Mechanisms of maternal high-fat diet induced brain changes

母亲高脂饮食引起大脑变化的机制

• 批准号: 10523046
• 负责人: Alexis Marie Ceasrine
• 金额: $ 3.26万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-05 至 2022-11-04
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10523046
• 关键词: Address; Adult; Adult Children; Affect; Anxiety; Area; Behavior; Behavioral; Biological Availability; Brain; Catabolism; Chronic; Correlative Study; Data; Decidua Basalis; Defect; Development; Disease; Embryo; Environment; Fat-Restricted Diet; Female; Fetal Development; Genetic; Goals; Growth; High Fat Diet; High Pressure Liquid Chromatography; Homeostasis; Immune; Impairment; Incidence; Inflammation; Inflammatory; Inflammatory Response; Kynurenine; Link; Mediator of activation protein; Mental Depression; Mental disorders; Metabolic; Microglia; Mus; Nature; Neonatal; Neuroimmune; Neurological outcome; Neurons; Neurophysiology - biologic function; Obesity; Outcome; Overweight; Perinatal; Phagocytosis; Placenta; Play; Predisposition; Prefrontal Cortex; Pregnancy; Preventive treatment; Production; Prosencephalon; Research; Rodent; Role; Serotonergic System; Serotonin; Sex Bias; Signal Transduction; Source; Stress; Supplementation; Systems Development; Testing; Toll-like receptors; Translating; Tryptophan; United States; Woman; Yolk Sac; autism spectrum disorder; behavior change; behavioral outcome; brain shape; cytokine; dietary control; fetal; immune activation; in utero; inflammatory marker; macrophage; male; maternal obesity; molecular targeted therapies; mouse model; nerve stem cell; nerve supply; neural circuit; neural network; neurodevelopment; novel; offspring; pregnant; prenatal; prevent; progenitor; raphe nuclei; relating to nervous system; response; sex

Project Summary More than 50% of women in the United States are overweight or obese when they become pregnant. Maternal high-fat diet (HFD) and obesity create an environment of chronic inflammation and are associated with a range of detrimental outcomes for offspring, including metabolic dysregulation and increased susceptibility to psychiatric disorders such as autism spectrum disorder, anxiety, and depression. Despite these observations, many studies are correlative and do not propose a mechanism through which maternal HFD or obesity contribute to psychiatric disorder development in the offspring. The placenta acts as a critical interface between the maternal environment and the developing fetal brain, and as such is uniquely poised to translate maternal insults into neural outcomes in offspring. The placenta is the primary source of serotonin for the fetal forebrain during mid-gestation, and decreased serotonin signaling is correlated with increased vulnerability to stress in rodents. Importantly, serotonin levels can be decreased in the context of inflammation, and we hypothesize that placental inflammation induced by maternal HFD may reduce placental serotonin levels thus altering the development of the central serotonin system and causing serotonin circuit-dependent behavior changes in mice. Preliminarily, we see that maternal HFD increases placental inflammation particularly in males. Increased placental inflammation in males is correlated with decreased placental and fetal forebrain serotonin levels. Moreover, male maternal HFD offspring also display behavior alterations consistent with disrupted central serotonin circuit function. Therefore, in Aim 1, I will determine if maternal HFD-induced serotonin deficiency is causal to male-specific behavior changes. Building upon this, I will then use a mouse model incapable of producing a pro-inflammatory response in placental macrophages to asses if maternal HFD-induced perinatal inflammation is causal to (i) male-specific serotonin deficiency and (ii) serotonin-circuit relevant behavior changes. Finally, I will address a possible mechanism through which maternal HFD affects the central serotonin system. Previous studies have suggested that microglia regulate neural development and behavioral outcomes, and that the number and activation state of microglia in utero influences microglia phagocytosis of neuronal progenitors. This has not been explored in the context of serotonergic neuronal progenitors. Therefore, I will assess if microglia phagocytosis of serotonin neurons is increased in maternal HFD offspring, and whether this results in decreased serotonin levels in the forebrain thus influencing maternal HFD-dependent neurological outcomes. I expect this project to result in several novel findings by bridging three bodies of research that are only beginning to collaborate: (i) the contribution of maternal HFD to sex-biased psychiatric disorder development, (ii) the role of the placenta in neurodevelopment and disease, and (iii) the influence of microglia on the development of the serotonergic neural network.

