Neurovascular coupling in cerebral hypoperfusion

There are almost a million people living with dementia in the UK. Most of these cases comprise Alzheimer’s Disease (AD), vascular dementia (VaD) or, as is increasingly recognised, a mixed picture phenotype with evidence of the two conditions co-existent in the same patient. AD and VaD both converge on the cerebral microvasculature, causing small vessel disease of the brain, seen in almost all patients and leads to a reduction in cerebral blood flow. This reduction in cerebral blood flow is thought to contribute to cognitive decline, by creating a mismatch between the supply of nutrients and the metabolic demands of the brain. This PhD studentship looks to build on recent studies from the microvascular group at the University of Manchester^{1, 2}, to determine the impact of cerebral hypoperfusion on neurovascular coupling.

Cerebral vascular dysfunction will be induced in a novel mouse model that impairs cerebral autoregulation, which determines the volume of blood the brain receives. This model is predicted to receive around a 20% reduction in blood flow compared to their wild-type litter mates. Other groups have shown that a reduction in blood flow to the brain leads to an impaired neurovascular coupling (NVC) response, the process behind a localised increase in blood flow to active brain regions. NVC is facilitated by the capillary endothelial cells sensing neuronal activity and sending a message upstream to the blood vessels, to divert more blood to that region³. This message is a hyperpolarisation signal, that is generated by the activation of the inwardly rectifying K⁺ channel (Kir2.1). This project will determine if there is impaired Kir2.1 activity in the novel mouse model.

The central methodology in this fellowship will be pressure myography to measure arterial diameter control. A novel configuration of pressure myography is the capillary to arterial (CaPA) preparation, used to study NVC in an ex vivo setting. This method will be complemented with teaching and experience with animal models, electrophysiology, in vivo blood flow and mouse behavioural techniques. The student will be required to obtain a personal home office licence, if they do not already hold one.

The outcome from this study will help us learn more about the impact of cerebrovascular damage in brain heath and function, and pinpoint targets for restoring cerebrovascular function in dementia.

 Entry Criteria

Applicants are expected to hold (or about to obtain) a minimum upper second-class undergraduate honours degree (or equivalent) in Biomedical Sciences, Physiology, Pharmacology or similar. Experience in vascular physiology is desirable. 

How to Apply

For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (https://www.bmh.manchester.ac.uk/study/research/apply/).   Interested candidates must first make contact with the Primary Supervisor prior to submitting a formal application, to discuss their interest and suitability for the project. On the online application form select PhD Cardiovascular Sciences