced oligodendrogenesis is sufficient to recover visual cortical function
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 func...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56092-6 |
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| author | 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 Ethan G. Hughes |
| author_facet | 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 Ethan G. Hughes |
| author_sort | Gustavo Della-Flora Nunes |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-ed9151ce5e1c40ed9789ae0a9e4a7196 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-ed9151ce5e1c40ed9789ae0a9e4a71962025-01-19T12:31:01ZengNature PortfolioNature Communications2041-17232025-01-0116112210.1038/s41467-025-56092-6Incomplete remyelination via therapeutically enhanced oligodendrogenesis is sufficient to recover visual cortical functionGustavo Della-Flora Nunes0Lindsay A. Osso1Johana A. Haynes2Lauren Conant3Michael A. Thornton4Michael E. Stockton5Katherine A. Brassell6Amanda Morris7Yessenia I. Mancha Corchado8John A. Gaynes9Anthony R. Chavez10Michaelanne B. Woerner11Deidre A. MacKenna12Aryan Alavi13Anne Danks14Alon Poleg-Polsky15Rohan Gandhi16Jeffrey A. Vivian17Daniel J. Denman18Ethan G. Hughes19Department of Cell and Developmental Biology, University of Colorado School of MedicineDepartment of Cell and Developmental Biology, University of Colorado School of MedicineDepartment of Cell and Developmental Biology, University of Colorado School of MedicineDepartment of Cell and Developmental Biology, University of Colorado School of MedicineDepartment of Cell and Developmental Biology, University of Colorado School of MedicineDepartment of Cell and Developmental Biology, University of Colorado School of MedicineDepartment of Cell and Developmental Biology, University of Colorado School of MedicineDepartment of Cell and Developmental Biology, University of Colorado School of MedicineDepartment of Cell and Developmental Biology, University of Colorado School of MedicineDepartment of Physiology and Biophysics, University of Colorado School of MedicineDepartment of Cell and Developmental Biology, University of Colorado School of MedicineAutobahn Therapeutics IncAutobahn Therapeutics IncAutobahn Therapeutics IncAutobahn Therapeutics IncDepartment of Physiology and Biophysics, University of Colorado School of MedicineAutobahn Therapeutics IncAutobahn Therapeutics IncDepartment of Physiology and Biophysics, University of Colorado School of MedicineDepartment of Cell and Developmental Biology, University of Colorado School of MedicineAbstract 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.https://doi.org/10.1038/s41467-025-56092-6 |
| spellingShingle | 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 Ethan G. Hughes Incomplete remyelination via therapeutically enhanced oligodendrogenesis is sufficient to recover visual cortical function Nature Communications |
| title | Incomplete remyelination via therapeutically enhanced oligodendrogenesis is sufficient to recover visual cortical function |
| title_full | Incomplete remyelination via therapeutically enhanced oligodendrogenesis is sufficient to recover visual cortical function |
| title_fullStr | Incomplete remyelination via therapeutically enhanced oligodendrogenesis is sufficient to recover visual cortical function |
| title_full_unstemmed | Incomplete remyelination via therapeutically enhanced oligodendrogenesis is sufficient to recover visual cortical function |
| title_short | Incomplete remyelination via therapeutically enhanced oligodendrogenesis is sufficient to recover visual cortical function |
| title_sort | incomplete remyelination via therapeutically enhanced oligodendrogenesis is sufficient to recover visual cortical function |
| url | https://doi.org/10.1038/s41467-025-56092-6 |
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