Understanding brain regeneration in a zebrafish larval model of intracerebral haemorrhage

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Brain haemorrhages are the most severe type of stroke, and patients are often left with disabilities due to brain damage. We currently do not know much about how the brain tissue adapts after the bleed. Presently, the research into brain regeneration following haemorrhage mostly uses invasive, surgically-induced rodent models that do not accurately recreate the spontaneous nature of the human condition. Experimentally, stem cells and synthetic scaffolds are injected into the brain to encourage regrowth, however once delivered into the body, the response is very difficult to measure accurately. Zebrafish can regenerate from injuries, including damage to the central nervous system. We have previously shown that zebrafish larvae, a small, transparent, immature organism can exhibit spontaneous brain bleeds like humans and then quickly recover from injury, growing into healthy adults. I think that we can learn more from the zebrafish brain recovery after a haemorrhage, and utilise their unique transparency, to non-invasively visualise the live recovery response, something that is impossible in rodent models. This work would lead to a reduction in the number of protected animals required for such experiments, as a single pair of breeding zebrafish can produce ~200 embryos.The first step of my project will be to image the cells inside the brain responding to the bleed, to answer the following questions: How quickly do immune cells clear the blood? What fills the space left by the haematoma? Do new brain cells form in the space, or do existing ones spread across the gap? The second part of my project will require extracting these brain stem cells from the zebrafish and investigating the genetic and proteomic factors that influence their behaviour. In the final stage of my project I will apply what I have learnt to human brain stem cell cultures in a dish and determine if turning on the same genes, or exposing them to the same proteins, encourages the same regenerative behaviours we observe in the zebrafish. The ultimate aim of this work is to enable scientists to develop better models of brain regeneration in which to investigate regenerative therapies for patients that could potentially prevent long-term disability after a brain haemorrhage, and reduce the need for animal models in the long term.