Regulation of cellular pathways in human brain development

调节人类中间神经元（IN）和胶质细胞亚型的产生和迁移以及在围产期阶段功能整合到神经回路中的机制仍然知之甚少。这些过程可能在新生儿神经损伤中被破坏，这可能导致严重的长期认知障碍和沉重的社会和经济负担。该计划将使用死后人脑组织和啮齿动物实验系统研究IN，OPCs和小胶质细胞的发育起源，多样性和细胞相互作用。过去的主要调查结果包括：（i）发现IN在出生后广泛迁移到专门的皮质区域，表明神经回路的形成发生在延长的时期（Paredes，Science; Sorrels，Nature）;（ii）HIF途径是少突胶质细胞前体细胞（OPC）成熟的关键调节剂，并且OPC在缺氧条件下在皮质白色物质中变得血管生成（Yuen，Cell）。我们的结果表明，OPC使用脉管系统作为支架来通过发育中的脑（Tsai，Science），和（iii）INS在人类新生儿脑中沿沿着大血管成簇迁移（Paredes，Science）。对于竞争性更新，我们在Arturo Alvarez- Buylla的指导下扩大了研究者团队，招募了有前途的初级研究者（Mercedes Paredes、Steve Fancy、Tom Nowakowski）和新的项目负责人Xian Piao。项目1研究迁移到人类新生儿皮层和杏仁核的年轻IN的起源和多样性。项目2研究了新生血管形成和新生神经元沿着血管迁移的机制。项目3将为小胶质细胞编码的GPR 56通路在调节IN成熟中的功能提供证据。行政核心（A）提供预算监督、协调和获得资源的机会。所有项目都将使用由神经病理学核心（B）和转录组学核心（C）支持的死后新生儿人类神经病理学标本，以支持细胞多样性研究（Velmeshev，Science; Schirmer，Nature）。这些研究旨在揭示新生儿脑损伤和先天性神经遗传性疾病影响的细胞和遗传机制。

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.