Reduction of the Olfactory Bulb and Reuse of its Inhibitory Neurons in the Primate Cerebrum

灵长类大脑中嗅球的减少及其抑制性神经元的再利用

• 批准号: 10689297
• 负责人: Matthew T Schmitz
• 金额: $ 2.24万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10689297
• 关键词: Adult; Animal Model; Automobile Driving; Basal Ganglia; Birth; Brain; Cell Density; Cell Lineage; Cell Nucleus; Cells; Cerebral cortex; Cerebrum; Cognition; Computer Vision Systems; Corpus striatum structure; Coupled; Cues; Data; Destinations; Development; Disease; Disparate; Equilibrium; Evolution; External Capsule; Failure; Fellowship; Fostering; Foundations; Future; Genomics; Goals; Hand; Health; Heterogeneity; Human; Image; Immunofluorescence Immunologic; Immunofluorescence Microscopy; In Vitro; Interneurons; Lateral; Location; Logic; Macaca; Macaca mulatta; Maps; Medial; Medicine; Methods; Modality; Modeling; Mus; Neurons; Neurosciences; Olfactory Cortex; Parkinson Disease; Periodicity; Phenotype; Pluripotent Stem Cells; Pollen; Population; Pregnancy; Primates; Reporting; Resolution; Role; Schizophrenia; Scientist; Series; Signal Transduction; Specific qualifier value; Stream; Structure; System; Testing; Translating; Tyrosine 3-Monooxygenase; Work; cell type; density; dopamine system; induced pluripotent stem cell; inhibitory neuron; migration; mouse model; nerve stem cell; nervous system disorder; newborn neuron; novel; olfactory bulb; single nucleus RNA-sequencing; single-cell RNA sequencing; stem cell differentiation; stem cell model; transcriptomics; white matter

PROJECT SUMMARY/ABSTRACT Inhibitory neurons are critical to the balance of excitation and inhibition, rhythmic activity and logic-based computation that underlies healthy brain function. The lateral ganglionic eminence (LGE) of the developing brain is well known to give rise to inhibitory olfactory bulb neurons and projection neurons of the basal ganglia in the mouse. In the rhesus macaque brain, I have shown that the LGE also generates large numbers of white matter inhibitory neurons and tyrosine hydroxylase-expressing striatal interneurons. These poorly-understood cell types have not been studied in the human brain. However striatal dopamine system failure in Parkinson's disease and an abnormal density of neurons in the white matter in schizophrenia suggests possible intersection between this lineage of neurons and devastating neurological diseases. While the olfactory bulb is diminished relative to the cerebral cortex in rhesus macaques when compared to mice, it is even more so in humans. Understanding what has changed in primate brain evolution is key to translating findings in animal models to human medicine, and how neurological disease may arise due to novel features, which have not been "tuned" by extended evolution. I hypothesize that evolutionary forces increasing the size of the cortex and conjoined LGE domain, coupled with the simultaneous decrease in size of the olfactory bulb has caused a progressive redistribution of olfactory bulb inhibitory neurons to the cortex and striatum. In my first aim, I propose to use imaging to quantify these cell densities across species and to test the sufficiency of olfactory bulb reduction to cause redistribution. In my second aim I propose to study the transcriptomic divergence of newborn neurons from their common LGE origin to distinct cortical and olfactory bulb types using single nucleus RNA sequencing. Then, I will examine the signaling cues that may drive this divergence using an induced pluripotent stem cell differentiation system. My sponsor Alex Pollen has pioneered the use of pluripotent stem cell models of brain development to study the context of human brain evolution across species. My co-sponsor Arturo Alvarez-Buylla has performed much of the foundational work in mapping the birth of the inhibitory neurons of the mouse olfactory bulb, and has deep expertise in experimental developmental neuroscience. My co-sponsor, Dr. Chun (Jimmie) Ye, has an expertise in experimental and statistical single cell genomics and has developed cutting-edge methods that will facilitate the project. This work will investigate uncharacterized, novelly redistributed cells in the primate brain, and will inform future efforts toward understanding the role of these cells in health and disease. Fellowship support for this project will foster my developing expertise to achieve my ultimate goal of becoming an independent academic scientist leading a combined experimental and computational developmental neuroscience group.

项目摘要/摘要 抑制性神经元对兴奋和抑制的平衡、节律性活动和基于逻辑的 作为健康大脑功能基础的计算。发育中的外侧神经节隆起(LGE) 众所周知，大脑产生抑制性嗅球神经元和基底神经节的投射神经元。 在老鼠身上。在恒河猴的大脑中，我已经证明了LGE也会产生大量的白色 物质抑制神经元和表达酪氨酸羟基酶的纹状体中间神经元。这些鲜为人知的东西 在人脑中还没有研究过细胞类型。然而，帕金森病患者的纹状体多巴胺系统衰竭 精神分裂症患者的疾病和白质神经元密度异常提示可能 这种神经元谱系和毁灭性的神经疾病之间的交集。而嗅球是 与小鼠相比，猕猴大脑皮质的相对含量降低，在 人类。了解灵长类动物大脑进化的变化是翻译动物研究结果的关键 人类医学的模型，以及神经疾病如何由于新的特征而发生，这些新特征还没有 通过扩展进化进行了“调整”。我假设进化的力量增加了 皮质和连接的LGE区域，伴随着嗅觉大小的同时减小 嗅球抑制神经元逐渐重新分布到大脑皮层， 纹状体。在我的第一个目标中，我建议使用成像来量化这些跨物种的细胞密度，并测试 是否有足够的嗅球缩小以引起再分配。在我的第二个目标中，我建议研究 新生神经元从共同的LGE来源到不同的皮质和嗅觉的转录分化 鳞茎类型采用单核RNA测序。然后，我将研究可能驱动这一点的信号提示 利用诱导多能干细胞分化系统进行分化。我的赞助人亚历克斯·波伦 首创使用大脑发育的多潜能干细胞模型来研究人类大脑的背景 物种间的进化。我的联合赞助人Arturo Alvarez-Buylla在 绘制小鼠嗅球抑制神经元的诞生图，并在实验方面拥有深厚的专业知识 发展神经科学。我的联合赞助人，春(吉米)叶博士，在实验和 统计单细胞基因组学，并开发了将促进该项目的尖端方法。这 这项工作将研究灵长类动物大脑中未表征的、新的重新分布的细胞，并将向未来提供信息 努力了解这些细胞在健康和疾病中的作用。对该项目的奖学金支持 将培养我的发展专长，以实现我成为一名独立学术科学家的最终目标 领导一个实验和计算相结合的发育神经科学小组。