White matter impairments are a major component of various neurodegenerative diseases, including Alzheimer’s disease(1,2). White matter is composed of neuronal axons and their encasing myelin; a lipid-rich material produced by the oligodendroglia. Myelin insulates axons to sustain optimal action potential conduction, and therefore its loss causes neuronal transmission impairment. Accordingly, remyelination could represent an effective therapeutic target. Indeed, a recent report found that promoting myelin renewal in an in vivo model of Alzheimer’s disease improved cognitive function(3). However, we currently lack an effective way to promote remyelination in the brain.
Ultrasound has been used extensively as a diagnostic imaging tool in medicine for over 60 years. Surprisingly, studies in humans and animal models have revealed that when ultrasound is directed across the skull, it can profoundly modulate brain activity(4–6). We have shown that ultrasound exposure enhances neuronal function(7). Importantly, oligodendrocytes express various mechanosensors, whose activation drives proliferation and differentiation of oligodendrocyte precursor cells and myelination8. This presents the intriguing possibility that extraneously applied movement forces – such as those induced by ultrasound – could be used to drive an active state of oligodendrocytes and ultimately promote myelination.
Aims and objectives
Aim 1: Determine ultrasound effects on oligodendrocytes.
Objectives: 1. Characterise ultrasound parameters and how they relate with effects on oligodendrocytes. 2. Examine consequences of ultrasound on remyelination.
Hypothesis: Ultrasound stimulates the proliferation, migration and differentiation of oligodendroglial progenitor cells and promotes remyelination of demyelinated axons.
Aim 2: Determine how targeted transcranial ultrasound affects neurodegenerative pathology in an Alzheimer’s disease mouse model.
Objectives: 1. Test disease-modifying effects of ultrasound. 2. Characterise effects of ultrasound on remyelination. 3. Examine how ultrasound affects cognition.
Hypothesis: Transcranial ultrasound exposure induces remyelination in a rodent Alzheimer’s disease model, with beneficial effects on cellular and cognition.
We will prepare rat organotypic hippocampal slice cultures, and test how ultrasound exposure affects the extent of remyelination in a chemically induced model of demyelination. This will be assessed through immunocytochemistry and high-resolution imaging using established markers of oligodendroglial lineage in the CNS. The consequences of this on neuronal function will be explored through electrophysiology. In complementary studies informed by the in vitro work, we will test the effects of ultrasound exposure in vivo in an established and previously validated transgenic mouse model of Alzheimer’s disease and the consequences for behaviour and cognition. The student will therefore develop a range of highly sought-after technical skills, including electrophysiology, protein analysis, high-resolution cell imaging, in vivo expertise, and animal behaviour analysis.
Apply for this project
This project will be based in Bristol Medical School - Translational Health Sciences.
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