Biological sex and normative cognitive aging across spatial learning, flexibility, and working memory in Fischer 344 rats.

Abstract

Aging is associated with decline in spatial learning, cognitive flexibility, and working memory, yet the extent to which biological sex modulates changes in cognitive function remains unresolved. While sex differences are evident in pathological brain aging, sparse insights from healthy aging populations suggest that sex effects on cognition are modest and domain specific. To systematically test effects of biological sex across the lifespan on specific aspects of cognitive function, we examined age- and sex-related changes in spatial cognition in a large cohort of Fischer 344 rats (N = 373), including young (4-8 months), middle-aged (12-16 months), and older aged (22-26 months) males and females. Rats were assessed on spatial reference learning, reversal learning, and working memory versions of the Morris water maze, with performance quantified using proximity-based measures, providing sensitive, individualized indices of spatial learning. Across all tasks, age accounted for the largest proportion of variance, with older rats exhibiting impairments in spatial learning, flexibility, and working memory relative to young adults. In contrast, effects of sex or interactions with age were limited to certain aspects of performance and were substantially smaller relative to age and training effects. Specifically, a female-specific association between spatial reference memory and reversal learning was observed despite comparable overall performance. Performance on visible-platform control trials did not indicate gross sensorimotor impairments that would account for age-related spatial deficits. Together, findings demonstrate age is the primary determinant of spatial cognitive decline under normative conditions, while sex-related influences, if present, are subtle and task dependent. (PsycInfo Database Record (c) 2026 APA, all rights reserved).