Impact of Mid and Late-gestation Toll-like Receptor 7 Stimulation on Development and Anxiety-like Behavior in Offspring

Abstract

Maternal immune activation (MIA) can occur during pregnancy due to exposure to infectious diseases or other inflammatory conditions. MIA is a risk factor for various psychiatric disorders, such as major depressive disorder, as well as cardiac disorders in the offspring. Resiquimod (R-848), a toll-like receptor (TLR) 7 agonist, induces systemic inflammatory responses and mimics responses to viral infections. Previous studies have shown that MIA with a TLR 4 agonist lipopolysaccharide or the viral mimic, TLR 3 agonist polyinosinic:polycytidylic acid produces neuropsychiatric effects in the offspring. The current project investigates the degree to which mid and late-gestation MIA with R-848 impacts offspring development and anxiety-like behavior. Pregnant rat dams received vehicle (phosphate-buffered saline) or R-848 (1 mg/kg, s.c.) injections on gestation day (GD) 14 (mid-gestation) or GD18 (late gestation). Maternal body weight as well as offspring body weight, developmental milestones, and anxiety-like behavior were assessed. Although all dams gained weight throughout pregnancy, the R-848 dams from both injection days displayed pronounced weight fluctuations post-injection, with a trend toward attenuated weight gain in dams injected in late gestation. On postnatal day 21 (PND21), the R-848 dams injected on GD14 had significantly lower body weights (p=0.007) compared to the vehicle dams, whereas the body weights of the R-848 dams injected on GD18 did not differ significantly from the vehicles. Litter size, male-to-female ratio, and birth weight were also not affected by R-848. Semi-weekly offspring weights were not statistically different between any experimental groups by sex during any measured week in the mid-gestation-exposed cohort, but both male and female R-848-exposed offspring in the late-gestation exposure cohort displayed significantly decreased body weights at week 7 (males, p=0.0282 and females, p=0.0009). Eye opening, an important developmental milestone, was not different between the vehicle and R-848 pups regardless of the timing of exposure. Open field testing in the mid-gestation-exposed adult offspring revealed no significant locomotion differences or differences in time spent in the center zone. Open field testing in the late-gestation-exposed adult offspring also revealed no locomotion differences, however, the R-848-exposed female offspring spent markedly less time in the center zone than all other groups. These findings suggest that late gestation R-848 exposure results in attenuated maternal weight gain as well as increased anxiety-like behaviors in female offspring. Future exploration of pre-pubertal stages and assessments of autonomic regulation in offspring exposed to R-848 in late gestation will provide further insight into the long-term consequences of immune activation during pregnancy. NIH U54 MH118919. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.