Abstract: A Multimodal Atlas of Human Brain Cell Types Cell types are the building blocks of the brain, including the neuron types forming specific neuronal circuits responsible for perception, cognition and action, and the non-neuronal elements performing other essential roles for proper brain function. A deep understanding of cell types is essential to understand brain structure and function, as well as mechanisms underlying dysfunction in disorders and injury, which in general affect specific cellular components either through underlying genetic abnormalities or through selective vulnerability to insults and injury. Despite the obvious importance of cell types, our understanding of their diversity, specific properties and discreteness is highly incomplete. This is particularly true in the human brain, where technological limitations, lack of access to living brain tissues, and the sheer size and complexity has hampered progress; however, a new set of molecular, anatomical and physiological tools and techniques are now available that work in brain tissue both from model organisms and human. Standardization and scale-up of these techniques offers to dramatically change the field by providing a broad and deep understanding of the building blocks of the human brain, and their conserved and unique features. We propose here to bring together an interdisciplinary consortium of world leaders in single cell transcriptomics, human cellular physiology and anatomy, and neuronal modeling to create a comprehensive atlas of human brain cell types as a community data resource. The foundation of this atlas is a molecular classification of cell types based on large-scale single cell transcriptomics, combining a broad survey of cell types across the entire brain and spinal cord with a deep analysis of the neocortex and hippocampus, regions in which it is possible to analyze functional and anatomical properties of cells in living neurosurgical resections. The distribution of these molecular cell types will be mapped on tissue sections using single molecular multiplex fluorescent in situ hybridization to create a quantitative census of cell types in different brain regions. To understand the properties of these molecular cell types, we will standardize methods across a consortium of experts in human slice patch clamp electrophysiology to study the structure, function and molecular properties of cortical cell types. Finally, we will derive tools to classify cell types, perform neuronal modeling to understand and predict the function of cell types, and compare cell type properties between mouse and human. The outcome will be the first detailed atlas of human brain cell types and the development of standardized methods for human brain study that are likely to catalyze rapid progress in basic and clinical neuroscience.

Narrative: The brain is a complex organ consisting of a huge number of cell types, and many if not all brain disorders are a consequence of disruptions in specific cell types either through underlying genetic abnormalities or selective consequences of injury or trauma. Our understanding of brain cell types is highly incomplete, even in experimentally tractable model organisms, much to the detriment of basic and applied clinical research, but a new set of molecular, anatomical and physiological techniques are available to study them in human postmortem and living neurosurgically-resected brain tissues. The atlas of human brain cell types proposed here will fill this information void by standardizing and scaling methods for single cell analysis in human tissue and generating a first of its kind community data resource that will catalyze a new field of inquiry in brain function and disease at the level of its component cell types.