Pregnancy History and Estradiol Influence Spatial Memory, Hippocampal Plasticity, and Inflammation in Middle-aged Rats

Pregnancy and motherhood (parity) can have long-term effects on cognition and brain aging in both humans and rodents. Estrogens are related to cognitive function and neuroplasticity. Estrogens can improve cognition in postmenopausal women, but the evidence is mixed, in part due to differences in hormone therapy dose and composition. In addition, past pregnancy influences brain aging and cognition, with earlier age of first pregnancy being associated with poorer outcomes with aging. However, few studies have examined specific features of pregnancy history such as the age of first pregnancy or the possible mechanisms underlying these changes. We examined whether maternal age at first pregnancy and estradiol treatment differentially affected hippocampal neuroplasticity, inflammation, activation, and cognition in middle-age. Thirteen-month-old rats (who were nulliparous (never mothered) or previously primiparous (had a litter) at 3 months or 7 months) received daily injections of estradiol (or sesame oil vehicle) for sixteen days and were tested on the Morris Water Maze. An older age of first pregnancy was associated with impaired spatial memory but improved performance on reversal training, and increased new neurons in the ventral hippocampus compared to the other groups. Estradiol decreased total activation and percent activation of new neurons in the dorsal hippocampus, regardless of parity history. Estradiol also decreased the production of anti-inflammatory cytokines based on age of first pregnancy. This work suggests that estradiol affects neuroplasticity and neuroinflammation in middle age, and that pregnancy history can have long lasting effects on hippocampus structure and function.