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Sex-specific cognitive deficits and regional brain volume loss in mice exposed to chronic, sublethal hypoxia
Wen-Chun J Lan1, Matthew Priestley, Sonia R Mayoral
1Department of Pediatrics, Stanford University School of Medicine, Stanford, California 94305, USA.
Insights
Male preterm infants exposed to chronic sublethal hypoxia (CSH) experience long-term cognitive and brain growth deficits. This vulnerability, particularly in males, mirrors findings in human preterm infants, highlighting sex-specific risks from hypoxic brain injury.
Area of Science:
- Neuroscience
- Developmental Biology
- Perinatal Medicine
Background:
- Male sex is a risk factor for neurologic deficits in preterm infants.
- Preterm brain injury models show sex-specific vulnerabilities.
- Chronic sublethal hypoxia (CSH) causes acute brain injury with male susceptibility.
Purpose of the Study:
- To investigate the long-term, sex-specific effects of CSH on cognition and brain growth.
- To compare cognitive and brain development outcomes between male and female mice post-CSH exposure.
- To assess the relevance of the CSH mouse model to human preterm infant outcomes.
Main Methods:
- Neonatal mice were exposed to CSH for 8 days, followed by normoxia.
- Behavioral testing at 6 weeks of age assessed hippocampal-dependent functions.
- Adult brain volumes, including hippocampus and cerebellum, were analyzed.
Main Results:
- CSH-exposed males showed significant impairments in associative learning, spatial memory, and social memory.
- CSH-exposed females exhibited less severe cognitive impairments compared to males.
- Adult CSH-exposed males had persistent reductions in hippocampal and cerebellar volumes, unlike females.
Conclusions:
- Male mice exposed to CSH exhibit long-term cognitive deficits and reduced brain growth.
- Females show greater resilience to the long-term effects of CSH-induced preterm brain injury.
- The CSH mouse model effectively replicates sex-specific vulnerabilities observed in human preterm infants.
Abstract:
Male sex is an independent risk factor for long-term neurologic deficits in human preterm infants. Using a chronic, sublethal hypoxia (CSH) mouse model of preterm brain injury, we recently demonstrated acute brain volume loss with an increased male susceptibility to hippocampal volume loss and hypomyelination. We now characterize the long-term, sex-specific effects of CSH on cognition and brain growth. Neonatal mice were treated with CSH for 8 d, raised in normoxia thereafter and underwent behavioral testing at 6 wk of age. Behavioral assays sensitive to hippocampal function were chosen. CSH-treated males had impairments in associative learning, spatial memory, and long-term social memory compared with control males. In contrast, CSH-treated females were less impaired. Persistent reductions in hippocampal and cerebellar volumes were found in adult CSH-treated males, whereas regional brain volumes in adult CSH-treated females were indistinguishable from controls. Similar to human preterm infants, males exposed to hypoxia are especially vulnerable to short-term and long-term deficits in cognition and brain growth.
