Transcranial direct current stimulation (tDCS) promotes myelin repair and plasticity in the mouse motor cortex

Cortical myelin loss and oligodendroglial dysfunction, hallmarks of numerous neurodegenerative and psychiatric disorders, compromise executive, sensory, and cognitive functions by altering circuit activity and integrity. Promoting cortical myelin repair therefore represents a critical therapeutic goal. In this frame, modulation of neuronal activity through non-invasive brain stimulation may represent a promising non-pharmacological approach to support remyelination. To address this issue, we investigated the effects of anodal transcranial direct current stimulation (A-tDCS) in a mouse model of unilateral myelin injury in the motor cortex. A-tDCS was delivered over the contralateral uninjured cortex during a bilateral motor task (locomotion), to enhance the physiological activity of interhemispheric M1-M1 projections and indirectly stimulate the lesioned cortex. When applied during the late phase of demyelination and the onset of repair, A-tDCS accelerated remyelination and increased oligodendroglial survival and maturation in the lesioned cortex, compared with unstimulated controls. Increased myelin was also detected in the directly stimulated uninjured cortex despite unchanged oligodendroglial cell numbers, suggesting de novo myelin formation or remodeling of existing internodes. These structural changes were accompanied by preservation of interhemispheric M1-M1 functional connectivity upon injury. Collectively, our findings demonstrate that A-tDCS promotes cortical myelin repair in vivo, supporting its therapeutic potential for disorders characterized by myelin damage. Notably, the observed effects of tDCS on myelin plasticity in the uninjured cortex - reported here for the first time - reveal a previously unrecognized mechanism underlying tDCS-mediated neuromodulation. HighlightsO_LIAnodal tDCS (A-tDCS) promotes remyelination in the mouse motor cortex (M1) and restores M1-M1 synchrony after demyelinating injury C_LIO_LIA-tDCS enhances oligodendroglial survival and maturation in the injured motor cortex C_LIO_LIA-tDCS induces myelin plasticity in the uninjured cortex C_LI