Middle-aged females are resistant to LPS-induced learning deficits: Sex comparison

Preclinical data have repeatedly shown learning and memory disruption following administration of the bacterial endotoxin lipopolysaccharide (LPS). Normal aging is reported to enhance vulnerability to LPS-induced cognitive impairments. However, a limitation is the primary use of male subjects. Recent evidence indicates sex-related differences in vulnerability to LPS-induced cognitive deficits [1,2], with young females showing resilience. Whether middle-aged females are susceptible to LPS-induced cognitive impairment is unknown. The current experiment compared associative learning in young and middle-aged male and female C57BL/6J mice following a systemic LPS challenge. While LPS impaired acquisition of the two-way active avoidance conditioning task in adult and middle-aged males, females' learning was unaffected. The sex difference in LPS-induced cognitive impairments appears unrelated to responsivity to LPS, as males and females mount a comparable sickness-like response. Additionally, relative to males, females produce higher brain levels of interleukin-6 (IL-6) and comparable splenic IL-6 levels following LPS. These data demonstrate that female resilience to LPS-induced learning deficits persists into middle age, whereas males are vulnerable as both young and middle-aged adults. Our findings confirm the importance of considering sex as a biological variable and extend the existing literature by evaluating sex-related responsivity to LPS in middle-aged males and females.