Selective vulnerability of intracortical projection neurons drives long-term cortical circuit rewiring after perinatal hypoxia

Abstract

Cortical circuits are built at perinatal times and gradually refined in an activity-dependent manner during a so-called postnatal period of critical plasticity. Although lesions of the central nervous system (CNS) happening during this period typically recover better than those occurring later in life, they are often associated with long-term behavioral deficits. This suggests that neuronal circuits rewiring, in particular within the cortex, may either be incomplete or inappropriate. To address this possibility, we used chronic perinatal hypoxia, a mouse model of very premature birth. We confirmed that chronic hypoxia induced a decrease in cortical thickness frequently observed in very preterm babies, which rapidly recovered 8 days later. To explore the transcriptional correlates of this recovery we next performed singlenuclei transcriptomic analysis of the cortex at short (P11) and long (P45) timepoints following hypoxia. This revealed persistent transcriptional changes within neurons, including of genes involved in mitochondrial metabolism, axonogenesis and synaptogenesis. Further, histological analysis using anterograde and retrograde tracing as well as mitochondrial labelling support persistent alterations in upper cortical neurons resulting in increased corticocortical connectivity within the cortex of adult hypoxic mice. Finally, behavioral testing revealed altered social behavior in mice exposed to chronic hypoxia, which amplified with age. Altogether, our results unravel how brain lesions happening early in life, alter normal cortical development and have long term consequences on cortical wiring, contributing to the observed behaviors defects appearing later in life.