UPDATED
Scientists unveil complete cell map of a whole mammalian brain
NIH-funded atlas characterizes over 32 million cells across the mouse brain
For the first time ever, an international team of researchers has created a complete cell atlas of a whole mammalian brain. This atlas serves as a map for the mouse brain, describing the type, location, and molecular information of more than 32 million cells and providing information on connectivity between these cells. The mouse is the most commonly used vertebrate experimental model in neuroscience research, and this cellular map paves the way for a greater understanding of the human brain—arguably the most powerful computer in the world. The cell atlas also lays the foundation for the development of a new generation of precision therapeutics for people with mental and neurological disorders of the brain.
The findings were funded by the National Institutes of Health’s Brain Research Through Advancing Innovative Neurotechnologies® Initiative, or The BRAIN Initiative®, and appear in a collection of 10 papers published in Nature.
“The mouse atlas has brought the intricate network of mammalian brain cells into unprecedented focus, giving researchers the details needed to understand human brain function and diseases,” said Joshua A. Gordon, M.D., Ph.D., Director of the National Institute of Mental Health, part of the National Institutes of Health.
The cell atlas describes the types of cells in each region of the mouse brain and their organization within those regions. In addition to this structural information, the cell atlas provides an incredibly detailed catalog of the cell’s transcriptome—the complete set of gene readouts in a cell, which contains instructions for making proteins and other cellular products. The transcriptomic information included in the atlas is hierarchically organized, detailing cell classes, subclasses, and thousands of individual cell clusters within the brain.
The atlas also characterizes the cell epigenome—chemical modifications to a cell’s DNA and chromosomes that alter the way the cell’s genetic information is expressed—detailing thousands of epigenomic cell types and millions of candidate genetic regulation elements for different brain cell types.
Together, the structural, transcriptomic, and epigenetic information included in this atlas provide an unprecedented map of cellular organization and diversity across the mouse brain. The atlas also provides an accounting of the neurotransmitters and neuropeptides used by different cells and the relationship among cell types within the brain. This information can be used as a detailed blueprint for how chemical signals are initiated and transmitted in different parts of the brain. Those electrical signals are the basis for how brain circuits operate and how the brain functions overall.
“This product is a testament to the power of this unprecedented, cross-cutting collaboration and paves our path for more precision brain treatments,” said John Ngai, Ph.D., Director of the NIH BRAIN Initiative.”
Of the 10 studies included in this collection, seven are funded through the NIH BRAIN Initiative Cell Census Network (BICCN), and two are funded through the larger NIH BRAIN Initiative. The core aim of the BICCN, a groundbreaking, cross-collaborative effort to understand the brain’s cellular makeup, is to develop a comprehensive inventory of the cells in the brain—where they are, how they develop, how they work together, and how they regulate their activity—to better understand how brain disorders develop, progress, and are best treated.
“By leveraging the unique nature of its multi-disciplinary and international collaboration, the BICCN was able to accomplish what no other team of scientists has been able to before,” said Dr. Ngai. “Now we are ready to take the next big step—completing the cell maps of the human brain and the nonhuman primate brain.”
The BRAIN Initiative Cell Atlas Network (BICAN) is the next stage in the NIH BRAIN Initiative’s effort to understand the cell and cellular functions of the mammalian brain. BICAN is a transformative project that, together with two other large-scale projects—the BRAIN Initiative Connectivity Across Scales and the Armamentarium for Precision Brain Cell Access—aim to revolutionize neuroscience research by illuminating foundational principles governing the circuit basis of behavior and informing new approaches to treating human brain disorders.
Reference: Yao, Z., van Velthoven, C. T. J., Kunst, M., Zhang, M., McMillen, D., Lee, C., Jung, W., Goldy, J., Abdelhak, A., Aitken, M., Baker, K., Baker, P., Barkan, E., Bertagnolli, D., Bhandiwad, A., Bielstein, C., Bishwakarma, P., Campos, J., Carey, D., … Zeng, H. (2023). A high-resolution transcriptomic and spatial atlas of cell types in the whole mouse brain. Nature. https://www.nature.com/articles/s41586-023-06812-z
JOURNAL
Nature
Scientists unveil first complete cellular map of adult mouse brain
High-resolution atlas charts neural neighborhoods for more than 5,300 cell types
IMAGE:
DETAILED CLASSIFICATION AND DISTRIBUTION OF CELL TYPES IN THE ENTIRE MOUSE BRAIN BASED ON THE EXPRESSION OF THEIR GENES. MORE THAN 5000 CELL TYPES HAVE BEEN IDENTIFIED AND CAN BE GROUPED BASED ON THEIR SIMILARITY TO EACH OTHER. EACH OF THE GROUPS WAS PLOTTED AS A UMAP TO HIGHLIGHT THE RELATIONSHIPS BETWEEN CELL TYPES IN SPECIFIC GROUPS AND EACH GROUP CAN BE ASSIGNED TO SPECIFIC ANATOMICAL LOCATION.
view moreCREDIT: ALLEN INSTITUTE
By Jake Siegel
Six years and 32 million cells later, scientists have created the first full cellular map of a mammalian brain. In a set of 10 papers in Nature today, a network of researchers unveiled an atlas cataloging the location and type of every cell in the adult mouse brain. Using advanced technologies that profile individual cells, the teams identified over 5,300 cell types – far more than known before – and pinpointed their locations within the brain’s intricate geography.
