The protective role of environmental enrichment on placental mediators of hypothalamic pituitary adrenal axis dysfunction in a prenatal inflammatory rat model

环境富集对产前炎症大鼠模型下丘脑垂体肾上腺轴功能障碍胎盘介质的保护作用

• 批准号: 10064732
• 负责人: Amanda Kentner
• 金额: $ 2.75万
• 依托单位: MCPHS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10064732
• 关键词: 11-beta-Hydroxysteroid Dehydrogenases; Accounting; Adolescence; Adolescent; Adrenal Glands; Adverse event; Affect; Animals; Attenuated; Behavioral; Brain; Clinical; Cognitive; Complex; Corticosterone; Corticotropin-Releasing Hormone; DNA Methylation; Data; Development; Disease; Down-Regulation; Elderly; Environment; Epigenetic Process; Event; Exposure to; Female; Female Adolescents; Fetal Development; Fetus; Functional disorder; Gene Expression; Glucocorticoid Receptor; Glucocorticoids; Growth; Hippocampus (Brain); Housing; Hypothalamic structure; Immune response; Impairment; Inflammation; Inflammatory; Inflammatory Response; Life; Longevity; Male Adolescents; Maternal Exposure; Mediating; Mediator of activation protein; Medical; Mental disorders; Metabolism; Modeling; National Institute of Mental Health; Neurosecretory Systems; Pathogenesis; Physiological; Pituitary Gland; Placenta; Plasma; Play; Predisposition; Pregnancy; Rattus; Regulation; Risk Factors; Rodent Model; Role; Social Behavior; Social Discrimination; Social Functioning; Social Interaction; Strategic Planning; Stress; System; Time; adolescent offspring; behavioral impairment; biological adaptation to stress; brain behavior; critical period; environmental enrichment for laboratory animals; experimental study; fetal; fetal programming; histone methylation; hypothalamic-pituitary-adrenal axis; immune activation; male; mental development; offspring; postnatal development; prenatal; prevent; prophylactic; protective factors; receptor expression; response; social; stressor

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.

项目摘要：由于参与增长的复杂和高度协调的事件 在怀孕期间，发育中的胎儿的大脑容易受到影响大脑的不良事件的影响。 母体环境尤其是胎盘这些不良事件可能会导致适应性 对后代的优势或持久的脆弱性。这些胎儿损伤的机制 导致疾病的发展是未知的，但涉及相互作用之间的 母体环境和发育中的胎儿有证据表明，产前侮辱，如 炎症，影响下丘脑-垂体-肾上腺（HPA）轴，这在 神经内分泌系统，可能是外部应激影响大脑的机制 发展，占生理中断和相关的行为障碍， 后来的生活。具体来说，由糖皮质激素受体介导的“应激”轴的失调 (GR)，是支持疾病发展发病机制的机制。我们有令人兴奋 大鼠的初步数据显示，产前炎症导致社会交往受损 雄性海马GR表达降低/皮质酮水平升高 青春期的动物值得注意的是，同样的挑战也破坏了青少年中的社会歧视。 雌性后代重要的是，这些影响是可以预防的， 富集（EE）。我们也有数据显示促肾上腺皮质激素释放激素 (CRH)在青春期雌性大鼠产前炎症后的水平，表明社会 雄性和雌性之间的破坏可以通过不同的机制来介导。此外，委员会认为， 我们有初步数据支持母体血浆皮质酮显著增加， 产前炎症后胎盘11-β羟类固醇脱氢酶2降低 挑战.基础和临床证据表明，这些反应在产前 挑战可导致胎儿过量的糖皮质激素暴露和GR表达改变， 在以后的生活中增加对行为变化的敏感性。因此，建议的实验 将研究母体在炎症激发时暴露于EE如何减轻 母体炎症反应直接，从而防止胎儿编程 糖皮质激素功能和后代的社会障碍。第二，我们计划阐明 EE暴露的关键时期（即产前、断奶前、断奶后或两者结合）， 保护暴露于产前炎症的男性和女性青少年后代。 最后，我们将考虑产前炎症和EE的一些表观遗传机制， 可以调节基因表达，解释社会行为的长期变化。