A unique peri-hippocampal mast cell population drives neurodevelopment

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 多因素作用，越来越多的证据表明小胶质细胞和外周血细胞等免疫细胞的作用 免疫细胞。了解免疫系统如何调节大脑发育的关键时期是很重要的 对于疾病发展的透彻理解。而常驻髓系细胞、小胶质细胞可以支持细胞 发生、突触形成和髓鞘形成，不太清楚外周免疫细胞在这些过程中的作用 现象。这包括肥大细胞(MC)，这是一种天然免疫细胞，可以脱颗粒释放介质。 包括组胺、细胞因子、生长因子，以及在过敏、炎症和组织修复方面的更多。 我们发现，在大鼠的海马体旁的侧脑室内排列着大量的MC。 这种数量上升，并在出生后第7天达到顶峰，然后下降，因此MC是无法检测到的 第三周，让人想起一个发育关键期。这些高反应性免疫细胞的存在， 与过敏和寄生虫病有关，在严格监管的发育空间中引发了关于 他们此时在这个利基上的生理目的。神经发育的头两周标志着 以及海马神经发生、轴突生长和突触形成的扩张，所有这些都受到影响 通过免疫信号。此外，疾病与MC过多(如肥大细胞增多症)之间的联系 自闭症指出了MC在神经发育中的潜在病理作用。这项提议试图破译 海马区周围巨噬细胞在海马发育关键期的作用。重要的是，这些MC 与大多数组织驻留的MC不同，它具有复制性，并且不是来自外周骨髓来源。我 假设这些MC起源于胚胎卵黄囊，并在胚胎发育过程中为大脑播种，类似地 到小胶质细胞。一种结合流式细胞术的可诱导Cre命运映射系统将在小鼠身上验证这一假说 (Aim 1.1)，然后是RNAScope在大鼠中寻找候选卵黄囊基因(Aim 1.2)，将这一调查带回 我们最初的老鼠模型。对这些MC的初步RNAseq分析发现了与以下相关的基因本体论术语 神经元投射和突触形成等过程，告诉我们这些MC 参与海马区突触发生。在视前区，MC通过组胺改变突触模式 释放，这是一个可行的策略，我们将通过诱导海马区MC脱颗粒和确定 对齿状回树突棘密度的影响2.这些实验将有助于破译 MCS在海马神经发育中的作用，为神经免疫相互作用之谜提供了另一块 在开发过程中。这些实验的完成，以及发育神经学家的指导 玛格丽特·麦卡锡博士和过敏免疫学家Achsah Keegan博士将在 神经免疫学，并为儿科神经病学的内科-科学家职业生涯奠定坚实的基础。

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.