Tahmasian Nareh, Feng Min Yi, Arbabi Keon, Rusu Bianca, Cao Wuxinhao, Kukreja Bharti, Lubotzky Asael, Wainberg Michael, Tripathy Shreejoy J, Kalish Brian T
Program in Neuroscience and Mental Health, SickKids Research Institute, Toronto, Ontario M5G 1L7, Canada
Department of Laboratory Medicine and Pathology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
eNeuro. 2024 Dec 26;11(12). doi: 10.1523/ENEURO.0224-24.2024. Print 2024 Dec.
Preterm infants are at risk for brain injury and neurodevelopmental impairment due, in part, to white matter injury following chronic hypoxia exposure. However, the precise molecular mechanisms by which neonatal hypoxia disrupts early neurodevelopment are poorly understood. Here, we constructed a brain-wide map of the regenerative response to newborn brain injury using high-resolution imaging-based spatial transcriptomics to analyze over 800,000 cells in a mouse model of chronic neonatal hypoxia. Additionally, we developed a new method for inferring condition-associated differences in cell type spatial proximity, enabling the identification of niche-specific changes in cellular architecture. We observed hypoxia-associated changes in region-specific cell states, cell type composition, and spatial organization. Importantly, our analysis revealed mechanisms underlying reparative neurogenesis and gliogenesis, while also nominating pathways that may impede circuit rewiring following neonatal hypoxia. Altogether, our work provides a comprehensive description of the molecular response to newborn brain injury.
早产儿有脑损伤和神经发育障碍的风险，部分原因是慢性缺氧暴露后发生的白质损伤。然而，新生儿缺氧破坏早期神经发育的精确分子机制仍知之甚少。在这里，我们使用基于高分辨率成像的空间转录组学构建了新生脑损伤再生反应的全脑图谱，以分析慢性新生儿缺氧小鼠模型中的80多万个细胞。此外，我们开发了一种新方法，用于推断细胞类型空间邻近性与条件相关的差异，从而能够识别细胞结构中特定生态位的变化。我们观察到与缺氧相关的区域特异性细胞状态、细胞类型组成和空间组织的变化。重要的是，我们的分析揭示了修复性神经发生和神经胶质生成的潜在机制，同时还确定了可能阻碍新生儿缺氧后神经回路重新布线的途径。总之，我们的工作全面描述了对新生脑损伤的分子反应。
