Sex Differences in the Neuro-immune Profile of the Developing Brain

大脑发育中神经免疫特征的性别差异

• 批准号: 10405947
• 负责人: Erin Reinl
• 金额: $ 3.63万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2022-03-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10405947
• 关键词: Address; Adhesions; Adult; Affect; Anterior; Antibodies; Area; Biological Assay; Biological Factors; Blocking Antibodies; Blood - brain barrier anatomy; Bone Marrow; Brain; Brain region; Cell Adhesion; Cells; Cerebellum; Chronic; Communication; Complement; Development; Dextrans; Disease; Dyes; Endothelium; Etiology; Exhibits; Exposure to; Extravasation; Female; Flow Cytometry; Focused Ultrasound; Gene Expression; Hippocampus (Brain); Immune; Immune system; Immunofluorescence Immunologic; Immunohistochemistry; Immunologic Surveillance; Inflammation; Inflammatory; Knowledge; Label; Laboratories; Life; Location; Measures; Meninges; Mental Health; Methods; Microglia; Minocycline; Neonatal; Nervous system structure; Neurodevelopmental Disorder; Neuroimmune; Neurons; Neuropil; New York City; Organ; Outcome; Perinatal; Perinatal Infection; Peripheral; Permeability; Preoptic Areas; Prostaglandins; Rattus; Reporting; Risk; Schizophrenia; Sex Differences; Signal Transduction; Signaling Molecule; Stains; Stimulus; Subway; Testing; Tolonium chloride; Travel; Tube; Work; autism onset; blood-brain barrier permeabilization; bone; cell motility; developmental disease; developmental neurobiology; differences in access; early onset; high risk; immune activation; immunoregulation; male; mast cell; neonatal brain; neonate; neurodevelopment; neuropsychiatric disorder; novel; postnatal; postnatal period; reproductive tract; response; seal; sex; sexual dimorphism; social defeat; trafficking

Project Summary Though once considered completely isolated from the immune system, we now know the brain is under constant immune surveillance and that there is two-way communication between the CNS and immune organs like the bone marrow. Similarly, we have come to understand that sex is one of the strongest biological factors influencing development, and that sex differences extend far beyond the reproductive tract. Males are at higher risk for developmental disorders including autism and early onset schizophrenia, diseases associated with maternal immune activation (MIA). Additionally, there are surprisingly consistent reports of the developing male brain exhibiting higher levels of inflammatory signaling molecules, immune cells and gene expression profiles indicative of immune activation compared to female brains even under normal healthy conditions. The McCarthy laboratory has recently observed an increased number of mast cells in the sexually dimorphic preoptic area (POA) of male rats, and that female rats had a greater number of mast cells in the surrounding meninges than in the neuropil of the POA, suggesting differential regulation of immune cell migration to this area. The central hypothesis of this proposal is that inherent sex differences in neonatal neuro-immune cell trafficking increases male vulnerability to neurodevelopmental disorders in response to immune activation. The rationale and long- term objective for this work is to elucidate sex differences in the neonatal neuro-immune profile, in order to better understand the etiology of neurodevelopmental disease. This will be addressed by three aims. 1) Quantify the immune cell composition of the meninges and periventricular neuropil. The hypothesis is that differential immune cell trafficking to the CNS in males and females is important to healthy neural development. This predicts that the sexes will differ in the immune cell content of their meninges and neuropil compartments. Immune cell composition of the meninges and the periventricular neuropil of male and female neonatal rats will be quantified by flow cytometry and immunohistochemistry of meninges, POA, hippocampus and anterior cerebellum. 2) Compare blood-brain-barrier integrity in male and female neonatal rats. The working hypothesis is that under basal conditions during the early postnatal period, the male brain is more accessible to immune cell trafficking by way of increased barrier permeability. This will be tested by measuring sex differences in BBB integrity and expression of endothelial, immune cell adhesion, and extravasation markers, and assessing the relationship between BBB permeability and immune cell migration. 3) Determine the effect of maternal immune activation on immune cell trafficking in the neonate, maintaining sex as a factor. The working hypothesis is that males have more negative outcomes in response to perinatal immune activation because their BBB is more fragile in response to inflammation. This hypothesis predicts that males exposed to MIA will have reduced BBB integrity, increased adhesion and extravasation markers, and increased immune cell migration to periventricular brain regions.

项目摘要 虽然曾经被认为与免疫系统完全隔离，但我们现在知道大脑处于 持续的免疫监视，CNS和免疫器官之间存在双向交流 比如骨髓同样地，我们也逐渐了解到，性是最强的生物因素之一 影响发育，性别差异远远超出生殖道。男性在更高的 发育障碍的风险，包括自闭症和早发性精神分裂症， 母体免疫激活（MIA）。此外，有令人惊讶的一致报告说，发展中的男性 大脑表现出更高水平的炎症信号分子、免疫细胞和基因表达谱 这表明即使在正常健康条件下，与女性大脑相比，也存在免疫激活。麦卡锡 一个实验室最近观察到在性二态视前区肥大细胞数量增加 (POA)雄性大鼠，雌性大鼠脑膜周围的肥大细胞数量多于雄性大鼠， 在POA的神经细胞中，表明免疫细胞迁移到该区域的差异调节。中央 该建议的假设是，新生儿神经免疫细胞运输的固有性别差异增加 男性易受免疫激活引起的神经发育障碍的影响。其基本原理和长期- 这项工作的长期目标是阐明新生儿神经免疫谱的性别差异，以便更好地 了解神经发育疾病的病因。这将通过三个目标来解决。1)量化 免疫细胞组成的脑膜和脑室周围神经。假设是， 在雄性和雌性中，免疫细胞向CNS的运输对于健康的神经发育是重要的。这 预测男女在脑膜和神经节隔室的免疫细胞含量上会有所不同。 雄性和雌性新生大鼠脑膜和脑室周围神经鞘的免疫细胞组成将 通过脑膜、POA、海马和前额叶的流式细胞术和免疫组织化学定量 小脑2)比较雄性和雌性新生大鼠的血脑屏障完整性。工作 假设是，在出生后早期的基础条件下，男性大脑更容易接触到 免疫细胞通过增加屏障通透性的方式运输。这将通过测量性别差异来检验 BBB完整性和内皮细胞、免疫细胞粘附和外渗标志物的表达，并评估 血脑屏障通透性与免疫细胞迁移的关系。3)确定产妇的效果 免疫激活对新生儿免疫细胞运输的影响，维持性别作为一个因素。工作 一种假设是，男性对围产期免疫激活的反应具有更多的负面结果， 血脑屏障对炎症的反应更脆弱。这一假设预测，暴露于MIA的男性将有 BBB完整性降低，粘附和外渗标志物增加，免疫细胞迁移增加， 脑室周围脑区