From birth, vertebrates are colonized by a rich and complex microbiome. Growing evidence suggests that metabolites generated by members of the microbiome can profoundly influence the development and function of nervous tissue. However, the role of these interactions remains to be fully explored. In this project, we will use the zebrafish as a model for the study of microbiome-nervous system interactions. The zebrafish is an excellent model for such studies as its optical transparency permits the visualisation of nervous system development in a living animal. Moreover, this transparency allows us to monitor interactions between fluorescently-labelled microbes and nervous tissue. Finally, as zebrafish develop outside the mother, it is relatively easy to manipulate the microbiome during early development. For example, it is possible to raise zebrafish in germ-free environments and subsequently colonize animals with specific bacteria.
In this project, we will use zebrafish to determine how the microbiome shapes nervous system development. We will first generate germ-free zebrafish so that the effects on nervous system development and function can be explored with a battery of established imaging, physiological and behavioural methods. For example, we will use in vivo imaging to study the effect of the absence of the microbiota in the genesis and growth of neurons in transgenic fish that express green fluorescent protein in specific neuronal subpopulations. We will also use in vivo electrophysiology to determine how germ-free environments affect the early wiring and excitability of neurons during early periods of development. Finally, we will use a suite of behavioural methods to assess changes in motor activity. After examining the effects of raising fish in germ-free conditions, complementation will be attempted by monoassociation with individual members of the zebrafish microbiota. In addition, as the microbiome has recently been implicated in degenerative diseases such amyotropic lateral sclerosis (ALS), zebrafish harbouring mutations in ALS-causing genes will be tested using the techniques described above to investigate if the microbiota modulates disease phenotype. With these approaches, we will delineate the role of the microbiome in shaping nervous system development and its contribution to nervous system disease.