Something in the air - investigating the impact of air pollution on neurodevelopment in the zebrafish model.

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Early-life exposure to particulate matter (PM) may cause neuronal deficits. It is notknown whether PM is directly responsible or rather primes the nervous system torespond adversely to other environmental challenges. One proposed mechanism ofaction is neuroinflammation, mediated by microglial cells, but we are hampered bylack of real-time in utero imaging to prove this or identify whether additional stressorsare required. Additionally, we lack understanding of how PM impacts upon genetranscription in the developing nervous system, which may contribute to life-longneurological impairment. In this project, we will used both the developing zebrafishembryo model and human fMRI and dMRI datasets to investigate these questions. Wewill test the hypothesis that PM activates microglial cells directly resulting inneuroinflammation but that additional stressors are required to induceneurodevelopmental deficits. We will test this hypothesis using the followingobjectives: Objective 1: Additive impacts of environmental stress on braindevelopment (RVC) Zebrafish embryos/larvae will be raised in the presence of PM withor without additional stressors (cortisol/LPS). Outputs of survival, morphology andbehaviour will be evaluated. Objective 2: Cellular contribution to PM-mediated stressphenotypes (RVC) Immunohistochemistry and/or transgenic lines will be used todissect relative contributions of microglia and neurons to the phenotype. Cellularbioenergetics, metabolic flux, signalling and cell death will also be examined.Objective 3: Transcriptomic analysis of pathways impacted by PM (RVC) RNAseqprofiles of PM exposed embryos will be analysed to determine whichneurodevelopmental pathways are impacted and if additional stressors change thetranscription profile. Objective 4: Impact of exposure to PM on neurodevelopment interm born infants (KCL) Neuroinflamation analyses will be performed using fMRI anddMRI datasets from infants enrolled in the Developing Human Connectome project.Quantitative connectomic measures will be incorporated into statistical models withpollution, genetic, clinical and demographic data.