Project No. 2329

STANDARD PROJECT

Primary Supervisor

Dr Catherine Hall – University of Sussex

Co-Supervisor(s)

Prof Diego Gomez-Nicola – University of Southampton

Summary

As we age, the brain’s regulation of its blood flow is reduced, hypoxic events are more common, and activation of the brain’s main resident immune cells (microglia) increases.

This likely increases the risk of age-related diseases such as Alzheimer’s Disease (AD). However we do not yet understand how these changes interact with each other to influence age-related decline in brain function. To this end, this project will investigate how the reduced cerebral blood flow observed during ageing affects microglial activation and interactions with the vasculature, in response to hypoxia.

During hypoxia, microglia contact blood vessels, attenuating hypoxia-induced leakage of blood borne molecules into the brain (Halder and Milner, 2019; 2020). This vascular leakiness correlates with sites of angiogenesis suggesting it may be necessary for compensatory vascular remodelling (Halder and Milner, 2020). However, persistent hypoxia (or decreased cerebral blood flow) and vascular leakage could lead to microglia entering a pathologically active state.

Previous studies are limited by not being able to track changes in microglial and vascular function in real time. It is therefore not clear whether microglia respond first to hypoxia and then to leakage or vice versa, and whether sites of new vascular contact by microglia correspond to sites of angiogenesis and vascular remodelling. We will answer these questions by concurrently measuring vascular permeability and microglial calcium signals, morphology and motility using chronic two photon imaging of microglia and blood vessels in awake mice, using our optimised cranial windows over the hippocampus and corpus callosum. This unique setup will be complemented by follow up characterisation of the microglial phenotype at the transcriptomic and protein expression level in post mortem tissue. We will study the impact of acute then chronic changes in blood oxygenation, tracking the location of vascular structural changes with respect to microglial location.

To be successful in this project, a student should have a good degree in Neuroscience or a related subject, and have an interest in understanding neurogliovascular function, and/or processes that lead to dementia.