Having a complete “parts list” of the brain will help accelerate efforts to unravel how it works, said Hongkui Zeng, Ph.D., Executive Vice President and Director of the Allen Institute for Brain Science.
“This is a landmark achievement that really opens the door for the next stage of investigations of the brain’s function, development and evolution, akin to the reference genomes for studying gene function and genomic evolution,” said Zeng, who led one of the studies. “My colleagues said that the 5,000 cell types we identified will keep neuroscientists busy for the next 20 years trying to figure out what these cell types do and how they change in disease.”
The collective work is a capstone for the National Institutes of Health’s BRAIN Initiative Cell Census Network, or BICCN. Hundreds of researchers contributed to the project, which was funded by the NIH’s Brain Research Through Advancing Innovative Neurotechnologies® (BRAIN) Initiative, or The BRAIN Initiative®.
“Where we previously stood in darkness, this milestone achievement shines a bright light, giving researchers access to the location, function, and pathways between cell types and cell groups in a way we couldn’t imagine previously,” said John Ngai, Ph.D., Director of the NIH BRAIN Initiative. “This product is a testament to the power of this unprecedented, cross-cutting collaboration and paves our path for more precision brain treatments.”
Location, location, location
By combining single-cell RNA sequencing with spatial transcriptomics—methods for determining which genes are expressed in individual cells and where those cells are located—Zeng and her collaborators revealed the brain’s astonishing complexity and diversity.
One of the atlas's major revelations is the deep connection between a cell's genetic identity and its spatial position, Zeng said. This relationship underscores how location shapes function, offering clues into the evolutionary history and intricate interactions of different brain regions.
“We’re seeing the building blocks of the brain’s circuits,” she said. “The brain’s organization likely reflects its evolutionary history.”
One intriguing finding is the distinct cellular organization between the lower (“ventral”) versus the upper (“dorsal”) parts of the brain. While the ancient ventral part features a mosaic of interrelated cells, the more recent dorsal part contains fewer but highly divergent cell types. This distinction could be a key to deciphering how different brain regions evolved unique roles, for example, the ventral part for basic survival and the dorsal part for adaptation, Zeng said.
The researchers also found that transcription factors – proteins that regulate gene activity – comprise a 'code' that specifies a cell’s identity.
The atlas also uncovered how brain cells talk to each other via a diverse cast of signaling molecules, which carry messages from cell to cell. That diversity enables complex interactions between different cell types.
The strong alignment across independently collected genomic, epigenomic, and spatial datasets provides high confidence that this atlas maps more than just cell identities – it captures the true organizational blueprints underlying mammalian brain development, Zeng said.
Looking ahead, the atlas can serve as a model for similar mappings in the brains of other species—namely our own. That work is already underway.
It also provides a guide to genetically target specific cell types, enabling tools to study specific functions and disease. This could pave the way for precision treatments, Zeng said.
“We know that many diseases originate in specific parts of the brain, and probably in specific cell types,” she said. “With this map in hand, we can gain a more precise view of the dysfunction of disease and then create genetic or pharmacologic tools to target those specific cell types, to achieve greater efficacy and minimal side effects.”
Allen Institute scientists also co-led a study to create a detailed map of the neurons that connect the brain to the spinal cord, enabling movement and sensory modulation. In this study, a team led by Zhigang He, Ph.D., and Carla Winter, M.D., Ph.D., of Harvard provide the most in-depth characterization of these spinal-projecting neurons (SPNs) to date. By integrating the molecular identities and locations of these neurons into one atlas, scientists gain insight into how this intricate network controls function and movement. "And by having a baseline map of these cell types, we can now study how spinal cord injuries or stroke alter them and hopefully develop targeted therapies," said Winter.
Allen Institute scientists contributed to five other studies, including:
- A spatial atlas of cell types in the whole mouse brain. In this study, led by Xiaowei Zhuang, Ph.D., of Harvard, scientists used spatially resolved transcriptomic profiling of >1,100 genes to reveal the spatial organization of >5,000 transcriptionally distinct clusters across the entire mouse brain. Registration of the cell atlas to the Allen Common Coordinate Framework allows quantification of cell type composition and organization in each brain region. The high-resolution spatial map reveals cell-cell interactions and molecular underpinnings between hundreds of cell-type pairs.
- A comparison of gene regulatory programs across different species, including humans. In this study, researchers analyzed certain regions of DNA that act like switches, turning genes on or off and controlling a cell’s identity. The team found that so-called jumping genes—DNA sequences that can flit about the genome—make up the bulk of human-specific “switches” in the neocortex. As these same regions can also be involved in neurodegenerative diseases, further study could point the way to new therapies, the authors said. “This data is a gold mine for geneticists who can now start to uncover the molecular basis of complex traits like schizophrenia,” said Bing Ren, Ph.D., of UCSD, who co-led the study with the Salk Institute’s Joseph Ecker, Ph.D.
