Destruction of oligodendrocytes and myelin sheaths in cortical gray matter profoundly alters neural activity and is associated with cognitive disability in multiple sclerosis (MS). Myelin can be restored by regenerating oligodendrocytes from resident progenitors; however, it is not known whether regeneration restores the complex myelination patterns in cortical circuits. Here, we performed time lapse in vivo two photon imaging in somatosensory cortex of adult mice to define the kinetics and specificity of myelin regeneration after acute oligodendrocyte ablation. These longitudinal studies revealed that the pattern of myelination in cortex changed dramatically after regeneration, as new oligodendrocytes were formed in different locations and new sheaths were often established along axon segments previously lacking myelin. Despite the dramatic increase in axonal territory available, oligodendrogenesis was persistently impaired in deeper cortical layers that experienced higher gliosis. Repeated reorganization of myelin patterns in MS may alter circuit function and contribute to cognitive decline.

37Destruction of oligodendrocytes and myelin sheaths in cortical gray matter profoundly alters 38 neural activity and is associated with cognitive disability in multiple sclerosis (MS). Myelin can 39 be restored by regenerating oligodendrocytes from resident progenitors; however, it is not 40 known whether regeneration restores the complex myelination patterns in cortical circuits. Here 41 we performed time lapse in vivo two photon imaging in somatosensory cortex of adult mice to 42 define the kinetics and specificity of myelin regeneration after acute oligodendrocyte ablation. 43These longitudinal studies revealed that the pattern of myelination in cortex changed 44 dramatically after regeneration, as new oligodendrocytes were formed in different locations and 45 new sheaths were often established along axon segments previously lacking myelin. Despite 46 the dramatic increase in axonal territory available, oligodendrogenesis was persistently impaired 47 in deeper cortical layers that experienced higher gliosis. The repeated reorganization of myelin 48 patterns in MS may alter circuit function and contribute to cognitive decline. 49 50 51 INTRODUCTION 52 53 Oligodendrocytes form concentric sheets of membrane around axons that enhance the speed of 54 action potential propagation, provide metabolic support and control neuronal excitability through 55 ion homeostasis. Consequently, loss of oligodendrocytes and myelin can alter the firing 56 behavior of neurons and impair their survival, leading to profound disability in diseases such as 57 multiple sclerosis (MS), in which the immune system inappropriately targets myelin for 58 destruction. In both relapsing-remitting forms of MS and the cuprizone model of demyelination in 59 mouse, the CNS is capable of spontaneous remyelination through mobilization of 60 oligodendrocyte precursor cells (OPCs) (Baxi et al., 2017; Chang, Nishiyama, Peterson,

These results suggest that subcortical WMLs are correlated with focal dementia in classic DM1 patients. Temporal and insular WMLs may be responsible for the global intellectual dysfunction of adult DM1 patients.

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