Conant, L. | Search bioRxiv

bioRxiv2024

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

Myelin loss induces deficits in action potential propagation that result in neural dysfunction and contribute to the pathophysiology of neurodegenerative diseases, injury conditions, and aging. Because remyelination is often incomplete, better understanding endogenous remyelination and developing remyelination therapies that seek to restore neural function are clinical imperatives. Here, we used 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 focused on the visual pathway, which is uniquely positioned to provide insights into structure-function relationships during de/remyelination. We show that 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 too quickly. Testing a novel thyromimetic compared to clemastine fumarate, we find it better enhances oligodendrocyte gain during remyelination and hastens recovery of neuronal function. Surprisingly, its therapeutic benefit was temporally restricted, and it acted exclusively following moderate to severe demyelination to eliminate endogenous remyelination deficits. However, complete remyelination is unnecessary as partial oligodendrocyte restoration was sufficient to recover visual neuronal function. These findings advance our understanding of remyelination and its impact on functional recovery to inform future therapeutic strategies.

neuroscience↗

bioRxiv2021

Motor Learning Drives Dynamic Patterns of Intermittent Myelination onBehaviorally-Activated Axons

Myelin plasticity occurs when newly-formed and pre-existing oligodendrocytes remodel existing patterns of myelination. Recent studies show these processes occur in response to changes in neuronal activity and are required for learning and memory. However, the link between behaviorally-relevant neuronal activity and circuit-specific changes in myelination remains unknown. Using longitudinal, in vivo two-photon imaging and targeted labeling of learning-activated neurons, we explore how the pattern of intermittent myelination is altered on individual cortical axons during learning of a dexterous reach task. We show that behavior-induced plasticity is targeted to learning-activated axons and occurs in a staged response across cortical layers in primary motor cortex. During learning, myelin sheaths retract, lengthening nodes of Ranvier. Following learning, addition of new sheaths increases the number of continuous stretches of myelination. Computational modeling suggests these changes initially slow and subsequently increase conduction speed. Finally, we show that both the magnitude and timing of nodal and myelin dynamics correlate with behavioral improvement during learning. Thus, learning-activated, circuit-specific changes to myelination may fundamentally alter how information is transferred in neural circuits during learning.

neuroscience↗