Developmental origin of oligodendrocytes determines their function in the adult brain.

In the mouse embryonic forebrain, developmentally distinct oligodendrocyte progenitor cell populations and their progeny, oligodendrocytes, emerge from three distinct regions in a spatiotemporal gradient from ventral to dorsal. However, the functional importance of this oligodendrocyte developmental heterogeneity is unknown. Using a genetic strategy to ablate dorsally derived oligodendrocyte lineage cells (OLCs), we show here that the areas in which dorsally derived OLCs normally reside in the adult central nervous system become populated and myelinated by OLCs of ventral origin. These ectopic oligodendrocytes (eOLs) have a distinctive gene expression profile as well as subtle myelination abnormalities. The failure of eOLs to fully assume the role of the original dorsally derived cells results in locomotor and cognitive deficits in the adult animal. This study reveals the importance of developmental heterogeneity within the oligodendrocyte lineage and its importance for homeostatic brain function.

Cortical neurons exhibit diverse myelination patterns that scale between mouse brain regions and regenerate after demyelination.

Axons in the cerebral cortex show a broad range of myelin coverage. Oligodendrocytes establish this pattern by selecting a cohort of axons for myelination; however, the distribution of myelin on distinct neurons and extent of internode replacement after demyelination remain to be defined. Here we show that myelination patterns of seven distinct neuron subtypes in somatosensory cortex are influenced by both axon diameter and neuronal identity. Preference for myelination of parvalbumin interneurons was preserved between cortical areas with varying myelin density, suggesting that regional differences in myelin abundance arises through local control of oligodendrogenesis. By imaging loss and regeneration of myelin sheaths in vivo we show that myelin distribution on individual axons was altered but overall myelin content on distinct neuron subtypes was restored. Our findings suggest that local changes in myelination are tolerated, allowing regenerated oligodendrocytes to restore myelin content on distinct neurons through opportunistic selection of axons.

Automated in vivo Tracking of Cortical Oligodendrocytes.

Oligodendrocytes exert a profound influence on neural circuits by accelerating action potential conduction, altering excitability, and providing metabolic support. As oligodendrogenesis continues in the adult brain and is essential for myelin repair, uncovering the factors that control their dynamics is necessary to understand the consequences of adaptive myelination and develop new strategies to enhance remyelination in diseases such as multiple sclerosis. Unfortunately, few methods exist for analysis of oligodendrocyte dynamics, and even fewer are suitable for in vivo investigation. Here, we describe the development of a fully automated cell tracking pipeline using convolutional neural networks (Oligo-Track) that provides rapid volumetric segmentation and tracking of thousands of cells over weeks in vivo. This system reliably replicated human analysis, outperformed traditional analytic approaches, and extracted injury and repair dynamics at multiple cortical depths, establishing that oligodendrogenesis after cuprizone-mediated demyelination is suppressed in deeper cortical layers. Volumetric data provided by this analysis revealed that oligodendrocyte soma size progressively decreases after their generation, and declines further prior to death, providing a means to predict cell age and eventual cell death from individual time points. This new CNN-based analysis pipeline offers a rapid, robust method to quantitatively analyze oligodendrocyte dynamics in vivo, which will aid in understanding how changes in these myelinating cells influence circuit function and recovery from injury and disease.

Remyelination alters the pattern of myelin in the cerebral cortex.

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.