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.
