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The structural integrity of myelin sheaths in the central nervous system (CNS) is crucial for the maintenance of its function. Electron microscopy (EM) is the gold standard for visualizing individual myelin sheaths. However, the tissue processing involved can induce artifacts such as shearing of myelin, which can be difficult to distinguish from true myelin abnormalities. Spectral confocal reflectance (SCoRe) microscopy is an imaging technique that leverages the differential refractive indices of compacted CNS myelin in comparison to surrounding parenchyma to detect individual compact myelin internodes with reflected light, positioning SCoRe as a possible complementary method to EM to assess myelin integrity. Whether SCoRe is sensitive enough to detect losses in myelin compaction when myelin quantity is otherwise unaffected has not yet been directly tested. Here, we assess the capacity of SCoRe to detect differences in myelin compaction in two mouse models that exhibit a loss of myelin compaction without demyelination: microglia-deficient mice ( Csf1r - FIRE Δ /Δ ) and wild-type mice fed with the CSF1R inhibitor PLX5622. In addition, we compare the ability to detect compact myelin sheaths using SCoRe in fixed-frozen versus paraffin-embedded mouse tissue. Finally, we show that SCoRe can successfully detect individual sheaths in aged human paraffin-embedded samples of deep white matter regions. As such, we find SCoRe to be an attractive technique to investigate myelin integrity, with sufficient sensitivity to detect myelin ultrastructural abnormalities and the ability to perform equally well in tissue preserved using different methods., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Craig, Ryan, Thapar, McNamara, Hoffmann, Page, Rose, Cox and Miron.)

Myelin is required for the function of neuronal axons in the central nervous system, but the mechanisms that support myelin health are unclear. Although macrophages in the central nervous system have been implicated in myelin health 1 , it is unknown which macrophage populations are involved and which aspects they influence. Here we show that resident microglia are crucial for the maintenance of myelin health in adulthood in both mice and humans. We demonstrate that microglia are dispensable for developmental myelin ensheathment. However, they are required for subsequent regulation of myelin growth and associated cognitive function, and for preservation of myelin integrity by preventing its degeneration. We show that loss of myelin health due to the absence of microglia is associated with the appearance of a myelinating oligodendrocyte state with altered lipid metabolism. Moreover, this mechanism is regulated through disruption of the TGFβ1-TGFβR1 axis. Our findings highlight microglia as promising therapeutic targets for conditions in which myelin growth and integrity are dysregulated, such as in ageing and neurodegenerative disease 2,3 ., (© 2022. The Author(s).)

Microglia, the resident myeloid cells in the central nervous system (CNS) play critical roles in shaping the brain during development, responding to invading pathogens, and clearing tissue debris or aberrant protein aggregations during ageing and neurodegeneration. The original concept that like macrophages, microglia are either damaging (pro-inflammatory) or regenerative (anti-inflammatory) has been updated to a kaleidoscope view of microglia phenotypes reflecting their wide-ranging roles in maintaining homeostasis in the CNS and, their contribution to CNS diseases, as well as aiding repair. The use of new technologies including single cell/nucleus RNA sequencing has led to the identification of many novel microglia states, allowing for a better understanding of their complexity and distinguishing regional variations in the CNS. This has also revealed differences between species and diseases, and between microglia and other myeloid cells in the CNS. However, most of the data on microglia heterogeneity have been generated on cells isolated from the cortex or whole brain, whereas white matter changes and differences between white and grey matter have been relatively understudied. Considering the importance of microglia in regulating white matter health, we provide a brief update on the current knowledge of microglia heterogeneity in the white matter, how microglia are important for the development of the CNS, and how microglial ageing affects CNS white matter homeostasis. We discuss how microglia are intricately linked to the classical white matter diseases such as multiple sclerosis and genetic white matter diseases, and their putative roles in neurodegenerative diseases in which white matter is also affected. Understanding the wide variety of microglial functions in the white matter may provide the basis for microglial targeted therapies for CNS diseases., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

In this issue of Neuron, Chen et al. (2021) reveal dynamic changes in myelin in an Alzheimer's disease (AD) mouse model. Enhancing myelination genetically or pharmacologically improves cognition in this model, supporting myelin as a therapeutic target for AD., Competing Interests: Declaration of interests V.E.M. has received consultancy funds from Novartis and Biogen and research funds from Biogen, Clene Nanomedicine, ReWind Therapeutics, and GSK., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Perinatal brain injury (PBI) to the developing white matter results in hypomyelination of axons and can cause long-term motor and cognitive deficits e.g. cerebral palsy. There are currently no approved therapies aimed at repairing the white matter following insult, underscoring the need to investigate the mechanisms underlying the pathogenesis of PBI. Microglia have been strongly implicated, but their function and heterogeneity in this context remain poorly understood, posing a barrier to the development of microglia-targeted therapies for white matter repair following PBI. In this review, we discuss the roles of microglia in normal white matter development and in PBI, and potential drug strategies to influence microglial responses in this setting., (Copyright © 2019 Elsevier B.V. All rights reserved.)