Untangling the mechanisms of white matter damage in cerebral hypoperfusion

点击翻译按钮获取中文摘要

White matter makes up over half of the human brain and its proper function is critical for fast communication between neurons. White matter damage that occurs during ageing and dementia is linked to chronically lowered brain blood flow (hypoperfusion) and appears to involve complex changes in multiple cell types in blood vessels and surrounding brain tissue at different times after disease onset. Progress in understanding these processes has been restricted by an inability to track cellular changes over time, and a lack of understanding of how one of the major targets, oligodendrocytes (cells which ensheath neurons allowing them to send fast signals), actually are damaged. However, our novel approach will allow major breakthroughs in understanding how white matter becomes damaged. We developed a new method that allows us to image different brain cells and blood vessels in a major white matter tract - the corpus callosum - of awake mice. Our approach feeds data from these new measurements into experiments in brain slices that allow underlying mechanisms to be identified, before in turn testing whether interfering with these mechanisms protects live mice from experiencing white matter damage during chronic cerebral hypoperfusion. By engaging a vital dialogue between these two approaches, we aim to untangle the processes by which white matter becomes damaged during chronically lowered brain blood flow and identify possible therapeutic targets. We will first measure the reduction in white matter oxygenation (hypoxia) during a model of chronic cerebral hypoperfusion in awake mice, and characterise tissue and cell damage in post mortem tissue. We will then recreate these levels of oxygenation in brain slices to understand what mechanisms in white matter cells are impacted by this level of hypoxia. To understand how cell function changes during hypoperfusion, we will track, in vivo functional changes due to hypoperfusion in lots of white matter cells (oligodendrocytes, neurons, microglia - the brain's resident immune cell - and blood vessels) to understand which cells are first affected, to better understand which cells might be primary drivers of white matter damage. Using this information, we will test, in brain slices, if hypoxia causes the same damage to these cells as does hypoperfusion, or whether other possible pathways are also involved - such as leakage of specific molecules into the brain from the blood, or release of molecules associated with inflammation.We will then apply different drugs to determine the effects on different cells of manipulating the pathways which we find are disrupted in brain slices, where necessary using a combination of treatments to protect different cell types. Interventions designed this way will finally be tested in vivo to see if they can preserve both vascular and oligodendrocyte function. Our approach will therefore enable previously impossible in vivo functional characterisation of the changes that occur during cerebral hypoperfusion to inform detailed interrogation of mechanisms leading to cell damage. It will enable design of interventions that account, from the onset, for the effect of different drugs on different cell types and then allow testing of the efficacy of these designs in the intact animal. We expect it to lead to a powerful new understanding of the effect of chronic hypoperfusion on white matter, with huge potential clinical relevance for understanding the progression of small vessel disease and white matter damage in humans.