About the Allen Institute
The Allen Institute is an independent, 501(c)(3) nonprofit research organization founded by philanthropist and visionary, the late Paul G. Allen. The Allen Institute is dedicated to answering some of the biggest questions in bioscience and accelerating research worldwide. The Institute is a recognized leader in large-scale research with a commitment to an open science model. Its research institutes and programs include the Allen Institute for Brain Science, launched in 2003; the Allen Institute for Cell Science, launched in 2014; the Allen Institute for Immunology, launched in 2018; and the Allen Institute for Neural Dynamics, launched in 2021. In 2016, the Allen Institute expanded its reach with the launch of The Paul G. Allen Frontiers Group, which identifies pioneers with new ideas to expand the boundaries of knowledge and make the world better. For more information, visit alleninstitute.org.
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JOURNAL
Nature
METHOD OF RESEARCH
Imaging analysis
SUBJECT OF RESEARCH
Animals
ARTICLE TITLE
BICCN Whole Mouse Brain 2023 Paper Package
ARTICLE PUBLICATION DATE
13-Dec-2023
Scientists create a comprehensive atlas of cell types in a mammalian brain
Broad researchers use spatial transcriptomics to map the locations of thousands of cell types across a whole mouse brain, paving the way for similar efforts in humans.
IMAGE:
THE RESEARCHERS ANALYZED 101 SLIDE-SEQ SLICES ACROSS A SINGLE MOUSE BRAIN, GIVING THEM A DEEP AND COMPREHENSIVE VIEW OF CELL TYPES ACROSS THE BRAIN. IN THIS VISUALIZATION, SLICES ARE STACKED TO ILLUSTRATE COVERAGE OF KNOWN MAJOR REGIONS OF THE MOUSE BRAIN, SHOWN IN DIFFERENT COLORS FOR REFERENCE.
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CREDIT: MACOSKO AND CHEN LABS, BROAD INSTITUTE OF MIT AND HARVARD
December 13, 2023 (Cambridge, MA) — A team of scientists at the Broad Institute of MIT and Harvard has generated one of the first comprehensive maps of cell types in a mammalian brain using recently developed technology called spatial transcriptomics, which can reveal not just the gene activity of individual cells, but also their location within tissues and organs.
The atlas, described in Nature, delineates several thousand cell populations across the entire mouse brain, revealing surprising cellular diversity in understudied brain regions and offering deeper views of brain structures than were possible before. The effort was led by Evan Macosko, an institute member at the Broad and associate professor and attending psychiatrist at Massachusetts General Hospital, and Fei Chen, a core institute member at the Broad and an assistant professor in the Department of Stem Cell and Regenerative Biology at Harvard University. Both are senior authors on the paper.
The team measured the activity of all genes in the genome of individual cells throughout the mouse brain, and assigned the cells’ locations within the tissue. Their analysis uncovered an estimated 90 percent of all cell populations in the mouse brain. The scientists found most cellular diversity within relatively understudied subcortical areas of the brain, especially the midbrain, pons, medulla, and the hypothalamus. “We suspected the most diversity would be found in these areas, so we prioritized them in our profiling,” said Macosko. “A lot of the real nuts and bolts stuff that a brain is doing is in these basic areas, which have received very little attention compared to the cortex. Our results underscore the need to study them more deeply.” The researchers also discovered clues about cellular function and the potential roles of brain structures in disease.
“Efforts like these generate crucial resources for the neuroscience community, because the brain is so enormously complicated,” said Chen.
Macosko added, “Our atlas represents the culmination of a decade of work at the Broad. Fei and I developed the technology in our labs and used it to process the largest single-cell and spatial dataset ever generated, leading to the first comprehensive atlas of cell types in a mammalian brain.”
The study is one of a package of 10 papers in Nature that take distinct, yet complementary, approaches to mapping the mouse nervous system at the single-cell level. The studies are from groups at the Broad, Allen Institute for Brain Science, the Salk Institute for Biological Studies, and other institutions that are part of the National Institutes of Health’s Brain Research Through Advancing Innovative Neurotechnologies® Initiative, or The BRAIN Initiative — Cell Census Network (BICCN). Together the papers describe the first complete cell type atlas of a whole mammalian brain.
The package includes a spatial, single-cell atlas of the mouse brain and spinal cord that was first published online in September in Nature and was led by Xiao Wang, a Broad core institute member, a Merkin Institute Fellow, and an assistant professor of chemistry at MIT, and Jia Liu, an assistant professor of engineering at Harvard University. Independently of BICCN, Wang’s and Liu’s team used a spatial transcriptomics technology they developed to analyze the expression of more than 1,000 genes and detail the locations of individual cells with unparalleled sub-cellular resolution. They identified hundreds of cell types, generated highly precise tissue maps of the mouse brain and spinal cord, and demonstrated their method’s utility in revealing which cell types and brain regions are altered by gene-delivery viruses.
Mapping the brain
In the study from the Macosko and Chen labs, the scientists worked together to develop their spatial transcriptomic approach and apply it across the entire mouse brain. They also relied on the expertise of members of the Broad’s Genomics Platform and the team that supports Hail, an open-source tool for scalable genomic analysis.
The researchers identified several thousand unique cell populations, and mapped their locations in the whole tissue with near-cellular resolution. They estimated that their analysis captured about 90 percent of cell types in the mouse brain, including a large diversity in underexplored areas of the brain. The researchers created an online browser to house and share their datasets with the scientific community (http://www.BrainCellData.org/).
