A unique peri-hippocampal mast cell population drives neurodevelopment

独特的海马周围肥大细胞群驱动神经发育

• 批准号: 10823832
• 负责人: Anna Arkadievna Maximova
• 金额: $ 4.02万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10823832
• 关键词: Allergic Disease; Antihistamines; Aorta; Automobile Driving; Axon; Back; Bone Marrow; Brain; Cell Degranulation; Cells; Central Nervous System; Comprehension; Connective Tissue; Curiosities; Cytoplasmic Granules; Dendritic Spines; Development; Disease; Disease Progression; Embryo; Embryonic Development; Etiology; Flow Cytometry; Foundations; Genes; Goals; Growth Factor; Hematopoiesis; Hematopoietic; Hippocampus; Histamine; Histamine Release; Host Defense; Hypersensitivity; Immune; Immune signaling; Immune system; Immunologist; Infection; Infiltration; Inflammation; Injury; Investigation; Life; Link; Maps; Mediating; Mediator; Mentorship; Mesonephric structure; Microglia; Modeling; Mucous Membrane; Mus; Myeloid Cells; Neurodevelopmental Disorder; Neuroglia; Neuroimmune; Neurologic Process; Neurons; Ontology; Parasitic Diseases; Pathologic; Pattern; Pediatric Neurology; Peripheral; Physicians; Physiological; Play; Population; Population Sizes; Preoptic Areas; Process; Proliferating; Rattus; Rodent; Role; Schizophrenia; Scientist; Signal Transduction; Source; Structure; Supporting Cell; Synapses; System; Testing; Time; Tissues; Training; Transcript; Transgenic Mice; Yolk Sac; autism spectrum disorder; brain parenchyma; career; critical developmental period; critical period; cytokine; defined contribution; density; dentate gyrus; experimental study; inducible Cre; lateral line; lateral ventricle; mast cell; mastocytosis; myelination; nervous system development; neural circuit; neurodevelopment; neurogenesis; neuroimmunology; postnatal; synaptogenesis; tissue repair; transcriptome sequencing

Project Summary The etiology of neurodevelopmental diseases such as autism spectrum disorder and schizophrenia is multifactorial, with increasing evidence indicating a role for immune cells such as microglia and peripheral immune cells. Understanding how the immune system regulates critical periods in brain development is important for a thorough comprehension of disease progression. While resident myeloid cells microglia can support cell genesis, synapse formation, and myelination, less clear is the contribution of peripheral immune cells to these phenomena. This includes mast cells (MCs), a type of innate immune cell that degranulates to release mediators including histamine, cytokines, growth factors, and more in the settings of allergy, inflammation, and tissue repair. We have discovered a robust population of MCs lining the lateral ventricles next to the hippocampus in the rat. This population rises in number and peaks at postnatal day 7, then decreases so that MCs are undetectable by week 3, reminiscent of a developmental critical period. The presence of these highly reactive immune cells, associated with allergic and parasitic diseases, in a tightly regulated developmental space raises questions about their physiological purpose in this niche at this time. The first two weeks of neurodevelopment mark the beginning and expansion of hippocampal neurogenesis, axon outgrowth, and synaptogenesis, all of which are impacted by immune signaling. Additionally, links between diseases with an overabundance of MCs (e.g., mastocytosis) and autism point to a potential pathological role for MCs in neurodevelopment. This proposal seeks to decipher the role of peri-hippocampal MCs during a critical period in hippocampal development. Importantly, these MCs are replicative, unlike most tissue-resident MCs, and do not originate from peripheral bone marrow sources. I hypothesize that these MCs originate from the embryonic yolk sac and seed the brain in embryogenesis, similarly to microglia. An inducible Cre fate-mapping system combined with flow cytometry will test this hypothesis in mice (Aim 1.1), followed by RNAscope for candidate yolk sac genes in rats (Aim 1.2), bringing this investigation back to our original rat model. Preliminary RNAseq analysis on these MCs uncovered gene ontology terms related to processes such as neuronal projection and synapse formation, informing our hypothesis that these MCs participate in hippocampal synaptogenesis. In the preoptic area, MCs alter synaptic patterning via histamine release, a viable strategy that we will explore by inducing peri-hippocampal MC degranulation and determining the effect on dentate gyrus dendritic spine density in Aim 2. These experiments will help decipher the role of MCs in hippocampal neurodevelopment, providing another piece in the puzzle of neuroimmune interactions during development. Completion of these experiments, as well as mentorship from developmental neuroscientist Dr. Margaret McCarthy and allergy immunologist Dr. Achsah Keegan, will provide comprehensive training in neuroimmunology and establish a strong foundation for a physician-scientist career in pediatric neurology.

项目摘要 自闭症谱系障碍和精神分裂症等神经发育疾病的病因是 多因素，越来越多的证据表明免疫细胞（如小胶质细胞和周围）的作用 免疫细胞。了解免疫系统如何调节大脑发育的关键时期很重要 为了彻底理解疾病进展。而常驻髓样细胞小胶质细胞可以支持细胞 创世纪，突触形成和髓鞘形成，周围免疫细胞对这些的贡献尚不清楚 现象。这包括肥大细胞（MCS），一种先天免疫细胞，脱粒以释放介体 在过敏，炎症和组织修复的环境中，包括组胺，细胞因子，生长因子以及更多。 我们发现了大鼠海马旁边的侧心壁架的强大人群。 该人口的数量上升，在产后第7天达到高峰，然后减少，以使MC无法检测到 第3周，让人联想到发展的关键时期。这些高反应性免疫细胞的存在， 与过敏和寄生疾病相关，在严格监管的发展空间中， 他们目前在这个利基市场中的生理目的。神经发育的前两周标志着开始 海马神经发生，轴突出生和突触发生的扩展，所有这些都受到影响 通过免疫信号传导。另外，与MC的过度疾病之间的联系（例如，肥大症） 自闭症指出了MC在神经发育中的潜在病理作用。该提议试图破译 在关键时期，海马在海马发育中的作用。重要的是，这些MC 具有复制性，与大多数组织居住的MC不同，并且不是源自外围骨髓来源。我 假设这些MC源自胚胎蛋黄囊，并在胚胎中播种大脑，类似地 至小胶质细胞。诱导的CRE命运映射系统与流式细胞术结合使用，将在小鼠中检验此假设 （AIM 1.1），其次是大鼠候选蛋黄基因的rnascope（AIM 1.2），将这项调查带回 到我们的原始大鼠模型。对这些MC的初步RNASEQ分析发现了与 神经元投影和突触形成等过程，告知我们这些MCS的假设 参与海马突触发生。在原始区域，MCS通过组胺改变突触模式 释放是一种可行的策略 AIM 2中对齿状回树突密度的影响。这些实验将有助于破译的作用 海马神经发育中的MC，在神经免疫相互作用的难题中提供了另一个作品 在开发过程中。这些实验的完成以及发展神经科学家的指导 玛格丽特·麦卡锡（Margaret McCarthy）博士和过敏免疫学家Achsah Keegan博士将提供全面的培训 神经免疫学并为儿科神经病学的医师科学家事业奠定了坚实的基础。