项目摘要 超过50%的美国女性在怀孕时超重或肥胖。 母亲的高脂饮食（HFD）和肥胖创造了一个慢性炎症的环境， 一系列对后代有害的结果，包括代谢失调和对 精神障碍，如自闭症谱系障碍、焦虑和抑郁。尽管有这些意见， 许多研究是相关的，没有提出母体HFD或肥胖的作用机制 与后代的精神疾病发展有很大关系胎盘作为一个重要的界面， 母亲的环境和发育中的胎儿大脑，因此是独特的准备翻译母亲的侮辱， 转化为后代的神经功能胎盘是胎儿前脑5-羟色胺的主要来源， 在啮齿类动物中，5-羟色胺信号的减少与对压力的脆弱性增加有关。 重要的是，血清素水平可以在炎症的情况下降低，我们假设胎盘 由母体HFD诱导的炎症可能降低胎盘5-羟色胺水平，从而改变 中枢5-羟色胺系统并引起小鼠5-羟色胺回路依赖性行为改变。 首先，我们看到母体HFD增加胎盘炎症，特别是在男性中。增加 男性的胎盘炎症与胎盘和胎儿前脑5-羟色胺水平降低相关。 此外，雄性母体HFD后代也表现出与中枢神经系统受损一致的行为改变， 血清素回路功能因此，在目标1中，我将确定母亲HFD诱导的5-羟色胺缺乏是否是 导致男性特有的行为变化。在此基础上，我将使用一种小鼠模型， 在胎盘巨噬细胞中产生促炎反应以评估母体HFD诱导的围产期 炎症是由（i）男性特异性5-羟色胺缺乏和（ii）肾上腺素循环相关行为引起的 变化最后，我将讨论一个可能的机制，通过母体HFD影响中枢5-羟色胺 系统先前的研究表明，小胶质细胞调节神经发育和行为结果， 子宫内小胶质细胞的数量和激活状态影响小胶质细胞对神经元的吞噬作用， 祖先这还没有在多巴胺能神经元祖细胞的背景下进行探索。所以我会 评估母体HFD后代中5-羟色胺神经元的小胶质细胞吞噬作用是否增加，以及这是否 导致前脑5-羟色胺水平降低，从而影响母体HFD依赖性神经系统 结果。我希望这个项目能通过连接三个研究机构， 才刚刚开始合作：（一）母亲HFD性别偏见的精神障碍的贡献 发育，（ii）胎盘在神经发育和疾病中的作用，以及（iii）小胶质细胞的影响 关于神经网络的发展。

项目成果

Maternal diet disrupts the placenta-brain axis in a sex-specific manner.

母体饮食以性别特定方式破坏胎盘脑轴。

• DOI: 10.1038/s42255-022-00693-8
• 发表时间: 2022-12
• 期刊: NATURE METABOLISM
• 影响因子: 20.8
• 作者: Ceasrine, Alexis M.;Devlin, Benjamin A.;Bolton, Jessica L.;Green, Lauren A.;Jo, Young Chan;Huynh, Carolyn;Patrick, Bailey;Washington, Kamryn;Sanchez, Cristina L.;Joo, Faith;Campos-Salazar, A. Brayan;Lockshin, Elana R.;Kuhn, Cynthia;Murphy, Susan K.;Simmons, Leigh Ann;Bilbo, Staci D.
• 通讯作者: Bilbo, Staci D.

Prenatal environmental stressors impair postnatal microglia function and adult behavior in males.

• DOI: 10.1016/j.celrep.2022.111161
• 发表时间: 2022-08-02
• 期刊: CELL REPORTS
• 影响因子: 8.8
• 作者: Block, Carina L.;Eroglu, Oznur;Mague, Stephen D.;Smith, Caroline J.;Ceasrine, Alexis M.;Sriworarat, Chaichontat;Blount, Cameron;Beben, Kathleen A.;Malacon, Karen E.;Ndubuizu, Nkemdilim;Talbot, Austin;Gallagher, Neil M.;Jo, Young Chan;Nyangacha, Timothy;Carlson, David E.;Dzirasa, Kafui;Eroglu, Cagla;Bilbo, Staci D.
• 通讯作者: Bilbo, Staci D.