A global collaboration has produced the world's most comprehensive atlas of the primate brain, containing 4.2 million cells, revealing the function of specific regions and links to neurological diseases, paving the way for future brain research and disease intervention. More than 4 million cells were analyzed to create the largest atlas to date, helping to explore the evolution of the human brain and new targets for disease and treatment.
科学界长期以来的一个谜团是，1亿多个独立的神经元如何协同工作形成一个网络，从而构成我们这个人的基础--人类的每一种思想、情感和行为。
作为美国国立卫生研究院"脑细胞普查网络"（BrainInitiativeCellCensusNetwork）项目的一部分，绘制这些细胞群的图谱并发现它们的功能一直是全球数十名21世纪分子制图师的长期目标。 The overall goal of the atlas is to aid the development of neuroscience research. The hope is that the project will allow scientists to better understand brain disorders and the elusive medical mysteries behind conditions such as autism and depression.
Now, a new series of studies is revealing broad features of the molecular workings inside the brain at an unprecedented level and scale.
为了更好地了解人类和动物大脑的进化过程，由亚利桑那州立大学、宾夕法尼亚大学、华盛顿大学和布罗特曼-巴蒂研究所的科学家领导的研究小组绘制了世界上最大的灵长类动物大脑图谱。
高级合著者、亚利桑那州立大学生命科学学院和进化与医学中心副教授诺亚-斯奈德-麦克勒（NoahSnyder-Mackler）说："绘制成年灵长类动物大脑中哪些细胞在哪里以及它们在做什么，对于理解人类认知和行为的进化以及确定当事情出错并导致神经系统疾病时会发生什么至关重要。"
Their goal is to identify and examine many brain cells (neuronal and non-neuronal) and perform comprehensive molecular analyzes using state-of-the-art single-cell techniques.
To do this, they used samples from 30 different brain regions to map and build the new map cell by cell. The final map consists of 4.2 million adult primate brain cell maps.
"Our data are the largest and most comprehensive multimodal molecular map of primates to date and are critical for exploring how many cells in the brain fit together to produce complex behaviors in primates, including humans," said senior co-author Jay Shendure, professor of genomic sciences and director of the Brotman Baty Institute at the University of Washington.
"These data will also provide a critical and much-needed map of complex human-related social behaviors and diseases, and provide a basis for determining how these cells and networks are similar and different across species," said senior co-author Michael Platt, a professor in Penn's departments of neuroscience, psychology, and marketing.
The scientists analyzed gene expression (2.58 million transcriptomes) and a complete set of complementary DNA gene regulatory regions (1.59 million episomes) in each cell nucleus. Taken together, this "multi-omics" analysis allowed the authors to study the molecular blueprints that make up different brain cell types, providing the opportunity to study and even manipulate key cells in more detail.
Using gene expression profiling, they were able to identify hundreds of molecularly distinct brain cell types. They also found that cellular composition varies widely throughout the brain, revealing cellular signatures of specific region functions, from neurotransmitters involved in brain cell communication to support cells that help feed and protect the brain from diseases such as Alzheimer's.
They used the data to examine 53 phenotypes associated with risk for neurological diseases, disorders, syndromes, behaviors or other characteristics. Their findings capture known roles for a cell class implicated in neurological disease, including cells involved in myoembolic stroke, or ischemic stroke, the leading cause of death in neurological disease.
They also found that genes associated with Alzheimer's disease tend to be located in regulatory regions of DNA accessible only to microglia, the brain's main immune cells that protect neurons, consistent with the prominent role of microglia proliferation and activation in Alzheimer's disease found in genome-wide association studies (GWAS).
Many of the regulatory regions they discovered were novel, allowing the team to explore the genetic architecture of neurological disease risk at the cellular level. "We found many associations between genetic risk for neurological disease and the epigenomic state of specific cell types - some of which have not yet been linked," said co-first author Kenneth Chiou, a postdoctoral fellow in the UA Center for Evolution and Medicine and the School of Life Sciences.
Another type of cell—basket cells—enriched the most GWAS phenotypes, including diseases such as schizophrenia, bipolar disorder, major depressive disorder, and, most strongly, epilepsy. They also found that Parkinson's disease-related sites were also enriched in open areas of glial OPCs, oligodendrocytes, and astrocytes.
Finally, they found in their analysis that genetic loci associated with attention-deficit/hyperactivity disorder (ADHD) were enriched only in the open regions of medium spiny neurons. Mid-spiny neurons are associated with behavioral hyperactivity and attention disorders through activation of astrocyte-mediated synaptogenesis. Their results suggest that spiny neurons may be a promising new target for future ADHD-related research.
Together, the "polyatomic" maps now provide the global research community with an open resource to further study the evolution of the human brain and identify new targets for disease intervention.