Prenatal neuroinflammation: maternal microbiome contributions and behavioral consequences

产前神经炎症：母体微生物组的贡献和行为后果

• 批准号: 10608201
• 负责人: Tamar Gur
• 金额: $ 55.23万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10608201
• 关键词: Adult; Adult Children; Anxiety; Automobile Driving; Behavior; Behavioral; Blood Vessels; Brain; Breeding; CCL2 gene; Cell Line; Cell Survival; Cells; Central Nervous System; Cytokine Signaling; Data; Development; Exhibits; Exposure to; Fetal Development; Flow Cytometry; Foundations; Future; Gene Modified; Germ-Free; Goals; ITGAM gene; Immune; Immunohistochemistry; Inflammation; Inflammatory; Interdisciplinary Study; Intervention; Label; Ligands; Limbic System; Link; Macrophage; Meninges; Mental Depression; Mental disorders; Microbe; Microglia; Modeling; Mothers; Mus; Myelogenous; Myeloid Cells; Outcome; Pathogenicity; Pathology; Pathway interactions; Play; Population; Prefrontal Cortex; Pregnancy; Production; Resistance; Risk; Role; Social Behavior; Sorting; Source; Stress; Structure of choroid plexus; Testing; Time; Work; beta-Chemokines; chemokine; cytokine; experimental study; fetal; gliogenesis; in utero; intrauterine environment; maternal microbiome; mature animal; microbial; microbial community; microbiome; microbiota; monocyte; mouse model; neural circuit; neurobehavioral; neurodevelopment; neuroinflammation; novel; offspring; prenatal; prenatal stress; prevent; response; single-cell RNA sequencing; social deficits; transmission process

Summary: Prenatal stress is pervasive and negatively impacts both the mother and the developing fetus; offspring bear an increased risk of aberrant neurodevelopment and psychiatric disorders. Indeed, there is a critical window in utero where neurodevelopment is vulnerable to stress-induced alterations in the intrauterine environment, including inflammation; how alterations in the maternal milieu are transmitted to the developing brain, contributing to behavioral alterations, requires scrutinizing. We have established a mouse model of prenatal stress, which in addition to altering maternal and offspring microbiota, induces inflammation in utero, including increases in the chemokine C-C motif chemokine ligand 2 (CCL2), resulting in reduced social behaviors and longstanding neuroinflammation. Furthermore, we have exciting supporting and preliminary data suggesting that normal neurodevelopment is disrupted by prenatal stress in a microbe- and CCL2-dependent manner. As a chemokine, CCL2 has a key role in both attracting myeloid cells and enhancing their inflammatory profile. Within the brain, the myeloid compartment includes microglia, the resident macrophages of the central nervous system; border-associated macrophages (BAMs), which are found in the perivascular space, choroid plexus, and meninges; and circulating monocytes. However, the effects of prenatal stress and CCL2 on the composition of and cytokine production by these subpopulations has yet to be elucidated, and is critical as cytokine signaling is important for homeostatic functions during neurodevelopment, including regulating neuro- and gliogenesis. Therefore, the goal of this R01 is to investigate the relationship between prenatal stress, brain macrophages and monocytes, and social behavior. Our model of prenatal stress will be used to test the highly novel, and integrative hypothesis that, during prenatal stress, there are alterations in the composition of brain macrophages and monocytes in the fetal brain, increasing cytokine production, influencing neurodevelopment. Next, we will determine whether cell-specific elimination of CCL2 production is able to prevent neuroinflammation and subsequent alterations in social behavior. Finally, in an exploratory aim, we will test whether alterations in the maternal microbiome are necessary and sufficient to induce the persistent neuroinflammation and concomitant reduction in social behavior in adult offspring. Our overarching hypothesis is that prenatal stress leads to fetal neuroinflammation that results in long term behavioral abnormalities by altering the composition of macrophages and monocytes in the developing brain and increasing their inflammatory profile, which is driven by disruption of maternal microbes and CCL2. This hypothesis will be tested by pursuing these aims: 1) Determining whether prenatal stress alters the composition of fetal brain macrophages and monocytes 2) Elucidating whether CCL2 drives inflammation in fetal macrophages and monocytes following prenatal stress 3) Determining whether prenatal stress-induced microbiome disruptions drive offspring neuroinflammation and reduced social behaviors.

产前压力是普遍存在的，对母亲和发育中的胎儿都有负面影响; 后代具有增加的异常神经发育和精神障碍的风险。事实上，有一个 子宫内的关键窗口，其中神经发育易受子宫内应激诱导的改变的影响。 环境，包括炎症;母体环境的改变如何传递给发育中的 大脑，有助于行为改变，需要仔细检查。我们建立了一个小鼠模型， 产前压力，除了改变母体和后代的微生物群外，还会诱导子宫内的炎症， 包括趋化因子C-C基序趋化因子配体2（CCL 2）的增加，导致社会性免疫缺陷的减少。 行为和长期的神经炎症。此外，我们有令人兴奋的支持和初步数据， 这表明正常的神经发育被产前压力破坏，这是微生物和CCL 2依赖的。 方式作为一种趋化因子，CCL 2在吸引髓系细胞和增强其分化方面起着关键作用。 炎症特征在脑内，髓样区室包括小胶质细胞， 中枢神经系统;边缘相关巨噬细胞（BAM），发现于血管周围 间隙、脉络丛和脑膜;以及循环单核细胞。然而，产前压力和 CCL 2对这些亚群的组成和细胞因子产生的影响尚未阐明， 细胞因子信号传导对于神经发育过程中的稳态功能至关重要，包括 调节神经元和胶质细胞的生成。因此，本R 01的目标是研究 产前压力，脑巨噬细胞和单核细胞，以及社会行为。我们的产前压力模型 用于检验高度新颖的综合假设，即在产前应激期间， 胎儿脑中脑巨噬细胞和单核细胞的组成，增加细胞因子的产生，影响 神经发育接下来，我们将确定细胞特异性消除CCL 2的产生是否能够 预防神经炎症和随后的社会行为改变。最后，在探索性的目标，我们将 测试母体微生物组的改变是否是必要的和足够的，以诱导持续的 神经炎症和伴随的成年后代社会行为的减少。我们的总体 一种假说是产前应激导致胎儿神经炎症，导致长期的行为障碍， 通过改变发育中的大脑中巨噬细胞和单核细胞的组成， 增加其炎症特征，这是由母体微生物和CCL 2的破坏驱动的。 这一假设将通过以下目标进行检验：1）确定产前压力是否会改变胎儿的生长发育。 2）阐明CCL 2是否驱动胎儿脑巨噬细胞和单核细胞的炎症。 3）确定产前应激是否诱导了胎儿巨噬细胞和单核细胞 微生物组的破坏导致后代神经炎症和减少的社会行为。