Wednesday, February 5, 2025
2/5/2025
Project Summary: Due to the complex and highly orchestrated events that are involved in growth during gestation, the brain of the developing fetus is susceptible to adverse events that affect the maternal environment, specifically the placenta. These adverse events can confer either adaptive advantages or lasting vulnerabilities to the offspring. The mechanism by which these fetal insults contribute to the development of disease is not known but involves interactions between the maternal environment and the developing fetus. Evidence suggests that prenatal insults, such as inflammation, impact the hypothalamic-pituitary-adrenal (HPA) axis, which plays a major role in the neuroendocrine system and may be the mechanism by which external stressors impact brain development, accounting for physiological disruptions and associated behavioral impairments in later life. Specifically, the dysregulation of the “stress” axis, mediated by glucocorticoid receptors (GR), is a mechanism that supports the pathogenesis of disease development. We have exciting preliminary data in rats showing that prenatal inflammation leads to impaired social interactions and decreased GR expression/elevated corticosterone levels in the hippocampus of male adolescent animals. Notably, this same challenge disrupts social discrimination in adolescent female offspring. Importantly, these effects are preventable with lifelong housing in environmental enrichment (EE). We also have data demonstrating disrupted corticotropin-releasing hormone (CRH) levels in adolescent female rats following prenatal inflammation, suggesting that social disruptions between males and females may be mediated through separate mechanisms. Moreover, we have preliminary data supporting a significant increase in maternal plasma corticosterone and reduced placental 11-beta hydroxysteroid dehydrogenase 2 following prenatal inflammatory challenge. Converging basic and clinical evidence suggests that these responses following prenatal challenges can result in excess glucocorticoid exposure to the fetus and altered GR expression, increasing susceptibility to behavioral changes later in life. Therefore, the proposed experiments will examine how maternal exposure to EE at the time of inflammatory challenge may attenuate the maternal inflammatory response directly, thereby preventing fetal programming of glucocorticoid function and later social impairments in the offspring. Second, we plan to elucidate the critical periods of EE exposure (i.e. prenatal, preweaning, postweaning, or a combination) that confer protection to in male and female adolescent offspring exposed to prenatal inflammation. Finally, we will consider some epigenetic mechanisms by which prenatal inflammation and EE may regulate gene expression, accounting for long-term changes in social behaviors.
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