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 多因素的，越来越多的证据表明免疫细胞，如小胶质细胞和外周血淋巴细胞， 免疫细胞了解免疫系统如何调节大脑发育的关键时期非常重要 全面了解疾病进展。而常驻髓样细胞小胶质细胞可以支持细胞 在神经元发生、突触形成和髓鞘形成过程中，外周免疫细胞对这些过程的作用不太清楚。 现象。这包括肥大细胞（MC），一种脱颗粒释放介质的先天免疫细胞 包括组胺、细胞因子、生长因子，以及更多在过敏、炎症和组织修复中的应用。 我们已经发现了一个强大的人口MC内衬侧脑室旁边的大鼠海马。 这一群体的数量增加，并在出生后第7天达到峰值，然后下降，使得MC无法通过 第三周，让人想起一个发展的关键时期。这些高反应性免疫细胞的存在， 与过敏性和寄生虫病有关，在一个严格管制的发展空间提出了问题， 他们此时在这个生态位的生理目的。神经发育的前两周标志着 以及海马神经发生、轴突生长和突触发生的扩展，所有这些都受到影响， 免疫信号。此外，疾病与MC过多之间的联系（例如，肥大细胞增多症） 和孤独症指出了MC在神经发育中的潜在病理作用。这项提案旨在解读 海马周围MCs在海马发育关键期的作用。重要的是，这些MC 是复制型的，不像大多数组织驻留的MC，并且不起源于外周骨髓来源。我 假设这些MC起源于胚胎卵黄囊，并在胚胎发育中播种大脑，类似地， 到小胶质细胞一个可诱导的Cre基因定位系统结合流式细胞术将在小鼠中检验这一假设 (Aim 1.1），随后是大鼠中候选卵黄囊基因的RNAscope（目的1.2）， 我们最初的老鼠模型。对这些MC的初步RNAseq分析揭示了与以下相关的基因本体论术语： 过程，如神经元投射和突触形成，告知我们的假设，这些MC 参与海马突触的形成。在视前区，MC通过组胺改变突触模式 释放，一个可行的策略，我们将探索通过诱导海马周围MC脱粒和确定 目的2对齿状回树突棘密度的影响。这些实验将有助于破译 海马神经发育中的MC，提供了神经免疫相互作用的另一块拼图 在发展过程中。完成这些实验，以及来自发展神经科学家的指导 博士玛格丽特麦卡锡和过敏免疫学家博士Achsah基冈，将提供全面的培训， 神经免疫学，并建立了一个强大的基础，在儿科神经学的医生，科学家的职业生涯。