The team analyzed the full transcriptome of cells from nearly 100 regions across the mouse brain using high-throughput single-nucleus RNA sequencing, the preferred approach for efforts to create a human brain atlas. This resulted in more than four million profiles of gene activity, which they clustered into nearly 5,000 unique cell populations, most of which were neuronal cells.
The team next applied an approach developed in the Chen and Macosko labs known as Slide-seq. They transferred 101 serial sections, spanning the volume of a single mouse brain, onto arrays of beads covered in unique DNA barcodes, which bound to the mRNA transcripts in the brain tissue. They then sequenced those transcripts and aligned that spatial data to an existing 3D reference atlas, enabling them to assign each transcript to a known brain structure, representing more than 1.7 million mapped cells. The researchers combined detailed and well-sampled cell type profiles from the single-nucleus sequencing dataset to locate each cell type in each slice to generate a detailed and thorough atlas of the entire mouse brain. They also analyzed the dataset to come up with two or three marker genes that could be used to uniquely identify almost all of the cell populations.
The authors said that other scientific groups can use the transcriptomic profiles, spatial localizations, and sets of marker genes they identified to study particular cells of interest. Groups may also use the data by integrating it with their own more detailed examination of a particular brain region. “We hope that our atlas can both empower the community in their own work and allow them to further explore the cell types we identified,” said co-first author Jonah Langlieb, a computational biologist in the Macosko lab who led the work along with co-first author Nina Sachdev.
The team also revealed how signaling molecules known as neurotransmitters are used by different cell types in various brain regions. In addition, they demonstrated their atlas’s utility in revealing where disease-associated genes are active, for example, specific neuronal cells that are enriched for expression of genetic factors associated with schizophrenia.
Together, the 10 studies provide rich and profound new views of the remarkable complexity of the brain, and their datasets and methods set the stage for larger efforts to do the same for other mouse organs and for the human brain.
“By mapping the mouse brain, the primary mammalian system used in neuroscience, we’ve provided molecular, functional, and anatomical classifications that provide a key foundation for human brain mapping, which is what comes next,” said Macosko.
The research from the Macosko and Chen labs was funded by the National Institutes of Health’s Brain Research Through Advancing Innovative Neurotechnologies® Initiative, or The BRAIN Initiative, and by the Stanley Center for Psychiatric Research.
Papers cited:
Shi H, He Y, Zhou Y, et al. Spatial atlas of the mouse central nervous system at molecular resolution. Nature. Online September 27, 2023. DOI: 10.1038/s41586-023-06569-5.
Langlieb J, Sachdev NS, et al. The cell type composition of the adult mouse brain revealed by single cell and spatial genomics. Nature. Online December 13, 2023. DOI: 10.1038/s41586-019-0000-0.
JOURNAL
Nature
METHOD OF RESEARCH
Experimental study
SUBJECT OF RESEARCH
Animals
ARTICLE TITLE
The cell type composition of the adult mouse brain revealed by single cell and spatial genomics
ARTICLE PUBLICATION DATE
13-Dec-2023
Salk teams assemble first full epigenomic cell atlas of the mouse brain
Researchers at Salk catalogue all the chemical changes to the genetic structure that orchestrate cell behavior in the mouse brain, producing the most detailed atlas ever of the diversity and connections of neurons in the mouse brain
Peer-Reviewed PublicationIMAGE:
TOP LEFT: 3D RENDERING OF ANATOMICAL MOUSE BRAIN DIVIDED INTO SECTIONS BASED ON BRAIN REGION DISSECTED; BOTTOM LEFT: 3D RENDERING OF MOUSE BRAIN DIVIDED INTO MULTICOLORED SEGMENTS (YELLOW, BLUE, AQUA, GREEN, PINK, ORANGE, BROWN, RED) THAT REPRESENT THE DISSECTIONS MADE IN EACH BRAIN REGION.
TOP RIGHT: VERTICAL SLICE OF MOUSE BRAIN WITH DIFFERENT CELL TYPES REPRESENTED BY DIFFERENT COLORS (ORANGE, GREEN, BLUE, AQUA, RED, PURPLE) REPRESENTING THE SPATIAL LOCATION OF SPECIFIC CELL TYPES IN THAT SECTION; BOTTOM RIGHT: MULTICOLORED CIRCLES (YELLOW, BLUE, AQUA, GREEN, PINK, ORANGE, BROWN, RED) REPRESENTING THE AMOUNT AND DIVERSITY OF CELL TYPES FOUND IN THE MOUSE WHOLE BRAIN BASED ON EPIGENOMIC PROFILING.
view moreCREDIT: SALK INSTITUTE
LA JOLLA (December 14, 2023)—Salk Institute researchers, as part of a worldwide initiative to revolutionize scientists’ understanding of the brain, analyzed more than 2 million brain cells from mice to assemble the most complete atlas ever of the mouse brain. Their work, published December 14, 2023 in a special issue of Nature, not only details the thousands of cell types present in the brain but also how those cells connect and the genes and regulatory programs that are active in each cell.
The efforts were coordinated by the National Institutes of Health’s Brain Research Through Advancing Innovative Neurotechnologies® Initiative, or the BRAIN Initiative®, which ultimately aims to produce a new, dynamic picture of mammalian brains.
