Neuroscience
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Review Historical Article
The challenge of understanding cerebral white matter injury in the premature infant.
White matter injury in the premature infant leads to motor and more commonly behavioral and cognitive problems that are a tremendous burden to society. While there has been much progress in understanding unique vulnerabilities of developing oligodendrocytes over the past 30years, there remain no proven therapies for the premature infant beyond supportive care. ⋯ There has been an emphasis on hypoxia-ischemia and infection/inflammation as upstream etiologies, but less consideration of other contributory factors. This review highlights the evolution of white matter pathology in the premature infant, discusses the prevailing proposed etiologies, critically analyzes a sampling of common animal models and provides detailed support for our hypothesis that nutritional and hormonal deprivation may be additional factors playing critical and overlooked roles in white matter pathology in the premature infant.
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Since its introduction in the early 1990s, diffusion-weighted magnetic resonance imaging (MRI) has played a crucial role in the non-invasive evaluation of tissue microstructure of brain parenchyma in vivo. Diffusion anisotropy, in particular, has been extensively used to infer histological changes due to brain maturation and pathology, as it shows a clear dependence on tissue architecture. Although the resolution used in most studies lies in the macroscopic range, the information provided originates at the microscopic level and, as such, diffusion MRI serves as a microscope that can reveal profound details of tissue with direct clinical and research applications. ⋯ Animal models may provide insight into the mechanisms involved, but do not necessarily provide accurate representations of the human condition, making human diffusion MRI studies with direct histological confirmation crucial for our understanding of tissue changes secondary to neurodevelopment and disease. This work provides a synopsis of tissue characteristics that give rise to highly informative, specific diffusion patterns, and also of how methodological and artifactual aspects can provide erroneous diffusion measurements that do not accurately reflect tissue and may lead to misinterpretation of results. Examples of diffusion changes due to human conditions are provided to illustrate the wealth of applications of diffusion MRI in clinical and research fields.
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There are two ways to picture white matter: as a grid of electrical wires or a network of roads. The first metaphor captures the classical function of an axon as conductor of action potentials (and information) from one brain region to another. The second one points to the important role of axons in a bi-directional transport of biological molecules and organelles between the cell body and synapse. ⋯ We then provide examples of key features of maturation and aging of white matter, as well as some of the common abnormalities observed in neurodevelopmental and neurodegenerative disorders. Next, we review work that motivated our focus on axonal diameter, and explain the relationships between transport and cytoskeleton within the axon. We will conclude by describing molecular machinery of axonal transport and genes that may contribute to inter-individual variations in axonal diameter and axonal transport.
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The myelination of axons in the central nervous system (CNS) is essential for nervous system formation, function and health. CNS myelination continues well into adulthood, but not all axons become myelinated. Unlike the peripheral nervous system, where we know of numerous axon-glial signals required for myelination, we have a poor understanding of the nature or identity of such molecules that regulate which axons are myelinated in the CNS. ⋯ We discuss families of molecules with specific functions at different stages of synapse formation and address studies that implicate the same factors during axon-OPC synapse formation and myelination. We also address the possibility that the function of such synapses might directly regulate the myelinating behavior of oligodendrocyte processes in vivo. In the future it may be of benefit to consider these similarities when taking a candidate-based approach to dissect mechanisms of CNS myelination.
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Myelination by oligodendrocytes is a highly specialized process that relies on intimate interactions between the axon and the oligodendrocytes. Astrocytes have an important part in facilitating myelination in the CNS, however, comparatively less is known about how they affect myelination. This review therefore summarizes the literature and explores lingering questions surrounding differences between white matter and gray matter astrocytes, how astrocytes support myelination, how their dysfunction in pathological states contributes to myelin pathologies and how astrocytes may facilitate remyelination. ⋯ Dysfunctional astrocytes aberrantly affect oligodendrocytes, as exemplified by a number of leukodystrophies in which astrocytic pathology is known as the direct cause of myelin pathology. Conversely, in primary demyelinating diseases, such as multiple sclerosis, astrocytes may facilitate remyelination. We suggest that specific manipulation of astrocytes could help prevent myelin pathologies and successfully restore myelin sheaths after demyelination.