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Microglia in myelination

The formation of compact myelin and the refinement of its structure to adapt to the needs of axons is an essential, yet poorly understood, step in the development of a mature nervous system. In a surprising finding, it is apparent that microglia, a type of immune cell found in the brain, make an important contribution to the formation of myelin. This project will identify how microglia interact with myelin to fine-tune structure. Understanding how microglia modulates myelin formation will open up new avenues of research into neural plasticity, which by definition has implications for learning and memory.

Aims

This project aims to identify which specific aspects of myelin formation are modulated by microglia, and to determine the cellular and molecular mechanisms underpinning alterations in myelin formation and modelling.

Neural signaling within the central nervous system (CNS) of vertebrates depends upon efficient electrical impulse transmission along axons, an activity facilitated by the myelin sheath surrounding axons. Myelin enables fast, saltatory conduction of action potentials, reduces neuronal energy needs, and indirectly contributes to axonal metabolic support. In addition, recent evidence has shown that the remodelling of myelin, including alterations to its length and thickness, is a crucial component of neuroplasticity. It is therefore clear that the formation of myelin, and its maintenance in adulthood, is essential for the normal development of the brain.

Myelin is a multi-lamellar, compact specialised membrane that is produced by oligodendrocytes in the CNS. Myelination is a late event in development, with the majority occurring during the post-natal period, and continuing well into adulthood in a number of organisms, including mice and humans. The production of myelin appears to be a default pathway for oligodendrocytes, which when cultured in the absence of neurons still express major myelin components, and which ensheath inert glass nanofibers. Conversely, although the basic myelination programme occurs in a cell-autonomous manner, it is clear that other cellular interactions are central to ensuring the appropriate formation of mature myelin. Unsurprisingly, communication between neurons and oligodendrocytes forms an essential component of the myelination process, particularly in relation to activity-dependent myelination. Unexpectedly, evidence has also implicated another neural cell type, known as microglia, in the formation of myelin.

The investigation of the cellular and molecular mechanisms by which microglia regulate myelin formation by oligodendrocytes, and how disruption of this process affects neural function, is the central theme of this project. We will make use of genetically modified mouse lines to investigate in detail the molecular mechanisms underlying this interaction, and ultimately the functional changes associated with altered myelin structure.

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