PROJECT SUMMARY/ABSTRACT The development of the infant brain is a dynamic, intricate process that, when disrupted, can lead to long-term neurological disability. In humans, new inhibitory interneurons (INs) continue to be born and migrate extensively into specific cortical destinations late in gestation and into postnatal life. One common injury that occurs during late gestation and early infancy, is neonatal hypoxic injury (HI). HI is commonly associated with white matter injury, which has led to prior studies focusing on the myelinating cells of the brain – oligodendrocytes. Considering the growing awareness that INs migrate through the white matter and the frequency and clinical outcomes of HI, it is critical to understand the impact of hypoxia on late migrating INs. To overcome the limited access to neonatal human brain tissue, we have developed an innovative model system using the piglet brain. Using the piglet model, we have identified two migratory streams from the Arc targeting distinct cortical structures. Our preliminary data suggests that these streams differentially express genes encoding migratory-related receptors, most notably CXCR4. During hypoxic injury, CXCR4 is directly upregulated by hypoxia inducible factors. Therefore, I propose that HI results in aberrant migration of migratory INs in the postnatal cortex, a misdirection that is mediated through CXCR4 upregulation. First, I will use computational approaches to identify altered signaling pathways in human HI (Aim 1). Next, I will quantify the effect of hypoxia on interneuron migration (Aim 2). Finally, I will test the hypothesis that CXCR4 regulates Arc interneuron migration and mediates hypoxic induced misdirection (Aim 3). Completion of these aims will expand our knowledge of a fundamental mechanism in neonatal brain development and the effect of a common injury on this process. My primary sponsor, Dr. Mercedes Paredes, is an academic neurologist who is an expert in human inhibitory interneuron development and my co-sponsor, Dr. John Rubenstein, discovered the role of CXCR4 in inhibitory interneuron migration and other fundamental transcription factors regulating brain development. Together, their experience and commitment to my training will ensure that I learn to pursue a biomedically focused scientific question, complete the proposed research, and gain relevant clinical experiences to advance my long-term career goals. An F31 NRSA fellowship would allow me to deepen my expertise in developmental neuroscience and computational genomics. This training will provide a foundation to take the next steps towards becoming an academic pediatric neurologist who studies the intersection of genetics and neurodevelopment to advance neuroprotective and regenerative therapies for brain disorders.