SUN-019 Maternal Immune Activation Alters Adult Offspring Responses to Stress and Immune Stimulation

Abstract Disclosure: E.A. Castellanos: None. M. Roueinfar: None. L. Schwerdtfeger: None. S.A. Tobet: None. Maternal stressors can program offspring stress and immune responses into adulthood. This process has been linked to an increased risk of neuropsychiatric disorders, including major depressive disorder (MDD). Previous research in mice has used the toll-like receptor 7 (TLR7) agonist, resiquimod, in a maternal immune activation (MIA) model of prenatal stress [Sheng et al., 2024: Brain Behav Immun Integr. 8:100081]. Offspring from resiquimod treated mothers show changes in anxiety-like traits, social deficits and female selective changes in anhedonia and hypothalamic-pituitary-adrenal (HPA) axis sensitivity to restraint stress. The current study administered resiquimod to mothers in late gestation (E12.5) and subsequently injected post-pubertal offspring i.p. with the pro-inflammatory cytokine TNFα (63 µg/kg). Plasma samples were collected at 90 minutes to assess corticosterone release and 4 hours post-injection to assess the release of IL-6, IL1β, IL-17a, and IL-10. Preliminary results show a decrease in corticosterone levels at 90 minutes in prenatal resiquimod exposed mice, regardless of sex. At 4 hours post TNFα injection, there was greater increase in plasma IL-6 concentrations in MIA offspring compared to vehicle-treated controls (p<0.05). There was a trend for IL-6 to be impacted more in female mice than males (females p<0.0001, males p<0.01). No significant differences in plasma concentrations of IL-1β and IL-17a were observed among groups. Brains from other mice processed for immunohistochemistry (IHC) for the transcription factor zinc finger and BTB domain containing 16 (Zbtb16; a gene known to impact cytokine secretion) showed stress and glucocorticoid induction of mRNA and protein in the paraventricular nucleus of the hypothalamus (PVN). In the context of the current study after post-pubertal TNFα injection, neurons in the PVN also upregulated immunoreactive cFOS and Zbtb16. These findings suggest that MIA exposure induces heightened immune reactivity, with MIA-dependent increases in IL-6 after challenge with TNFα, potentially overriding an HPA corticosterone response. The integration of past and current findings underscores the significant impact of prenatal immune stress on neuroendocrine and immune system function after puberty. Ongoing studies of the interactions between autonomic and HPA-associated nuclei, with peripheral pro-inflammatory cytokine challenges, may indicate brain substrates susceptible to developmental programming of immune responses. Presentation: Sunday, July 13, 2025