U01 - Lein 1U01MH114812-01

A Multimodal Atlas of Human Brain Cell Types

This project takes an international consortium approach using single cell transcriptomics, human cellular physiology and anatomy, and neuronal modeling to begin to create an atlas of human brain cell types as a community data resource.  The project is structured around two main components to study different cellular properties in human tissues.  The first approach uses transcriptomics to survey cell types across the brain, and to study detailed cellular diversity in several structures relevant for neuropsychiatric disease including the hippocampus and dorsolateral prefrontal cortex.  The second approach aims to characterize the anatomical and physiological properties of transcriptionally-defined cortical neurons in living human tissues derived from neurosurgical resections to treat epilepsy or brain tumors. The project aims to standardize methods for human Patch-seq using patch clamp slice electrophysiology to study the structure, function and molecular properties of cortical cell types.  Finally, tools will be developed 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.  All of these data will be mapped to a 3D human common coordinate framework.  The outcome will be the first detailed study of human brain cell types and the development of standardized methods for human brain study.

This project includes the following research goals:

  • Broad transcriptomic survey of ~100 regions of adult postmortem human brain and spinal cord
  • Deep transcriptomic analysis of hippocampus and dorsolateral prefrontal cortex
  • Molecular, anatomical and physiological characterization of human cell types in living human cortical slices
  • Histological analysis of neurosurgical specimens
  • 3D annotation of MNI human common coordinate space for mapping human samples
  • Cell type classification, neuronal modeling and cross-species comparative analysis

 


Project Leadership

Ed Lein, PhD (Principal Investigator) 
Investigator, Allen Institute for Brain Science, Seattle, Washington, USA 
https://www.alleninstitute.org/what-we-do/brain-science/about/team/staff-profiles/ed-lein/ 

 

Sten Linnarsson, PhD (Co-Investigator) 
Professor of Molecular Systems Biology, Karolinska Institutet, Stockholm, Sweden 
http://linnarssonlab.org/ 

 

Gábor Tamás, PhD (Co-Investigator) 
Professor, MTA-SZTE Research Group for Cortical Microcircuits, Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged, Hungary 
http://tamaslab.org/ 

 

Huib Mansvelder, PhD (Co-Investigator) 
Professor, Center for Neurogenomics and Cognitive Research, Vrije Universiteit, Amsterdam, Netherlands 
https://inf.cncr.nl/people/mansvelder_hd 

 

Idan Segev, PhD (Co-Investigator) 
Professor of Computational Neuroscience, The Hebrew University, Jerusalem, Israel 
http://lobster.ls.huji.ac.il/idan/ 


Project Data Types

  • Deep transcriptomic analysis of hippocampus and dorsolateral prefrontal cortex in adult human postmortem brain using single nucleus RNA-seq employing SMART-Seq v4 methodology
  • Broad survey of ~100 regions of adult human brain and spinal cord using a modified  10X Genomics Chromium V2 methodology
  • Triple modality (electrophysiology, morphology and transcriptomics) Patch-seq analysis of excitatory and inhibitory neurons in neurosurgically resected human cortical tissues
  • Histological analysis of neurosurgical specimens used for Patch-seq analysis

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