Optical assay of the functional impact of cuprizone-induced demyelination and remyelination on interhemispheric neural communication in the anterior cingulate cortex via the corpus callosum.

Cuprizone (CPZ) is a widely used toxin that induces demyelinating diseases in animal models, producing multiple sclerosis (MS)-like pathology in rodents. CPZ is one of the few toxins that triggers demyelination and subsequent remyelination following the cessation of its application. This study examines the functional consequences of CPZ-induced demyelination and the subsequent recovery of neural communication within the anterior cingulate cortex (ACC), with a particular focus on inter-hemispheric connectivity via the corpus callosum. By employing wide-field, high-speed, voltage-sensitive dye imaging, we were able to provide real-time mapping of neural activity in the ACC of CPZ-fed mice. Although we could not record physiological signals from the corpus callosum, the results demonstrated a notable impairment in inter-hemispheric connections within the ACC via the corpus callosum, with the most pronounced loss observed in a specific coronal slice among a series of slices examined. Notably, the latency of neural signal propagation remained largely unaltered despite connectivity loss, indicating that demyelination affects the extent, rather than the temporal dynamics, of neural communication. It is noteworthy that while functional connectivity appeared to recover fully after the cessation of CPZ, histological analysis revealed only partial recovery of myelination, indicating a discrepancy between functional and structural recovery. These findings enhance our understanding of how demyelination affects the ACC's role in orchestrating neural activity, particularly in light of the slice-specific nature of interhemispheric communication impairments. These findings offer new insights into MS pathology, particularly regarding the role of the corpus callosum in interhemispheric communication and potential therapeutic strategies.Significance Statement Cuprizone (CPZ) is widely used to model multiple sclerosis in rodents by inducing demyelination. While the demyelination effects of CPZ have been widely studied, this study explores CPZ's impact on the prefrontal cortex (PFC). Using voltage-sensitive dye imaging (VSDI), we identified disruptions in PFC connectivity within and between hemispheres in CPZ-fed mice, though signal timing remained unaffected. This finding suggests that demyelination impairs connectivity without slowing transmission speed. Remarkably, connectivity restoration aligned with brain remyelination, providing insights into recovery pathways in MS.