“With this work, we have not only gained a lot of information about what cells make up the mouse brain, but also how genes are regulated within those cells and how that drives the cells’ functions,” says Salk Professor, International Council Chair in Genetics, and Howard Hughes Medical Institute Investigator Joseph Ecker, who contributed to four of the new papers. “When you take this epigenome-based cell atlas and start to look at genetic variants that are known to cause human disease, you get new insight into what cell types may be most vulnerable in the disease.”
The NIH BRAIN Initiative was launched in 2014 and has provided more than $3 billion in funding to researchers to develop transformative technologies and apply them to brain science.
In 2021, researchers supported by the BRAIN Initiative—including teams at Salk—unveiled the first draft of the mouse brain atlas, which pioneered new tools to characterize neurons and applied those tools to small sections of the mouse brain. Earlier this year, many of the same techniques were used to assemble an initial atlas of the human brain. In the latest work, researchers expanded the number of cells studied and which areas of the mouse brain were included, as well as used new, single-cell technologies that have only emerged in the last few years.
“This is the entire brain, which hasn’t been done before,” says Professor Edward Callaway, a senior author on two of the new papers. “There are ideas and principles that come out of looking at the whole brain that you don’t know from looking at one part at a time.”
To help assist other researchers studying the mouse brain, the new data is publicly available through an online platform, which can not only be searched through a database but also queried using the artificial intelligence tool ChatGPT.
“There is an incredibly large community of people who use mice as model organisms and this gives them an incredibly powerful new tool to use in their research involving the mouse brain,” adds Margarita Behrens, a Salk research professor who was involved in all four new papers.
The special issue of Nature has 10 total NIH BRAIN Initiative articles, including four co-authored by Salk researchers that describe the cells of the mouse brain and their connections. Some highlights from these four papers include:
Single-cell DNA methylation atlas
To determine all the cell types in the mouse brain, Salk researchers employed cutting-edge techniques that analyze one individual brain cell at a time. These single-cell methods studied both the three-dimensional structure of DNA inside cells and the pattern of methyl chemical groups attached to the DNA—two different ways that genes are controlled by cells. In 2019, Ecker’s lab group pioneered approaches to simultaneously make these two measurements, which lets researchers work out not only which genetic programs are activated in different cell types, but also how these programs are being switched on and off.
The team found examples of genes that were activated in different cell types but through different ways—like being able to flip a light on or off with two different switches. Understanding these overlapping molecular circuits makes it easier for researchers to develop new ways of intervening in brain diseases.
“If you can understand all the regulatory elements that are important in these cell types, you can also begin to understand the developmental trajectories of the cells, which becomes critical to understanding neurodevelopmental disorders like autism and schizophrenia,” says Hanqing Liu, a postdoctoral researcher in Ecker’s lab and first author of this paper.
The researchers also made new discoveries about which areas of the brain contain which cell types. And when cataloguing those cell types, they additionally found that the brain stem and midbrain have far more cell types than the much larger cortex of the brain—suggesting that these smaller parts of the brain may have evolved to serve more functions.
Other authors of this paper include Qiurui Zeng, Jingtian Zhou, Anna Bartlett, Bang-An Wang, Peter Berube, Wei Tian, Mia Kenworthy, Jordan Altshul, Joseph Nery, Huaming Chen, Rosa Castanon, Jacinta Lucero, Julia Osteen, Antonio Pinto-Duarte, Jasper Lee, Jon Rink, Silvia Cho, Nora Emerson, Michael Nunn, Carolyn O’Connor, and Jesse Dixon of Salk; Yang Eric Li, Songpeng Zu, and Bing Ren of UC San Diego; Zhanghao Wu and Ion Stoica of UC Berkley; Zizhen Yao, Kimberly Smith, Bosiljka Tasic, and Hongkui Zeng of the Allen Institute; and Chongyuan Luo of UC Los Angeles.
Single-cell chromatin maps
Another way of indirectly determining the structure of DNA, and which stretches of genetic material are being actively used by cells, is testing what DNA is physically accessible to other molecules that can bind to it. Using this approach, called chromatin accessibility, researchers led by Bing Ren of UC San Diego—including Salk’s Ecker and Behrens—mapped the structure of DNA in 2.3 million individual brain cells from 117 mice.
Then, the group used artificial intelligence to predict, based on those patterns of chromatin accessibility, which parts of DNA were acting as overarching regulators of the cells’ states. Many of the regulatory elements they identified were in stretches of DNA that have already been implicated in human brain diseases; the new knowledge of exactly which cell types use which regulatory elements can help pin down which cells are implicated in which diseases.
Other authors of this paper include co-first authors Songpeng Zu, Yang Eric Li, and Kangli Wang of UC San Diego; Ethan Armand, Sainath Mamde, Maria Luisa Amaral, Yuelai Wang, Andre Chu, Yang Xie, Michael Miller, Jie Xu, Zhaoning Wang, Kai Zhang, Bojing Jia, Xiaomeng Hou, Lin Lin, Qian Yang, Seoyeon Lee, Bin Li, Samantha Kuan, Zihan Wang, Jingbo Shang, Allen Wang, and Sebastian Preissl of UC San Diego, Hanqing Liu, Jingtian Zhou, Antonio Pinto-Duarte, Jacinta Lucero, Julia Osteen, and Michael Nunn of Salk; and Kimberly Smith, Bosiljka Tasic, Zizhen Yao, and Hongkui Zeng of the Allen Institute.
