Neonatal Brain Injury Triggers Niche-Specific Changes to Cellular Biogeography

Abstract

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.Significance statementChildren born prematurely are at risk for white matter injury and cerebral dysmaturation, which predispose to life-long neurological impairments. Here, we used a mouse model of chronic neonatal hypoxia that mimics some of the features of preterm brain injury and performed high resolution spatial transcriptomics using multiplexed error-robust fluorescencein situhybridization (MERFISH). We developed a new approach to map cell-cell relationships, which revealed profound changes to cellular organization in response to newborn brain injury. We defined cellular communication networks and signaling pathways that likely contribute to hypoxia-responsive neurogenesis and gliogenesis, as well as cell- and region-specific factors that may disrupt neurologic recovery and repair.