Regulation of cellular pathways in human brain development

在围产期，调节人类中间神经元（IN）和胶质亚型的产生和迁移以及神经回路的功能整合的机制仍然知之甚少。这些过程可能在新生儿神经损伤中中断，从而导致严重的长期认知障碍和沉重的社会和经济负担。该计划将利用死后人类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。过去的主要发现包括：(i)发现出生后神经元向特定皮层区域的广泛迁移，表明神经回路的形成是在一个漫长的时期内进行的（Paredes, Science; Sorrels, Nature）；（ii） HIF通路是少突胶质前细胞（OPC）成熟的关键调节因子，缺氧条件下的OPC在皮质白质中生成血管（Yuen, cell）。我们的研究结果表明，OPCs使用血管系统作为支架，通过发育中的大脑（Tsai, Science），并且（iii）在人类新生儿大脑中，ins沿着大血管成群迁移（Paredes, Science）。在Arturo Alvarez- Buylla的指导下，我们扩大了调查团队，招募了有前途的初级调查人员（Mercedes Paredes, Steve Fancy, Tom Nowakowski）和新的项目负责人Xian Piao。项目1研究迁移年轻INs到人类新生儿皮层和杏仁核的起源和多样性。项目2研究了人类发育中的皮质和HIE中血管生成和IN沿血管迁移的机制。项目3将提供证据证明小胶质编码的GPR56通路在调节in成熟中的作用。行政核心(A)负责预算监督、协调和取得资源。所有项目将使用死后新生儿神经病理标本，由神经病理学核心(B)和转录组学核心(C)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.