Increased Anxiety-like Behavior and Stress Responses in the Adult Rat Offspring of Maternally Immune-activated Dams

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Maternal immune activation (MIA) can occur during pregnancy due to infectious diseases or other inflammatory conditions. Resiquimod (RQ), a toll-like receptor (TLR) 7 agonist, induces inflammatory responses and mimics responses to viral infections. We previously showed that prenatal stressors increase anxiety-like behavior and dysregulation of neuroendocrine and autonomic function in adult offspring. The current project further investigates the degree to which late-gestation MIA with RQ impacts offspring development, anxiety-like behavior, and neuroendocrine function. Pregnant rat dams were injected with vehicle (phosphate-buffered saline) or RQ (1 mg/kg, s.c.) on gestation day 18. Tests were conducted in offspring before (3-4wks old) and after (8-10wks old) puberty. Open field tests assessed anxiety-like behavior, and a 20-minute restraint tube stress test assessed products of hypothalamic-pituitary-adrenal (HPA) axis activation. In-utero MIA exposure did not affect birth weights or early-life developmental milestones (i.e., the timing of eye opening, righting reflex). The female offspring of MIA dams experienced a significant delay (~1 day) in vaginal opening, suggesting delayed pubertal onset. Before puberty, MIA did not affect offspring open field assessments, nor were there differences in levels of the glucocorticoid corticosterone (CORT) in plasma following restraint. After puberty, male and female offspring of MIA dams showed increased anxiety-like behavior (F(1,42)=4.701, p=0.0359). Plasma CORT concentrations following restraint also trended higher in the adult female offspring of dams exposed to RQ (F(1,22)=3.337, p=0.0813), but with a higher suggested average in all the adult offspring of MIA dams compared to controls. We also measured proteins involved in the synthesis of norepinephrine/epinephrine (i.e., tyrosine hydroxylase (TH) and dopamine-beta-hydroxylase (DBH)), the degradation of norepinephrine/epinephrine (i.e., catechol-o-methyltransferase (COMT)), and the degradation of acetylcholine (i.e., acetylcholinesterase (AChE)) within the left ventricle of the heart. Adult female offspring express higher levels of TH (F(1,13) = 4.365, p=0.0569), DBH (F(1,13)=7.628, P=0.0162), COMT (F(1,13)=9.009, p=0.0102), and AChE (F(1,13)=4.105, p=0.0638) compared to males, regardless of prenatal MIA exposure. The results support MIA-induced dysregulation of the HPA axis and anxiety-like behavior only in adult offspring, suggesting that gonadal hormones and aging play a critical role in programming changes associated with in-utero MIA exposure. This project is funded by ORWH-NIMH 3U54MH118919 and ORWH-NIMH 3U54MH118919-04S3. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

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