Microbiome Modulation of Visual System Development - PROJECT SUMMARY Visual system dysfunction is a common and debilitating comorbidity for individuals diagnosed with a variety of neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD), schizophrenia, and attention deficit hyperactivity disorder. The microbiome is emerging as an important determinant of brain development, and recent research links these NDDs to intestinal dysbiosis, suggesting that a normal microbiome is a necessary component of typical brain neurodevelopment and function. To further connect these issues, microbial dysbiosis is also frequently associated with visual system dysfunction, yet practically nothing is known about the mechanisms by which the microbiota impacts visual system development. Therefore, a greater understanding of the dynamics between host and microbiome, including the specific cellular pathways and microbial products influencing neurodevelopment, is needed before effective treatments can be pursued. In this proposal, I will test the hypothesis that normal development of the visual system depends on sensing of specific secreted bacterial factors by specific cell types that mediate communication between the intestinal microbiome and the brain. To accomplish this, I will use the gnotobiotic zebrafish model to investigate how the microbiome interacts with intestinal cells and peripheral neurons to impact early visual neurodevelopment. This is a simple but powerful model system because it allows us to test the role that individual bacterial species and their byproducts play in neurodevelopment. I will use three approaches to determine the role specific host cell types and secreted bacterial products play in visual system development and its downstream behavioral output. Aim 1 tests the hypothesis that the microbiota is required for the normal development and function of a set of superficial interneurons involved in prey capture behavior. Aim 2 investigates the role of gut epithelial sensory cells and the vagus nerve in sensing bacterial products and relaying this information to promote visual system development. In Aim 3, I will identify the active product secreted from a gut bacterium that is sufficient to promote visual system development. These approaches allow an unbiased identification of the anatomical locations, cell types, and signaling pathways that relay microbial cues required for normal development of the visual system and its behavioral outputs. This work is significant because it lays the foundation for understanding mechanisms behind visual comorbidities associated with neurodevelopmental disorders like ASD, and ultimately serves to better inform intervention and treatment, and to one day prevent these complex NDDs and their associated comorbidities.
