Determining the role of maternal gut associated metabolites in thalamocortical circuit development and adolescent somatosensory behavior

PROJECT SUMMARY In 2020, approximately 12 million adolescents were diagnosed with a neurodevelopmental disorder (NDD) which arise from early life disturbances in key neurodevelopmental processes such as axonogenesis, synaptic pruning, and neuronal migration. These disruptions in brain development lead to debilitating neurobehavioral and cognitive disabilities such as sensory processing disorders, language delays, and social deficits, which can present as early as 6 months old. As such, the most effective therapies for NDD rely on early identification and intervention. This proposal aims to determine therapeutic targets during pregnancy with the goal of preventing neurodevelopmental and neurobehavioral consequences implicated in NDDs. Prenatal risk factors such as maternal nutrition, immune activation, and stress modify the maternal gut microbiota and disrupt offspring brain development and behaviors, suggesting the maternal gut microbiota and its associated metabolites are poised to be critical regulators of neurodevelopment and offers the potential for microbiota-based therapeutics for NDDs. The study of maternal microbiome-based therapies for NDDs align with the mission of the NICHD to “...improve reproductive health, enhance the lives of children and adolescents, and optimize abilities for all.” My preliminary data supports my central hypothesis that the maternal gut microbiota regulates key in utero microbial metabolites that promote thalamocortical development, allowing for typical adolescent somatosensory and behaviors. Further, my data provides evidence that maternal gut regulated metabolites act on embryonic microglia activity to shape thalamocortical circuit development and function that underlie adolescent somatosensory behavior. These findings support my rationale that the absence or disruption of the maternal gut microbiota decreases the in utero bioavailability of key microbially modulated metabolites that are necessary to shape microglia development and phagocytic activity at developing thalamocortical axons that then mediate somatosensory circuit dysfunction and behaviors in adolescence. I propose to test my central hypothesis with the following aims: Aim 1: Determine how 4MM regulates embryonic thalamocortical neuron and microglia morphology, growth, and function; Aim 2: Investigate the role of in utero 4MM on adolescent somatosensory circuitry and behaviors. The mechanistic approach that I have outlined in this proposal will elucidate a causal role of maternal gut microbiota associated metabolites on neurodevelopment and highlights the potential for microbiome-based interventions to improve childhood outcomes and livelihood. By completing the proposed research, I will identify a novel mechanism for how the maternal gut microbiota can regulate offspring brain development and behavior. My proposed research is essential to my predoctoral training as I will develop and master technical skills, experimental design and analysis, effective mentorship, and promote my contribution to the scientific field