The mechanisms that regulate the production and migration of human interneurons (IN) and glial sub-types and the functional integration into neural circuits during perinatal stages remains poorly understood. These processes are likely disrupted in neonatal neurological injuries, which can result in severe long-term cognitive disabilities and high social and financial burden. The proposed program will investigate the developmental origins, diversity and cellular interactions of IN, OPCs and microglia using post-mortem human brain tissue and rodent experimental systems. Key past findings include: (i) Discovery of extensive postnatal migration of INs to specialized cortical regions, suggesting that formation of neural circuits takes place over a protracted period (Paredes, Science; Sorrels, Nature); (ii) that the HIF pathway is a critical regulator of oligodendrocyte precursor cell (OPC) maturation and that OPCs under hypoxic conditions become angiogenic in cortical white matter (Yuen, Cell). Our results indicated that OPCs use vasculature as a scaffold to traffic through the developing brain (Tsai, Science), and (iii) that ins migrate in clusters along large vessels in human neonatal brain (Paredes, Science). For the competing renewal we have expanded the investigator team under direction of Arturo Alvarez- Buylla to recruit promising junior investigators (Mercedes Paredes, Steve Fancy, Tom Nowakowski) and new Project Leader Xian Piao. Project 1 investigates origins and diversity of migrating young INs to human newborn cortex and amygdala. Project 2 investigates the mechanisms underlying angiogenesis and IN migration along the blood vessels in human developing cortex and HIE. Project 3 will provide evidence for microglial-encoded GPR56 pathway function in regulation of IN maturation. The administrative core (A) provides budgetary oversight, coordination and access to resources. All projects will use postmortem neonatal human neuropathological specimens supported by a neuropathology core (B) and transcriptomic core (C) to support studies in cellular diversity (Velmeshev, Science; Schirmer, Nature). The studies are intended to reveal cellular and genetic mechanisms impacted by neonatal brain injury and congenital neurogenetic disease.
The project is intended to provide a new understanding of neuronal and glial development during late gestation and the early postnatal period. These are critical times in human neonatal brain development that are vulnerable to injuries, such as hypoxia, and can result in lifelong neuro-cognitive disabilities, including cerebral palsy and epilepsy.
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