The BRAIN initiative cell census network calls for large-scale, comprehensive approaches to define the composition of the mammalian brain at the cellular level and using an overall strategy that integrates multimodal information (morphology, connectivity, molecules etc..) within a Common Coordinated Framework (CCF) to enable distribution, validation, integration and use of the atlas by the community. The BICCN challenge is enormous and remains a scientific problem requiring new discovery, continuous innovation in methods, technologies and pipeline of analysis. Given the unparalleled cellular diversity of the mouse brain and the need for an informed cell classification scheme, we propose here an ambitious project that addresses both the need for scale (coverage of millions of cells) and depth of analysis of each cell and, further, that integrates molecular and anatomical information. To address this challenge, we have assembled a collaborative group of key knowledge leaders and innovators across various fields of neuroscience, genomics, and technology. First, we will apply transformative new droplet scRNA sequencing technologies and next-generation computational methods and data processing pipelines to compile a whole brain cell transcriptome atlas on a massive scale (millions of single cells and nuclei collected brainwide). This effort will generate an unprecedented inventory of cell type composition and distribution for the mouse brain within the CCF. Second, we will generate a forebrain neuronal atlas that will integrate detailed molecular information (to saturation) of anatomically defined populations with high-resolution morphological and connectivity information to provide an in-depth picture of a core portion of the mammalian brain. We will also generate highly specific driver lines for precise marking of cell types and to enable adaptive methods that refine cell sampling to achieve completeness. Finally, realizing the need for innovation in technology to enable work that is made difficult because it requires both scale and precision, we will devote key effort to develop new integrated technological platforms that combine multiple methods to relate neuronal connectivity with transcriptomes and cellular distribution at an unprecedented scale. Our Data Core will integrate, store, and manage multi-modal datasets and provide bioinformatics and computational expertise;? and our Administrative Core, will coordinate and oversee Center-wide activities. Our effort is unprecedented for scale and coverage, and it relies on a team of investigators with demonstrated academic track records of innovation in technology and neurobiology, working in an environment that allows for implementation of massive pipelines for production workflow. This will guarantee progressive evolution and innovation of methods, experimental design and analysis to meet future challenges and succeed at generating a comprehensive molecular and anatomical atlas of the mouse brain.
We propose to develop and integrate molecular, anatomic, imaging, and computational technologies and pipelines to build a broad Whole-Brain Cell Transcriptome Atlas that provides an overview of the cell diversity and composition within the mouse brain, integrated with a high-resolution Forebrain Neuronal Atlas that combines comprehensive and in-depth anatomic and molecular characterization of forebrain projection neurons, into a Common Coordinate Framework (CCF)-compatible spatial atlas.
| He, Miao; Huang, Z Josh (2018) Genetic approaches to access cell types in mammalian nervous systems. Curr Opin Neurobiol 50:109-118 |
