Impact of sex and hypoxia on brain region-specific expression of membrane androgen receptor AR45 in rats

Background Sex differences in oxidative stress-associated cognitive decline are influenced by sex hormone levels. Notably, oxidative stress-associated neuronal cell death can be exacerbated through testosterone signaling via membrane androgen receptor AR45, which is complexed with G protein G alpha q within plasma membrane-associated lipid rafts. The objective of this study was to elucidate the impact of sex on the expression of AR45 and G alpha q in brain regions associated with cognitive function, specifically hippocampus subregions and entorhinal cortex. Additionally, we investigated whether chronic intermittent hypoxia (CIH), an oxidative stressor with sex-specific effects, would modulate AR45 and G alpha q expression in these brain regions.Methods Adult male and female Sprague-Dawley rats were exposed to CIH or normoxia (room air) during their sleep phase for 14 days. We quantified AR45 and G alpha q protein expression in various cognition-associated brain regions [dorsal hippocampal CA1, CA3, dentate gyrus (DG), and entorhinal cortex (ETC)] via western blotting. For comparisons, AR45 and G alpha q protein expression were also assessed in brain regions outside the hippocampal-ETC circuit [thalamus (TH) and striatum (STR)].Results The highest AR45 levels were expressed in the hippocampal CA1 and DG while the lowest expression was observed in the extrahippocampal STR. The highest G alpha q levels were expressed in the hippocampal-associated ETC while the lowest expression was observed in the extrahippocampal TH. Females expressed higher levels of AR45 in the hippocampal DG compared to males, while no sex differences in G alpha q expression were observed regardless of brain region assessed. Moreover, there was no effect of CIH on AR45 or G alpha q expression in any of the brain regions examined. AR45 expression was positively correlated with G alpha q expression in the CA1, DG, ETC, TH, and STR in a sex-dependent manner.Conclusion Our findings reveal enrichment of AR45 and G alpha q protein expression within the hippocampal-ETC circuit, which is vulnerable to oxidative stress and neurodegeneration during cognitive decline. Nonetheless, CIH does not modulate the expression of AR45 or G alpha q. Importantly, there are sex differences in AR45 expression and its association with G alpha q expression in various brain regions, which may underlie sex-specific differences in cognitive and motor function-associated declines with aging.