Sex Differences in Memory Performance after Traumatic Brain Injury in Rats.

Traumatic brain injury (TBI) can result in long-lasting cognitive impairment. Accumulating clinical evidence indicates that outcomes often differ according to biological sex. Despite this, preclinical studies remain predominantly male-focused, which limits our understanding of sex-specific vulnerabilities. In this study, we investigated long-term memory outcomes in male and female rats following moderate-to-severe fluid percussion injury, with an additional examination of estrous cycle phases in females. Behavioral performance was assessed using the open field test, novel object location (NOL), novel object recognition (NOR), and the Barnes maze (BM) test. We found that, independent of injury, females exhibited greater locomotor activity than males. TBI significantly impaired performance in NOL and NOR tasks, with sex-dependent patterns of deficit. Female rats exposed to TBI showed greater impairment in novelty-driven memory tasks, including significantly poorer object recognition, than TBI-exposed males. In contrast, BM testing revealed more subtle effects, with TBI causing both sexes to shift towards nonspatial search strategies during the probe trial and males presenting greater disruption in learning-dependent spatial navigation. The phase of the estrous cycle during behavioral testing did not significantly influence the results. Overall, our findings suggest that sex differences in cognitive outcomes following TBI appear to be domain-specific. These results emphasize the importance of incorporating sex as a biological variable in preclinical TBI models, which could help to explain the variability in cognitive outcomes across studies.