A novel noninvasive murine model of neonatal hypoxic ischemic encephalopathy demonstrates developmental delay and motor deficits with activation of inflammatory pathways in monocytes [scRNA-seq]
Neonatal hypoxic ischemic encephalopathy (HIE) occurs in 1.5 per 1000 live births, leaving affected children with long-term motor and cognitive deficits. Few animal models of HIE incorporate maternal immune activation (MIA) despite the significant risk MIA poses to HIE incidence and diagnosis. Our non-invasive model of HIE pairs late gestation MIA with postnatal hypoxia. HIE pups exhibited a trend toward smaller overall brain size and delays in the ontogeny of several developmental milestones. In adulthood, HIE animals had reduced strength and gait deficits, but no difference in speed. Surprisingly, HIE animals performed better on the rotarod, an assessment of motor coordination. There was significant upregulation of inflammatory genes in microglia 24 hours after hypoxia, which were largely downregulated one week later. Single cell RNAseq revealed upregulation of epigenetic machinery in macrophages invading the brain following HIE. These results support a two-hit noninvasive model pairing MIA and hypoxia as a model for HIE in humans. This model results in a mild phenotype compared to established HIE models; however, HIE is a clinically heterogeneous injury resulting in a variety of outcomes in humans. The pathways identified in our model of HIE may yield novel targets for therapy for neonates with HIE. Overall design: scRNA-seq libraries were constructed from 24 mouse brain tissue samples, which are either CONTROL or HIE treated from P8 and P10 to timepoints