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Early testosterone modulated sex differences in behavioral outcome following neonatal hypoxia ischemia in rats
C A Hill1, S W Threlkeld, R H Fitch
1University of Connecticut, Department of Psychology, Behavioral Neuroscience, 406 Babbidge Road, Unit 1020, Storrs, CT 06269, USA.
Insights
Neonatal testosterone may worsen brain injury outcomes in male and female infants following hypoxia ischemia (HI). Early HI brain injury leads to significant cognitive and sensory deficits, with males experiencing more severe effects.
Area of Science:
- Neuroscience
- Developmental Biology
- Pediatrics
Background:
- Hypoxia ischemia (HI) is a common brain injury in infants, leading to cognitive and sensory deficits.
- Clinical data show males experience more severe long-term deficits than females after HI.
- Previous studies reported sex differences in HI-induced behavioral deficits in rats.
Purpose of the Study:
- To investigate the role of perinatal testosterone in modulating behavioral and neuropathological outcomes after early HI brain injury in rats.
- To assess the impact of testosterone administration on HI-injured female rats.
Main Methods:
- Male and female rats, along with testosterone-propionate (TP)-treated females, underwent postnatal day 7 (P7) HI or sham surgery.
- Auditory processing and spatial learning were assessed using behavioral testing from P30 onwards.
- Postmortem brain analyses, including weight and neuromorphometrics, were conducted.
Main Results:
- HI injury exacerbated deficits in auditory processing and spatial learning, with males showing more severe impairments.
- TP-treated HI females exhibited significantly worse performance than vehicle-treated HI females.
- HI males and TP-treated HI females showed decreased brain weight and increased ventricular enlargement compared to controls.
Conclusions:
- Neonatal testosterone appears to enhance the negative consequences of early HI brain injury.
- Findings suggest testosterone may exacerbate neuropathology and behavioral deficits following HI.
- This research highlights potential sex-specific therapeutic targets for HI brain injury.
Abstract:
Hypoxia ischemia (HI; reduced blood oxygenation and/or flow to the brain) represents one of the most common injuries for both term and preterm/very low birth weight (VLBW) infants. These children experience elevated incidence of cognitive and/or sensory processing disabilities, including language based learning disabilities. Clinical data also indicate more substantial long-term deficits for HI injured male babies as compared to HI injured females. Previously, we reported significant deficits in rapid auditory processing and spatial learning in male rats with postnatal day 1 (P1), P7, or P10 HI injury. We also showed sex differences in HI injured animals, with more severe deficits in males as compared to females. Given these findings, combined with extant clinical data, the current study sought to assess a putative role for perinatal testosterone in modulating behavioral outcome following early hypoxic-ischemic injury in rats. Male, female, and testosterone-propionate (TP) treated females were subjected to P7 HI or sham surgery, and subsequently (P30+) underwent a battery of auditory testing and water maze assessment. Results confirm previous reports of sex differences following HI, and add new findings of significantly worse performance in TP-treated HI females compared to vehicle treated HI females. Post mortem anatomic analyses showed consistent effects, with significant brain weight decreases seen in HI male and TP-treated HI females but not female HI or sham groups. Further neuromorphometric analysis of brain structures showed that HI male animals exhibited increased pathology relative to HI females as reflected in ventricular enlargement. Findings suggest that neonatal testosterone may act to enhance the deleterious consequences of early HI brain injury, as measured by both neuropathology and behavior.
