Differential impacts of advanced age and sex in age-related trace fear memory impairment in rats

Abstract

While cognitive function remains stable for majority of the lifespan, many functions sharply decline in later life. Women have higher rates of neurodegenerative diseases that involve memory loss, including Alzheimer's disease. This sex disparity may be due to longer life expectancies when compared to men; women outlive men by roughly 5 years globally. Despite this, most preclinical work compares aged male rodents to young adult counterparts, making it difficult to determine the relative contributions of advanced age and sex to memory function and neurodegeneration. We used male and female rats throughout old age (PND590-734) to examine the extent to which both sex and advanced age would impact trace fear memory and associated neural changes, including expression of the immediate early gene zif268, perineuronal nets (PNN) amount, and lysine-48 (K48) polyubiquitin protein tagging in brain regions necessary for trace fear memory: the prelimbic cortex (PL), the dorsal hippocampus (DH), and the basolateral amygdala (BLA). While both advanced age and biological sex impacted trace fear memory, they had no effect on acquisition or context fear retrieval. Advanced age was associated with decreased zif268 expression in the PL and DH, while biological sex had no influence. PNN amount corresponded with advanced aged in the PL, but not in the DH or BLA, and was not influenced by sex. Neither biological sex nor advanced age impacted K48 polyubiquitin levels in any region. Overall, these results suggest that advanced age has a more pronounced effect on memory impairment and associated neural changes than biological sex.