Improved myelin clearance and cognitive outcomes after TBI in female mice are mediated by ovarian steroids and sex chromosomes

Abstract

Traumatic brain injury (TBI) causes sex-specific memory deficits, yet the underlying mechanisms are not fully understood. Using a mouse TBI model, we investigated the role of reactive astrocytes in sex-specific outcome. TBI provoked long-term contextual memory impairment in males and ovariectomized females, but not in intact females. The synthetic steroid tibolone preserved memory and cFos+ neuronal density in the hippocampus of ovariectomized females. Hormone deprivation upregulated astrocytic GFAP and S100B, reduced Homer1, and impaired myelin phagocytosis by astrocytes in females. These effects were counteracted by tibolone. In Four-Core-Genotype mice, memory loss correlated with reduced astrocytic myelin uptake and neuronal activity in XX males and XY female animals. Astrocyte transplantation showed that female astrocytes exhibit superior myelin clearance capacity, especially in female brain environments, though they outperform male astrocytes in both sex contexts. These findings identify astrocyte-mediated myelin phagocytosis as a key mechanism for memory preservation after TBI, governed by both hormonal and chromosomal sex factors.