Neuron projections and connections
In another paper, co-authored by Behrens, Callaway, and Ecker, researchers mapped connections between neurons throughout the mouse brain. Then, they analyzed how these maps compared to patterns of methylation within the cells. This let them discover which genes are responsible for guiding neurons to which areas of the brain.
“We discovered certain rules dictating where a cell projects to based on their DNA methylation patterns,” says Jingtian Zhou, a postdoctoral researcher in Ecker’s lab and co-first author of the paper.
The connections between neurons are critical to their function and this new set of rules may help researchers study what goes awry in diseases.
Other authors of this paper include co-first author Zhuzhu Zhang of Salk; May Wu, Hangqing Liu, Yan Pang, Anna Bartlett, Wubin Ding, Angeline Rivkin, Will Lagos, Elora Williams, Cheng-Ta Lee, Paula Assakura Miyazaki, Andrew Aldridge, Qiurui Zeng, J. L. Angelo Salida, Naomi Claffey, Michelle Liem, Conor Fitzpatrick, Lara Boggeman, Jordan Altshul, Mia Kenworthy, Cynthia Valadon, Joseph Nery, Rosa Castanon, Neelakshi Patne, Minh Vu, Mohammed Rashid, Matthew Jacobs, Tony Ito, Julia Osteen, Nora Emerson, Jasper Lee, Silvia Cho, Jon Rink, Hsiang-Hsuan Huang, António Pinto-Duarte, Bertha Dominguez, Jared Smith, Carolyn O’Connor, and Kuo-Fen Lee of Salk; Zhihao Peng of Nanchang University in China; Zizhen Yao, Kimberly Smith, Bosiljka Tasic, and Hongkui Zeng of the Allen Institute; Shengbo Chen of Henan University in China; Eran Mukamel of UC San Diego; and Xin Jin of East China Normal University in China and New York University Shanghai.
Comparing mouse, monkey, and human motor cortexes
The motor cortex is the part of the mammalian brain involved in the planning and carrying out of voluntary body movements. Researchers led by Behrens, Ecker, and Ren studied the methylation patterns and DNA structure in more than 200,000 cells from the motor cortexes of humans, mice, and nonhuman primates to better understand how motor cortex cells have changed throughout human evolution.
They were able to identify correlations between how particular regulatory proteins have evolved and how, in turn, the expression patterns of genes evolved. They also discovered that nearly 80 percent of the regulatory elements that are unique to humans are transposable elements—small, mobile sections of DNA that can easily change position within the genome.
Other authors of this paper include co-first authors Nathan Zemke and Ethan Armand of UC San Diego; Wenliang Wang, Jingtian Zhou, Hanqing Liu, Wei Tian, Joseph Nery, Rosa Castanon, Anna Bartlett, Julia Osteen, Jonathan Rink, and Edward Callaway of Salk; Seoyeon Lee, Yang Eric Li, Lei Chang, Keyi Dong, Hannah Indralingam, Yang Xie, and Michael Miller of UC San Diego; Daofeng Li, Xiaoyu Zhuo, Vincent Xu, and Ting Wang of Washington University in Missouri; Fenna Krienen of Princeton University and Harvard Medical School; Qiangge Zhang and Guoping Feng of the Broad Institute and MIT; Steven McCarroll of Harvard Medical School and the Broad Institute; and Naz Taskin, Jonathan Ting, and Ed Lein of the Allen Institute and University of Washington in Seattle.
Summary
“I think in general this whole package serves as a blueprint for other people’s future studies,” says Callaway, also the Vincent J. Coates Chair in Molecular Neurobiology at Salk. “Someone studying a particular cell type can now look at our data and see all the ways those cells connect and all the ways they’re regulated. It’s a resource that allows people to ask their own questions.”
The work was supported by the National Institutes of Health BRAIN Initiative (U19MH11483, U19MH114831-04s1, 5U01MH121282, UM1HG011585, U19MH114830).
About the Salk Institute for Biological Studies:
Unlocking the secrets of life itself is the driving force behind the Salk Institute. Our team of world-class, award-winning scientists pushes the boundaries of knowledge in areas such as neuroscience, cancer research, aging, immunobiology, plant biology, computational biology, and more. Founded by Jonas Salk, developer of the first safe and effective polio vaccine, the Institute is an independent, nonprofit research organization and architectural landmark: small by choice, intimate by nature, and fearless in the face of any challenge. Learn more at www.salk.edu.
For more information
Visit all 10 papers in the Nature package here.
