There is mounting evidence that the intestinal microbiota play an important role in normal nervous system development, although the underlying molecular mechanisms are generally unknown. We propose to investigate the role of the intestinal microbiota in development of an identified population of superficial interneurons (SINs) in the zebrafish optic tectum that are required for visually-guided prey capture behavior. Previous work showed that prey capture is significantly impaired in larvae in which SINs are genetically ablated. We find that the microbiota are necessary for SINs to differentiate their GABAergic phenotype, and consequently larvae reared germ free (GF), in the absence of bacteria, phenocopy the prey capture deficit of larvae in which SINs have been ablated. We hypothesize that members of the zebrafish-associated microbiota normally produce molecular products that promote SIN differentiation. We will test this hypothesis using an unbiased screen to identify bacterial products that affect SIN differentiation. First we will use gnotobiotic zebrafish colonized with specific zebrafish bacterial isolates to learn which bacterial species are required for normal SIN development and prey capture behavior. We will then take advantage of a pipeline we established that utilizes bacterial genetics, bioinformatics, and biochemical approaches, to learn the molecular nature of the bacterial products. Discovering the molecular mechanisms by which host-associated bacteria promote normal nervous system development will provide important new insights into a fundamental process that is not well understood, reveal how this process can go awry during intestinal dysbiosis, an imbalance that has been linked to neurodevelopmental conditions such as autism spectrum disorder and schizophrenia, and provide new possibilities for developing targeted therapies.
This project will investigate now bacteria resident within the intestinal tract influence development of the visual system and thus affect visually guided behavior. These investigations will pave the way for possible microbiome-based diagnostics and therapies for visual system developmental disorders.
