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Regional vulnerability after traumatic brain injury: gender differences in mice that overexpress human copper, zinc
T Igarashi1, T T Huang, L J Noble
1Department of Neurological Surgery, University of California at San Francisco, San Francisco, California 94143, USA.
Abstract:
Neuronal loss was quantified in both cortical and subcortical brain regions after traumatic brain injury in male and female nontransgenic (nTg) and transgenic (Tg) mice that overexpress human copper, zinc superoxide dismutase. Mice were euthanized at 7 days after a controlled cortical impact injury. Sections of brain were processed for immunolocalization of NeuN, a neuronal nuclear antigen, and the complement type 3 receptor, a marker of microglia/macrophages, and stained for iron. Cortical lesion volume and neuronal loss in the medial and/or lateral ventroposterior thalamic nuclei were significantly less in the nTg female compared to the nTg male (P = 0.0373 and P = 0.0023, respectively). In contrast, in CA3 of the hippocampus and laterodorsal thalamic nucleus (LD), there were no gender differences in neuronal loss between these nTg groups. Cortical lesion volume was significantly reduced in Tg males compared to nTg males (P = 0.0137) and was unchanged in the Tg females compared to the nTg females. Neuronal loss was attenuated in the CA3 and LD in the Tg females compared to the nTg females (P = 0.0252 and P = 0.0244, respectively). A similar protection was not observed in the Tg males. Microglial activation paralleled the pattern of neuronal loss and was most consistently aligned with iron deposition in the cortex and hippocampus. No overt differences were found in the pattern of microglial activation or iron staining between nTg and Tg mice nor between genders. Our findings demonstrate that neuroprotection, afforded by overexpression of copper, zinc superoxide dismutase, exhibits both regional and gender specificity.
Insights
Overexpression of copper, zinc superoxide dismutase provided neuroprotection in female mice after brain injury, but this effect was region-specific and showed gender differences.
Area of Science:
- Neuroscience
- Traumatic Brain Injury Research
- Genetics and Molecular Biology
Background:
- Traumatic brain injury (TBI) leads to neuronal loss in both cortical and subcortical brain regions.
- The role of gender and genetic modification in TBI outcomes requires further investigation.
Purpose of the Study:
- To investigate the neuroprotective effects of overexpressing human copper, zinc superoxide dismutase (SOD1) in male and female mice following TBI.
- To determine if these neuroprotective effects are region-specific and gender-specific.
Main Methods:
- Controlled cortical impact injury was induced in nontransgenic (nTg) and transgenic (Tg) mice overexpressing human SOD1.
- Neuronal loss was quantified using NeuN immunolocalization.
- Microglial activation and iron deposition were assessed via immunolocalization and staining, respectively.
Main Results:
- Female nTg mice exhibited less cortical lesion volume and neuronal loss in the ventroposterior thalamus compared to males.
- Tg males showed reduced cortical lesion volume compared to nTg males.
- Tg females demonstrated attenuated neuronal loss in the hippocampus (CA3) and laterodorsal thalamic nucleus (LD) compared to nTg females.
- Microglial activation patterns correlated with neuronal loss and iron deposition, but showed no significant differences between nTg and Tg groups or genders.
Conclusions:
- Overexpression of human SOD1 confers neuroprotection against TBI, but this effect is both region-specific and gender-specific.
- Female mice showed inherent resilience in certain brain regions, while SOD1 overexpression provided additional benefits in specific areas for females but not males.