Journal title: Nature
Paper title: Single-cell DNA Methylome and 3D Multiomic Atlas of the Adult Mouse Brain
Authors: Hanqing Liu, Qiurui Zeng, Jingtian Zhou, Anna Bartlett, Bang-An Wang, Peter Berube, Wei Tian, Mia Kenworthy, Jordan Altshul, Joseph R. Nery, Huaming Chen, Rosa G. Castanon, Songpeng Zu, Yang Eric Li, Jacinta Lucero, Julia K. Osteen, António Pinto-Duarte, Jasper Lee, Jon Rink, Silvia Cho, Nora Emerson, Michael Nunn, Carolyn O’Connor, Zhanghao Wu, Ion Stoica, Zizhen Yao, Kimberly A. Smith, Bosiljka Tasic, Chongyuan Luo, Jesse R. Dixon, Hongkui Zeng, Bing Ren, M. Margarita Behrens, Joseph R Ecker
DOI: 10.1038/s41586-019-0000-0
Journal title: Nature
Paper title: Single-cell analysis of chromatin accessibility in adult mouse brain
Authors: Songpeng Zu, Yang Eric Li, Kangli Wang, Ethan Armand, Sainath Mamde, Maria Luisa Amaral, Yuelai Wang, Andre Chu, Yang Xie, Michael Miller, Jie Xu, Zhaoning Wang, Kai Zhang, Bojing Jia, Xiaomeng Hou, Lin Lin, Qian Yang, Seoyeon Lee, Bin Li, Samantha Kuan, Hanqing Liu, Jingtian Zhou, Antonio Pinto-Duarte, Jacinta Lucero, Julia Osteen, Michael Nunn, Kimberly A. Smith, Bosiljka Tasic, Zizhen Yao, Hongkui Zeng, Zihan Wang, Jingbo Shang, M. Margarita Behrens, Joseph R. Ecker, Allen Wang, Sebastian Preissl, Bing Ren
DOI: 10.1038/s41586-023-06824-9
Journal title: Nature
Paper title: Brain-wide Correspondence Between Neuronal Epigenomics and Long-Distance Projections
Authors: Jingtian Zhou, Zhuzhu Zhang, May Wu, Hanqing Liu, Yan Pang, Anna Bartlett, Zhihao Peng, Wubin Ding, Angeline Rivkin, Will N. Lagos, Elora Williams, Cheng-Ta Lee, Paula Assakura Miyazaki, Andrew Aldridge, Qiurui Zeng, J.L. Angelo Salinda, Naomi Claffey, Michelle Liem, Conor Fitzpatrick, Lara Boggeman, Zizhen Yao,
Kimberly A. Smith, Bosiljka Tasic, Jordan Altshul, Mia A. Kenworthy, Cynthia Valadon, Joseph R. Nery, Rosa G. Castanon, Neelakshi S. Patne, Minh Vu, Mohammad Rashid, Matthew Jacobs, Tony Ito, Julia Osteen, Nora Emerson, Jasper Lee, Silvia Cho, Jon Rink, Hsiang-Hsuan Huang, António Pinto-Duarte, Bertha Dominguez, Jared B. Smith, Carolyn O’Connor, Hongkui Zeng, Shengbo Chen, Kuo-Fen Lee, Eran A. Mukamel, Xin Jin, M. Margarita Behrens, Joseph R. Ecker, Edward M. Callaway
DOI: 10.1038/s41586-019-0000-0
Journal title: Nature
Paper title: Conserved and divergent gene regulatory programs of the mammalian neocortex
Authors: Nathan R. Zemke, Ethan J. Armand, Wenliang Wang, Seoyeon Lee, Jingtian Zhou, Yang Eric Li, Hanqing Liu, Wei Tian, Joseph R. Nery, Rosa G. Castanon, Anna Bartlett, Julia K. Osteen, Daofeng Li, Xiaoyu Zhuo, Vincent Xu, Lei Chang, Keyi Dong, Hannah Indralingam, Jonathan A. Rink, Yang Xie, Michael Miller, Fenna M. Krienen, Qiangge Zhang, Naz Taskin, Jonathan Ting, Guoping Feng, Steven A. McCarroll, Edward M. Callaway, Ting Wang, Ed S. Lein, M. Margarita Behrens, Joseph R. Ecker, Bing Ren
DOI: 10.1038/s41586-023-06819-6
JOURNAL
Nature
ARTICLE TITLE
Brain-wide Correspondence Between Neuronal Epigenomics and Long-Distance Projections
ARTICLE PUBLICATION DATE
14-Dec-2023
Mapping the mouse brain helps reveal what makes us human
UC San Diego researchers are translating the language of brain cells, and it’s helping them figure out what goes wrong in diseases of the brain
IMAGE:
BING REN, PHD, IS A PROFESSOR IN THE DEPARTMENT OF CELLULAR AND MOLECULAR MEDICINE AT UC SAN DIEGO SCHOOL OF MEDICINE.
view moreCREDIT: UC SAN DIEGO HEALTH SCIENCES
Despite all our cells sharing the same DNA, there are thousands of different cell types in the human brain, each with a unique structure and function. One longstanding problem in neuroscience is determining how genes are switched on and off to form the mosaic of different cell types within the brain. Today, scientists from University of California San Diego School of Medicine have published two new studies that bring us closer to solving this mystery.
The researchers analyzed more than 2.3 million individual brain cells from mice to create a comprehensive map of the mouse brain and used artificial intelligence to help predict what stretches of DNA are used to determine a brain cell’s type. The researchers also looked at the brains of humans and primates to study the evolution of the processes cells use to turn genes on and off. The findings published December 14, 2023 in a special edition of Nature.
