The quality of cortical network function recovery depends on localization and degree of axonal demyelination.

Abstract Myelin loss is a severe pathological hallmark common to a number of neurodegenerative diseases, including multiple sclerosis (MS). Demyelination in the central nervous system appears in the form of lesions affecting both white and graymatter structures. The functional consequences of demyelination on neuronal network and brain function are not well understood. Current therapeutic strategies for ameliorating the course of such diseases usually focus on promoting remyelination, but the effectiveness of these approaches strongly depends on the timing in relation to the disease state. In this study, we sought to characterize the time course of sensory and behavioral alterations induced by de- and remyelinationto establish a rational for the use of remyelinationstrategies. By taking advantage of animal models of general and focal demyelination, we tested the consequences of myelin loss on the functionality of the auditory thalamocortical system: a well-studied neuronal network consisting of both white and graymatter regions. We found that general demyelination was associated with a permanent loss of the tonotopic cortical organization in vivo , and the inability to induce tone-frequency-dependent conditioned behaviors, a status persisting after remyelination. Targeted, focal lysolecithin-induced lesions in the white matter fiber tract, but not in the graymatter regions of cortex, were fully reversible at the morphological, functional and behavioral level. These findings indicate that remyelinationof white and graymatter lesions have a different functional regeneration potential, with the white matter being able to regain full functionality while cortical graymatter lesions suffer from permanently altered network function. Therefore therapeutic interventions aiming for remyelinationhave to consider both region- and time-dependent strategies.