PROJECT SUMMARY / ABSTRACT The development of the nervous system is a complex, dynamic process that is dysregulated in neurodevelopmental disorders (NDDs). Although progress has been made to identify genetic and environmental NDD-risk factors, we lag behind with rigorous investigation of how environmental factors may act on certain genetic vulnerabilities to alter neurodevelopment. My dissertation project builds on my co-sponsor, Dr. Blaser’s, recent human epidemiological study that identified infant cephalosporin antibiotic exposure as an environmental factor associated with increased NDD risk. It is well established that antibiotics decrease the diversity and abundance of beneficial microbial taxa in the gut, which can consequently alter brain structure and function. However, the mechanism(s) by which an antibiotic-induced perturbed microbiome affects early neurodevelopmental processes implicated in NDD pathogenesis remains largely unexplored. My current work addresses this research gap by investigating gut-microbiome-brain interactions in a novel gene by environment (GxE) mouse model of NDDs under the supervision of Drs. Emanuel DiCicco-Bloom (sponsor, neuroscience) and Martin Blaser (co-sponsor, microbiology). The primary goal of Aim 1 is to receive rigorous training in microbiology and developmental neurobiology during the F99 phase to examine how early life cephalosporin exposure alters the gut microbiome and consequentially dysregulates neurodevelopment. The proposed experiments will utilize both wildtype and 16p11.2 microdeletion copy number variation (+/16pDel CNV) mice, which are a robust genetic risk model for investigating NDD pathogenesis due to their highly conserved 28 gene deletion region also observed in human +/16pDel heterozygotes. My preliminary findings indicate sex- and genotype-dependent effects of cephalosporin exposure on altered neurodevelopment. For the remaining F99 phase, I will finish characterizing how early life cephalosporin exposure alters neurodevelopment and the gut- microbiome and then incorporate a mechanistic approach to determine if microbiome restoration can rescue altered neurodevelopment. This training will provide me with a strong technical and intellectual skillset to continue investigating gut-microbiome-brain research as a postdoctoral scholar. However, a gap in my skillset that Aim 2 will expand on is the ability to analyze and interpret the metabolome and epigenome, two intermediate systems that mediate gut-microbiome-brain GxE interactions. To ensure I address this gap, I will identify a postdoctoral laboratory that can train me in routine and cutting-edge techniques to study and manipulate the metabolome and epigenome during the K00 phase. These studies will collectively establish and build on a mechanistic framework to investigate gut-microbiome-brain GxE interactions while simultaneously facilitating my path towards independence as a neuroscience investigator.

PROJECT NARRATIVE There is currently no mechanistic study that has examined the effects of infant antibiotic exposure on neurodevelopment despite its correlative evidence of being linked to increased neurodevelopmental disorder (NDD) risk. The work proposed in this F99/K00 application will be among the first to address this gap by investigating how environmental factors associated with NDDs interacts with genetic vulnerabilities to alter the gut-microbiome-brain axis. As a result, this project will provide rigorous training to an underrepresented predoctoral student to facilitate her path in becoming an independent neuroscience investigator.