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

项目概要/摘要 抑制性神经元对兴奋与抑制的平衡、节律性活动和基于逻辑的 健康大脑功能的基础。发育中的侧神经节隆起（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。在恒河猴的大脑中，我已经证明LGE也产生大量的白色 物质抑制性神经元和表达酪氨酸羟化酶的纹状体中间神经元。这些鲜为人知的 人类大脑中的细胞类型尚未研究过。然而，帕金森氏症患者的纹状体多巴胺系统衰竭 精神分裂症患者的白色物质中神经元密度异常提示可能存在 神经元谱系和毁灭性神经疾病之间的交叉点。当嗅球 与小鼠相比，恒河猴的大脑皮层相对减少， 人类了解灵长类动物大脑进化中的变化是将动物研究结果转化为现实的关键。 人类医学的模型，以及神经系统疾病如何可能由于新的特征而出现，这些特征还没有 被扩展进化所“调整”。我假设进化的力量增加了 皮质和相连的LGE结构域，加上嗅觉的大小同时减少， 嗅球引起嗅球抑制神经元向皮质进行性重新分布， 纹状体在我的第一个目标中，我建议使用成像来量化这些细胞密度， 嗅球的减少足以引起再分配。在我的第二个目标中，我建议研究 新生神经元从其共同的LGE起源到不同的皮层和嗅觉的转录组分歧 鳞茎类型使用单核RNA测序。然后，我将研究可能驱动这一点的信号线索， 使用诱导的多能干细胞分化系统的趋异。我的担保人亚历克斯·波伦 开创了使用大脑发育的多能干细胞模型来研究人类大脑的背景 跨物种进化我的共同赞助人Arturo Alvarez-Buylla在2010年完成了大部分基础工作， 绘制小鼠嗅球抑制性神经元的诞生，并在实验研究方面具有深厚的专业知识。 发展神经科学我的共同赞助人，博士春（吉米）叶，具有实验和 统计单细胞基因组学，并已开发出尖端的方法，将促进该项目。这 这项工作将研究灵长类动物大脑中未被表征的、新奇的重新分布的细胞，并将为未来的研究提供信息。 努力了解这些细胞在健康和疾病中的作用。对本项目的研究金支助 我将培养我不断发展的专业知识，以实现我成为一名独立的学术科学家的最终目标 领导一个实验和计算发展神经科学联合小组。

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.