Understanding brain cell type diversity across spatial and functional scales

最近的技术进步使神经科学家能够收集大量关于脑细胞功能的数据。这些数据类型包括神经元电活动，详细的树突和轴突形状，以及基因组中每个基因的mRNA表达模式。尽管在收集数据方面取得了这些进步，但我们组织和分析这些复杂数据集的能力并没有跟上。这项提案是为了支持我的研究项目，重点是进一步了解健康脑细胞的功能，以及这些功能在衰老和疾病中如何改变。我的研究项目有几个相互关联的方面：方面1)建立网络数据库来组织、存储和可视化神经元电活动模式。我们的工作包括加强NeuroElectro.org，这是我们的公共网络资源和细胞内电生理学数据库。了解基因表达如何驱动脑细胞结构和功能。这包括开发工具来处理强大的新数据类型，如PatchSeq，将细胞内电生理学与单细胞RNA测序相结合。方面3)发现进化如何促进了哺乳动物谱系中神经元功能的特化。通过与实验同事的合作，我们有独特的途径获取来自小鼠、猴子和人类的神经元生理学和基因表达谱数据集。识别大脑细胞类型，如抑制性神经元亚型和星形胶质细胞，如何在健康人类衰老过程中发生变化，在神经精神疾病中发生改变，并受到常见遗传变异的影响。我的研究项目是独一无二的，它将基础和临床神经科学与神经信息学和数据科学相结合。我们与多个实验小组密切合作，这些互动经常形成我们具体的研究问题。我们实验室的一个重点是开发可以被世界各地的研究人员广泛应用的开源工具和资源。该奖项将用于资助在上述各个方面工作的研究生和本科生以及博士后的培训。这些受训者代表了下一代神经科学家，他们同样精通神经生物学和遗传学，以及计算机科学和数据科学。

Recent technology advances have enabled neuroscientists to collect massive amounts of data on how brain cells function. These data types include neuron electrical activity, detailed dendrite and axon shapes, and mRNA expression patterns for every gene in the genome. Despite these advances in collecting data, our ability to organize and analyze these complex datasets has not kept up. This proposal is to support my research program focused on furthering our knowledge of how healthy brain cells function and how these functions are altered in aging and disease. My research program has several inter-related aspects: Aspect 1)Building web databases to organize, store, and visualize neuron electrical activity patterns. Our efforts include enhancing NeuroElectro.org, our public web resource and database for intracellular electrophysiology. Aspect 2)Understanding how gene expression drives brain cell structure and function. This includes developing tools for processing powerful new data types like PatchSeq, that combine intracellular electrophysiology with single-cell RNA sequencing. Aspect 3)Discovering how evolution has contributed to the specialization of neuron function across the mammalian lineage. By collaborating with experimental colleagues, we have unique access to datasets on neuron physiology and gene expression profiles from mice, monkeys, and humans. Aspect 4)Identifying how brain cell types, like inhibitory neuron subtypes and astrocytes, change over healthy human aging, are altered in neuropsychiatric disease, and are affected by common genetic variants. My research program is unique in its integration of basic and clinical neuroscience with neuroinformatics and data science. We work closely with multiple experimental groups and these interactions often shape our specific research questions. A key focus for our lab is developing open source tools and resources that can be broadly applied by researchers throughout the world. This award would be used to fund the training of graduate and undergraduate students and post-docs working on each of the aspects listed above. These trainees represent the next generation of neuroscientists who are equally versed in neurobiology and genetics as well as computer science and data science.