“A cell’s DNA is like its language,” said senior author Bing Ren, PhD, professor at UC San Diego School of Medicine. “Just like there are certain root words that many languages share, there are certain genes and gene expression patterns that are conserved across different species. Learning to understand and interpret the brain’s molecular language can help us learn more about how the brain works in general and about what happens to the brain in neuropsychiatric conditions.”
The two new papers are part of a package of 10 studies describing the first complete cell type atlas of a mammalian brain, led by researchers at UC San Diego, the Salk Institute for Biological Studies, the Allen Institute for Brain Science and other institutions. The research is part of the National Institutes of Health’s Brain Research Through Advancing Innovative Neurotechnologies® Initiative, or the BRAIN Initiative®, which launched in 2014 to deepen our understanding of the inner workings of the human mind and improve how we treat, prevent and cure disorders of the brain.
“This work is helping us establish a baseline understanding of what the brain is like at the cellular level,” said Ren. “This will make it possible to draw comparisons between our baseline and brains with neurological and psychiatric disorders. Studying the brain this way could help us discover new therapeutic approaches for these conditions.”
One of the most ambitious projects under the Brain Initiative is the Cell Census Network (BICNN), which seeks to describe human brain cells in unprecedented molecular detail, classifying them into more precise subtypes, pinpointing their locations in the brain and tracking how cellular features change over a lifetime. Earlier this year, Ren and other scientists from the BICCN published a first-of-its kind atlas of the human brain, which identified more than a hundred types of brain cell. Their new atlas of the mouse brain complements this work and expands upon it by drawing comparisons between the brains of different species.
For example, by comparing the brains of mice with those of humans and nonhuman primates, the researchers found that cell-type-specific patterns of gene expression evolve much more rapidly than patterns that are shared across cell types. This could help explain why there are so many different cell types in the brain.
“Humans have evolved over millions of years, and much of that evolutionary history is shared with other animals,” said Joseph Ecker, PhD, a professor at the Salk Institute for Biological Studies who co-led one of the new studies with Ren. “Data from humans alone is never going to be enough to tell us everything we want to know about how the brain works. By filling in these gaps with other mammalian species, we can continue to answer those questions and improve the machine-learning models we use by providing them more data.”
While the BRAIN Initiative and BICCN are still very much ongoing projects, some insights are already proving relevant to human diseases. For example, the researchers found that many of the genetic programs that determine cell type were in parts of the genome that have already been implicated in human diseases, such multiple sclerosis, anorexia nervosa and tobacco use disorder. This could help shed light on how neuropsychiatric disorders affect the brain.
“The brain isn’t homogenous, and diseases don’t affect all parts of the brain equally,” said Ren. “Insights from this research and the BRAIN initiative as a whole are helping us better understand what types of cells are affected in specific diseases. We hope this will pave the way for more precise, targeted therapies that can heal diseased cells without affecting the rest of the brain.”
Full link to first study: https://www.nature.com/articles/s41586-023-06824-9
Co-authors of the first study include: Songpeng Zu, Yang Eric Li, Kangli Wang, Ethan Armand, Sainath Mamde, Maria Luisa Amaral, Yuelai Wang, Andre Chu, Yang Xie, Michael Miller, Jie Xu, Zhaoning Wang, Kai Zhang, Bojing Jia, Xiaomeng Hou, Bin Li, Samantha Kuan, Zihan Wang, Jingbo Shang, Allen Wang and Sebastian Preissl at UC San Diego, Hanqing Liu, Jingtian Zhou, Antonio Pinto-Duarte, Jacinta Lucero, Julia Osteen, Michael Nunn and M. Margarita Behrens at the Salk Institute for Biological Studies, and Kimberly A. Smith, Bosiljka Tasic, Zizhen Yao and Hongkui Zeng at the Allen Institute for Brain Science.
The first study was supported, in part, by the NIH BRAIN Initiative (grants U19MH114831 and U19MH114830).
Full link to second study: https://www.nature.com/articles/s41586-023-06819-6
Co-authors of the second study include: Nathan R. Zemke, Ethan J Armand, Seoyeon Lee, Jingtian Zhou, Yang Eric Li, Daofeng Li, Xiaoyu Zhuo, Vincent Xu and Michael Miller at UC San Diego, Wenliang Wang Hanqing Liu, Wei Tian, Joseph R. Nery, Rosa G Castanon, Anna Bartlett, Julia K. Osteen, Edward M. Callaway, Margarita Behrens and Joseph R. Ecker at the Salk Institute for Biological Studies, Daofeng Li, Xiaoyu Zhuo, Vincent Xu and Ting Wang at Washington University School of Medicine, Fenna M. Krienen at Princeton University, Qiangge Zhang and Guoping Feng at The Broad Institute of MIT and Harvard, Naz Taskin, Jonathan Ting and Ed S. Lein at the Allen Institute for Brain Science and Steven A. McCarroll at Harvard Medical School.
The second study was supported, in part, by the NIH BRAIN Initiative (grants U19MH11483, U19MH114831-04s1, 5U01MH121282 and UM1HG011585).
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JOURNAL
Nature
COI STATEMENT
Bing Ren is a consultant of and has equity interests in Arima Genomics, Inc. and is a cofounder of Epigenome Technologies Inc.
