Pregnancy history and estradiol influence spatial memory, hippocampal plasticity, and inflammation in middle-aged rats.

Pregnancy and motherhood 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, partly due to differences in age of initiation, type of menopause, dose, formulation and route of administration. Additionally, past pregnancy influences brain aging and cognition as a younger age of first pregnancy in humans is associated with poorer aging outcomes. However, few animal studies have examined specific features of pregnancy history or the possible mechanisms underlying these changes. We examined whether maternal age at first pregnancy and estradiol differentially affected hippocampal neuroplasticity, inflammation, spatial reference cognition, and immediate early gene activation in response to spatial memory retrieval in middle-age. Thirteen-month-old rats (who were nulliparous (never mothered) or previously primiparous (had a litter) at three or seven months) received daily injections of estradiol (or 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 number of new neurons in the ventral hippocampus. Estradiol decreased 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 age of first pregnancy can have long lasting effects on hippocampus structure and function.

Beyond sex differences: short- and long-term effects of pregnancy on the brain.

Growing attention has been directed to the inclusion of females in neuroscience studies, and to the importance of studying sex as a biological variable. However, how female-specific factors such as menopause and pregnancy, affect the brain remains understudied. In this review, we use pregnancy as a case in point of a female-unique experience that can alter neuroplasticity, neuroinflammation, and cognition. We examine studies in both humans and rodents indicating that pregnancy can modify neural function in the short term, as well as alter the trajectory of brain aging. Furthermore, we discuss the influence of maternal age, fetal sex, number of pregnancies, and presence of pregnancy complications on brain health outcomes. We conclude by encouraging the scientific community to prioritize researching female health by recognizing and including factors such as pregnancy history in research.

Steroid hormones and hippocampal neurogenesis in the adult mammalian brain.

Hippocampal neurogenesis persists across the lifespan in many species, including rodents and humans, and is associated with cognitive performance and the pathogenesis of neurodegenerative disease and psychiatric disorders. Neurogenesis is modulated by steroid hormones that change across development and differ between the sexes in rodents and humans. Here, we discuss the effects of stress and glucocorticoid exposure from gestation to adulthood as well as the effects of androgens and estrogens in adulthood on neurogenesis in the hippocampus. Throughout the review we highlight sex differences in the effects of steroid hormones on neurogenesis and how they may relate to hippocampal function and disease. These data highlight the importance of examining age and sex when evaluating the effects of steroid hormones on hippocampal neurogenesis.

Sex Differences and Estradiol Effects in MAPK and Akt Cell Signaling across Subregions of the Hippocampus.

INTRODUCTION: Rapid effects of estrogens within the hippocampus of rodents are dependent upon cell-signaling cascades, and activation of these cascades by estrogens varies by sex. Whether these pathways are rapidly activated within the dentate gyrus (DG) and CA1 by estrogens across sex and the anatomical longitudinal axis has been overlooked. METHODS: Gonadally intact female and male rats were given either vehicle or physiological systemic low (1.1 µg/kg) or high (37.3 µg/kg) doses of 17ß-estradiol 30 min prior to tissue collection. To control for the effects of circulating estrogens, an additional group of female rats was ovariectomized (OVX) and administered 17ß-estradiol. Brains were extracted, and tissue punches of the CA1 and DG were taken along the longitudinal hippocampal axis (dorsal and ventral) and analyzed for key mitogen-activated protein kinase (MAPK) and protein kinase B (Akt) cascade phosphoproteins. RESULTS: Intact females had higher Akt pathway phosphoproteins (pAkt, pGSK-3ß, and pp70S6K) than males in the DG (dorsal and ventral) and lower pERK1/2 in the dorsal DG. Most effects of 17ß-estradiol on cell signaling occurred in OVX animals. In OVX animals, 17ß-estradiol increased cell signaling of MAPK and Akt phosphoproteins (pERK1/2, pJNK, pAkt, and pGSK-3ß) in the CA1 and pERK1/2 and pJNK DG. DISCUSSION/CONCLUSIONS: Systemic 17ß-estradiol treatment rapidly alters phosphoprotein levels in the hippocampus, dependent on reproductive status, and intact females have greater expression of Akt phosphoproteins than that in intact males in the DG. These findings shed light on underlying mechanisms of sex differences in hippocampal function and response to interventions that affect MAPK or Akt signaling.