A significant proportion of neurons in the brain undergo programmed cell death. In order to prevent the diffusion of damaging degradation products, dying neurons are quickly collected by microglia, specialised phagocytes that are resident in the brain. Despite the importance of these cells in several neuronal pathologies, many fundamental questions concerning microglial-neuronal interactions remain unaddressed. How these cells collectively ensure that the entire brain is surveyed and how they react to damage with high precision is still entirely unknown. Recent findings suggest that diffusible molecules such as lipids and nucleotides could attract microglia in response to neuronal apoptosis and injury, respectively. While these molecules can trigger dynamic changes in microglia motility in vitro, elucidating how their activity is controlled within the intact brain, both in space and time, remains the most important challenge in understanding this fascinating biological problem. We aim to further exploit the massive imaging potential of the transparent zebrafish embryo for studying microglial biology in vivo. By combining forward and reverse genetic approaches with quantitative imaging technology, we will directly address the mechanisms underlying the attraction of microglia towards apoptotic, sick and injured neurons. For the first time, we will define the collective behaviour of an entire microglial network within an intact brain under both physiological and pathological conditions.
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