Understanding the cellular neurobiology of paediatric stroke and moyamoya disease

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Stroke is often thought of as a disease affecting older adults, but it is a significant condition in children as well - with several hundred affected in the UK annually. Paediatric (children) and neonatal (newborn baby) stroke can lead to significant disabilities including cerebral palsy - a lifelong condition that costs the NHS millions of pounds per year. Although in adults stroke is most often due to atherosclerosis (narrowing of the arteries due to high cholesterol, smoking and other risk factors), in children an underlying condition such as moyamoya disease is often found. In moyamoya, the arteries of the brain narrow, causing a chronic reduction of blood flow to the brain. The presentation, course of, and recovery from stroke are different in children and adults, for reasons we do not yet fully understand.I am a paediatric neurosurgeon who looks after children with moyamoya and stroke. I am part of a multidisciplinary neurovascular team that has the largest caseload of moyamoya and paediatric stroke in the UK. Early in my training, I undertook a PhD project where I used basic neuroscience techniques to examine the response to injury of both neurons (nerve cells) and glial cells (specialized supporting cells) in the brain. I have always been interested in understanding the mechanisms in the brain that are involved in the response to injury and stroke, and hope to use this understanding to improve our treatments for children with these conditions. In this project I wish to link my clinical paediatric neurovascular practice with my basic neuroscience training to elucidate these mechanisms in the world-renowned laboratory of my research partner. The Attwell lab has great expertise in studying neurons, glial cells, and brain blood flow and its disorders, using state of the art techniques including patch-clamping, 2-photon microscopy and a range of transgenic animals allowing cell identification. Capillaries are tiny blood vessels which deliver oxygen and nutrients to brain tissue. My research partner has discovered that these are regulated by surrounding cells called "pericytes" which, in part via glial cells, respond dynamically to changes in blood flow and oxygen levels. I will study the responses of pericytes to ischaemia (when the brain does not get enough blood, e.g. during stroke or in moyamoya) in juvenile rodents of different ages, using 2-photon and confocal microscopy.Axons are the tiny "wires" that send signals between brain cells. During childhood the initially bare axons are progressively wrapped in an insulation called myelin, which is necessary for development of brain function. Employing rodent models of stroke and moyamoya, I will use immunohistochemical labelling, calcium imaging, mathematical conduction modelling and electrophysiology to examine the effect of ischaemia on axons, myelination and the nodes of Ranvier (gaps between myelin) in the developing brain. I will also characterise the stroke-relevant properties of microglia, which are the immune cells of the brain, carrying out surveillance of the microenvironment and responding to injury and cell death, as well as pruning unnecessary synapses. Using brain slices from transgenic rodents I will examine with 2 photon microscopy the responses of microglia to ischaemia in the developing brain and compare them to those of adults.As a neurosurgeon, I have access to brain tissue from operations: small pieces removed to access vascular malformations and tumours, which would otherwise be discarded. This gives me a unique opportunity to replicate rodent experiments on human brain slices and test whether the mechanisms are the same.These experiments will delineate the cellular mechanisms underlying the response of the child's brain to ischaemia, and may lead to the identification of targets for novel drug and surgical therapies to reduce the brain damage caused by, and improve recovery from, paediatric stroke and moyamoya.