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Neurobehavioral Assessments in a Mouse Model of Neonatal Hypoxic-ischemic Brain Injury
Published on: November 24, 2017
Neonatal hyperoxia in mice triggers long-term cognitive deficits via impairments in cerebrovascular function and
Marissa A Lithopoulos1,2, Xavier Toussay3, Shumei Zhong1
1Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
Insights
Bronchopulmonary dysplasia (BPD), a lung disease from oxygen therapy in premature infants, impairs brain development. This study shows BPD affects neural progenitor cells, leading to lifelong motor and cognitive deficits in mice.
Area of Science:
- Neonatal Medicine
- Neuroscience
- Developmental Biology
Background:
- Preterm birth is a leading cause of mortality in children under five.
- Bronchopulmonary dysplasia (BPD), a chronic lung disease, often develops in premature infants receiving oxygen therapy.
- BPD is associated with neurodevelopmental deficits, but the underlying mechanisms involving neural progenitor cells (NPCs) are not well understood.
Purpose of the Study:
- To investigate the role of neural progenitor cells (NPCs) in BPD-associated neurodevelopmental deficits.
- To determine the long-term effects of neonatal hyperoxia on cerebrovascular structure, NPC function, and neurogenesis.
- To identify molecular pathways disrupted by neonatal hyperoxia that contribute to persistent brain injury.
Main Methods:
- Induction of experimental BPD via hyperoxia in newborn mice.
- Assessment of cerebrovascular structure and function.
- Neurosphere assays using nonhuman primate preterm baboon NPCs to evaluate NPC function.
- Gene expression profiling to identify dysregulated molecular pathways.
- Evaluation of motor and cognitive function in aging mice exposed to neonatal hyperoxia.
Main Results:
- Neonatal hyperoxia induced lifelong cerebrovascular impairments and reduced NPC self-renewal and neurogenesis in mice.
- NPCs from preterm baboons also showed functional impairments when exposed to hyperoxia.
- Gene expression analysis revealed dysregulation of genes critical for cell proliferation, angiogenesis, vascular autoregulation, neurogenesis, and neurotransmission.
- These cellular and molecular changes correlated with motor and cognitive decline in aging mice.
Conclusions:
- Bronchopulmonary dysplasia is linked to abnormal neurodevelopmental outcomes due to persistent neonatal brain injury.
- Impaired neural progenitor cell function and cerebrovascular deficits are key contributors to BPD-associated neurodevelopmental issues.
- These findings identify potential therapeutic targets for early intervention in infants with BPD to mitigate long-term neurological consequences.
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.
