8611 Maternal Immune Activation During Mid-Gestation Leads to Impaired Neuroendocrine Stress Response and Blood-Brain Barrier Integrity in a Sex-Dependent Manner

Abstract Disclosure: J.A. Sheng: None. S.A. Tobet: None. Background and Hypothesis: Maternal immune activation (MIA) has been associated with increased risk for neuropsychiatric diseases in the offspring. Recently, our lab demonstrated toll-like receptor 7 (TLR7) activation during impaired stress-related behaviors (anxiety-, anhedonia-, social-like) (Sheng et al., 2023, Front. Neurosci.). Stress-related behaviors are regulated by neurons in the paraventricular nucleus of the hypothalamus (PVN), an anatomic region involved in the hypothalamic-pituitary-adrenal (HPA) stress response. We hypothesize immune system activation by TLR7 during mid-gestation impairs PVN neuroendocrine stress response and brain vasculature. Methods: Timed-pregnant female mice were administered the TLR7 agonist Resiquimod (RQ) or vehicle saline on embryonic day 12.5. Adult offspring underwent 20-minute acute restraint stress with 80-minutes of recovery to examine plasma corticosterone (ELISA assay) as an indicator of HPA function. Mice were transcardially perfused with fluorescein isothiocyanate (FITC; 100mg/mL) to visualize blood vessel integrity (FITC leakage; Frahm & Tobet, 2015, Brain Struct. Funct.). Sections through the PVN of offspring were also immunolabeled for Glial Fibrillary Acidic Protein (GFAP; astrocytic end feet) and IBA-1 (microglia). Only data from brains of offspring that did not undergo restraint stress are presented for baseline changes in blood-brain barrier components by MIA. Results: Plasma corticosterone was elevated in RQ-offspring (males p<0.0001, females p<0.01 vs. VEH) following stressor and recovery, suggesting delayed negative feedback to the HPA axis. Blood-brain barrier integrity diminished in RQ-adult offspring who showed greater FITC leakage in the PVN as indicated by an increase in the ratio of extravascular to intravascular FITC (males p<0.001, females p<0.01). GFAP+ coverage of FITC-labeled vessels was greater in the PVN only in RQ males compared to VEH (p<0.001). Microglia were examined in relation to vasculature, and data show more IBA-1+ cells in the PVN with close proximity (within 2µm) to blood vessels after maternal injection of RQ in females compared to VEH (p<0.05). In RQ-adult males, the average size of IBA-1+ cells in the PVN were greater than VEH counterparts (p<0.05), but number and proximity of IBA-1+ cells to blood vessels were unchanged. No changes in these measures were seen in control brain regions. Conclusions: This study provides support for sex-dependent influences of fetal immune antecedents on brain development and adult neuroendocrine function that could indicate a locus for increased susceptibility to adult neuropsychiatric disorders. While the current experiments found significant post-pubertal changes selectively in adult PVN, ongoing studies are examining whether these effects are evident prior to puberty. Supported by ORWH-NIMH U54 SCORE-MH118919. Presentation: 6/1/2024