PROJECT SUMMARY / ABSTRACT Aberrant development of the prefrontal cortex (PFC), including the axonal connections it receives, are hallmarks of neurodevelopmental and neuropsychiatric disorders (NDDs). Foundational studies have shown that axons that project to the PFC, particularly from thalamic nuclei, influence PFC development and function. Notably, these axons are often disrupted in NDDs. We hypothesize that aberrant thalamocortical connectivity seen in these disorders results from abnormal axon pruning, which in turn leads to deficits in PFC maturation and function. To test this hypothesis, I will use a novel mouse model to inhibit axonal pruning in this circuit and determine its role in PFC development. I will use a combination of neural tracers, genomic, and molecular analysis to quantify axon pruning within the thalamocortical circuit to determine whether its disruption in our mouse models affects critical aspects of PFC development including lamination, neuronal number, interneuron migration, and electrical activity. This proposal, undertaken with the intellectual support of the Tri-Institutional research community and guidance of a mentorship team, will address a significant gap in understanding of how axon refinement regulates normal cortical development and can lead to cortical dysfunction seen in NDDs.