Neonatal hyperoxia in mice triggers long-term cognitive deficits via impairments in cerebrovascular function and neurogenesis

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Lithopoulos, Marissa A. ; Toussay, Xavier ; Zhong, Shumei ; Xu, Liqun ; Mustafa, Shamimunisa B. ; Ouellette, Julie ; Freitas-Andrade, Moises ; Comin, Cesar H. ; Bassam, Hayam A. ; Baker, Adam N. ; Sun, Yiren ; Wakem, Michael ; Moreira, Alvaro G. ; Blanco, Cynthia L. ; Vadivel, Arul ; Tsilfidis, Catherine ; Seidner, Steven R. ; Slack, Ruth S. ; Lagace, Diane C. ; Wang, Jing ; Lacoste, Baptiste ; Thebaud, Bernard

• Document type: Journal article
• Source: Journal of Clinical Investigation; v. 132, n. 22, p. 21-pg., 2022-11-15.

Abstract

Preterm birth is the leading cause of death in children under 5 years of age. Premature infants who receive life-saving oxygen therapy often develop bronchopulmonary dysplasia (BPD), a chronic lung disease. Infants with BPD are at a high risk of abnormal neurodevelopment, including motor and cognitive difficulties. While neural progenitor cells (NPCs) are crucial for proper brain development, it is unclear whether they play a role in BPD-associated neurodevelopmental deficits. Here, we show that hyperoxia-induced experimental BPD in newborn mice led to lifelong impairments in cerebrovascular structure and function as well as impairments in NPC self-renewal and neurogenesis. A neurosphere assay utilizing nonhuman primate preterm baboon NPCs confirmed impairment in NPC function. Moreover, gene expression profiling revealed that genes involved in cell proliferation, angiogenesis, vascular autoregulation, neuronal formation, and neurotransmission were dysregulated following neonatal hyperoxia. These impairments were associated with motor and cognitive decline in aging hyperoxia-exposed mice, reminiscent of deficits observed in patients with BPD. Together, our findings establish a relationship between BPD and abnormal neurodevelopmental outcomes and identify molecular and cellular players of neonatal brain injury that persist throughout adulthood that may be targeted for early intervention to aid this vulnerable patient population. (AU)

• FAPESP's process: 21/12354-8 - Analysis and refinement of machine learning methods for blood vessel morphometry
• Grantee: Cesar Henrique Comin
• Support Opportunities: Regular Research Grants
• FAPESP's process: 18/09125-4 - Representation, characterization and modeling of biological images using complex networks
• Grantee: Cesar Henrique Comin
• Support Opportunities: Regular Research Grants