Investigating role of maternal gut microbiome in microglia-neuron dynamics and development of somatosensory circuits

Project Summary Sensory processing disorder is associated with neurodevelopmental disorders such as autism spectrum disorder and intellectual disability, affecting 1 in 20 children. Increasing evidence reveal that the maternal environment strongly impacts the etiopathogenesis of neurodevelopmental disorders, suggesting in utero factors such as the maternal gut microbiota holds profound influence on fetal brain development. Therefore, understanding the role of maternal gut microbes in the development of neural circuits and abnormal behaviors can provide insights to the underlying mechanisms of neurodevelopmental disorders. Recent work has illuminated mechanisms that occur during gestation whereby the absence of the maternal gut microbiota yields offspring with altered fetal brain gene expression, reduced fetal thalamocortical axon development, and abnormal tactile sensory behavior in later life. This proposal aims to explore how maternal gut microbiota alters fetal brain development. In Aim 1 (K99), the role of the maternal gut microbiome in the development of prenatal microglia will be determined by single-cell RNA sequencing of microglia gene expression, CLARITY imaging of microglia morphology and in vivo imaging of awake animals during somatosensory behaviors for microglia function. Aim 2 of this proposal (K99) will employ a depletion and novel “add-back” approach of embryonic microglia from specific pathogen-free (SPF) brains, which have a normal gut microbiota, into embryonic brains of offspring from dams that are germ-free (GF) or antibiotic-treated (ABX), which are depleted of the maternal gut microbiome. This set of experiments will address the causal role of microglia and test whether prenatal microglia mediate maternal gut microbiome effects on brain development. Since microglial activation is implicated in behavioral deficits seen in autism spectrum disorder and schizophrenia, R00 will leverage techniques developed in the K99 phase to ask whether maternal gut microbiota contributes to the effects of microglial activation on fetal brain development and later life behaviors. The successful completion of these aims could lead to new biological targets for therapeutic intervention, while also expanding our understanding of microbes during development of the central nervous system. These proposed experiments will provide me with new training in methodologies (single cell RNA sequencing and analysis, and in vivo imaging of awake behaving animals) and concepts (microglial biology) to serve as the foundation of an independent research laboratory that will study maternal gut microbes and neuroimmune development, and elucidate the cellular and molecular mechanisms governing neurodevelopmental disorders. This work will be completed at UCLA, where the opportunities for technical and intellectual growth are innumerable. I will attend regular meetings with mentors and collaborators to receive feedback on experimental design and career advice. I will attend grant writing and research seminars at UCLA, while also improving my communication skills by presenting at scientific conferences. Together, this career development award will help me establish and lead a successful neurodevelopmental biology research group.