12 Oct 2023

Understanding the human brain has entered a new era with the birth of a comprehensive cell atlas. Scientists used single-cell RNA sequencing, epigenetic analyses, and spatial mapping to study millions of brain cells from 100 brain regions, distinguishing 3,300 cell types. Researchers compared cell types to one another between brain regions and among people. “The data collected […] will now allow researchers to tackle fundamental scientific questions about the human brain,” wrote Mattia Maroso, senior editor at Science. “The era of cellular human brain research is knocking at our door!”

The findings were reported in 21 papers published in Science, Science Advances, or Science Translational Medicine on October 12 by scientists across North America, Europe, and Asia. These studies were funded through the NIH’s Brain Research through Advancing Innovative Neurotechnologies (BRAIN) initiative, specifically a project called the Cell Census Network. BICCN aims to catalog and compare brain cell types from people, primates, and mice (image below).

BICCN Strategy. BICCN aims to describe how the human brain is organized, how it differs from other animal brains, and how it develops in the womb, then mirror that organization in brain organoids. [Courtesy of Weninger and Arlotta, Science, 2023.]

Of the 21 papers, three in Science provide the basis for the atlas. Scientists led by Kimberly Stiletti and Sten Linnarsson of the Karolinska Institute in Sweden used single-nucleus RNA-Seq (snRNA-Seq) on postmortem tissue from 100 brain regions, reporting 3.3 million nuclei representing an impressive 3,300 subtypes of cells. Across the cortex, astrocytes and oligodendrocytes varied little, and neurons differed slightly from one neighboring area to the next. However, all cell types varied widely in the brainstem and they differed vastly from their cortical counterparts. Researchers led by Bing Ren, University of California, San Diego, analyzed single-cell chromatin accessibility to unravel gene regulation patterns in 1.1 million cells from 42 brain regions, while Joseph Ecker, Salk Institute, La Jolla, California, oversaw a project to map DNA methylation and three-dimensional chromatin structure in 517,000 cells across 46 regions, revealing epigenetics at cellular resolution.

Other papers took deep dives into fewer brain regions. Researchers led by Rebecca Hodge, Trygve Bakken, and Ed Lein, all at the Allen Institute for Brain Science, Seattle, compared gene expression of 1.1 million neurons in eight cortical areas of postmortem tissue. Excitatory and inhibitory neurons occurred in similar ratios in all but the primary visual cortex, which had twice as many excitatory neurons as the other areas, perhaps reflecting the power required to process visual information. Lein and Jonathan Ting, also at the Allen Institute, mapped the unique morphology and electrical activity of 780 inhibitory neurons in cortical layers 2 to 6 from tissue samples taken during surgery for epilepsy or brain cancer, finding four major types with distinct firing patterns (image below).

Neuron Diversity. The primary visual cortex (V1) supports twice as many excitatory neurons as other brain areas (left). Four types of GABAergic inhibitory neurons expressing specific markers (right) span different depths of the six cortical layers. Each fires in a distinct pattern. [Courtesy of Jorstad et al., Science, 2023; Lee et al., Science, 2023.]

What about brain cell diversity among people? Two papers addressed that question. Bakken, Hodge, Jeremy Miller, and colleagues at the Allen Institute analyzed snRNA-Seq and whole-genome sequences of 400,000 cells from fresh neocortical tissue samples. Gene expression in excitatory neurons and microglia varied considerably. Taking a different approach, scientists led by Liwei Zhang of Capital Medical University, Beijing, and Hanchuan Peng at Southeast University, Nanjing, China, traced the morphology of 1,750 cortical neurons from fresh tissue using adaptive cell tomography, which combines fluorescent and two-photon images to map individual neuron arbors in three dimensions. In contrast to gene expression, neuron morphology was more diverse across brain regions than it was among people.

A perspective article by Alyssa Weninger, University of North Carolina, Chapel Hill, and Paola Arlotta, Harvard University, summarizes nine of the 12 Science papers, including those studying human brain development during the first trimester and those comparing human and nonhuman primate brains. “The focus on primates distinguishes the current collection of studies from previous efforts [and] provides the first large-scale effort to characterize the fine cellular architecture of the primate brain,” wrote Takaki Komiyama of UC San Diego and editor of Science Advances in an editorial.

Explore all 21 papers listed in Primary Papers at right and Further Reading below.—Chelsea Weidman Burke

Comments

1. • Tara Spires-Jones
     University of Edinburgh
   • Posted: 16 Oct 2023

   It is exciting to start seeing results of the worldwide push to understand and map the complexity of the brain in order to both better understand what makes us human and to pave the way for treatments for neurological and psychiatric diseases. As a neuroscientist, it is fantastic to start seeing so much data come through, characterizing the remarkable diversity of cells in the human brain. We still have a long way to go for a complete brain map. For example, the paper by Siletti and colleagues identified hundreds of clusters of cells based on their gene expression profiles, but these cells all came from only three people. There is likely diversity in brain cells induced by our genetic background, lifestyle, and age, so expanding these maps to include more brain donors will be important in the future.

   View all comments by Tara Spires-Jones

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References

External Citations

1. BICCN 

Further Reading

Papers

1. Micali N, Ma S, Li M, Kim SK, Mato-Blanco X, Sindhu SK, Arellano JI, Gao T, Shibata M, Gobeske KT, Duque A, Santpere G, Sestan N, Rakic P. Molecular programs of regional specification and neural stem cell fate progression in macaque telencephalon. Science. 2023 Oct 13;382(6667):eadf3786. PubMed.
2. Braun E, Danan-Gotthold M, Borm LE, Lee KW, Vinsland E, Lönnerberg P, Hu L, Li X, He X, Andrusivová Ž, Lundeberg J, Barker RA, Arenas E, Sundström E, Linnarsson S. Comprehensive cell atlas of the first-trimester developing human brain. Science. 2023 Oct 13;382(6667):eadf1226. PubMed.
3. Velmeshev D, Perez Y, Yan Z, Valencia JE, Castaneda-Castellanos DR, Wang L, Schirmer L, Mayer S, Wick B, Wang S, Nowakowski TJ, Paredes M, Huang EJ, Kriegstein AR. Single-cell analysis of prenatal and postnatal human cortical development. Science. 2023 Oct 13;382(6667):eadf0834. PubMed.
4. Chartrand T, Dalley R, Close J, Goriounova NA, Lee BR, Mann R, Miller JA, Molnar G, Mukora A, Alfiler L, Baker K, Bakken TE, Berg J, Bertagnolli D, Braun T, Brouner K, Casper T, Csajbok EA, Dee N, Egdorf T, Enstrom R, Galakhova AA, Gary A, Gelfand E, Goldy J, Hadley K, Heistek TS, Hill D, Jorstad N, Kim L, Kocsis AK, Kruse L, Kunst M, Leon G, Long B, Mallory M, McGraw M, McMillen D, Melief EJ, Mihut N, Ng L, Nyhus J, Oláh G, Ozsvár A, Omstead V, Peterfi Z, Pom A, Potekhina L, Rajanbabu R, Rozsa M, Ruiz A, Sandle J, Sunkin SM, Szots I, Tieu M, Toth M, Trinh J, Vargas S, Vumbaco D, Williams G, Wilson J, Yao Z, Barzo P, Cobbs C, Ellenbogen RG, Esposito L, Ferreira M, Gouwens NW, Grannan B, Gwinn RP, Hauptman JS, Jarsky T, Keene CD, Ko AL, Koch C, Ojemann JG, Patel A, Ruzevick J, Silbergeld DL, Smith K, Sorensen SA, Tasic B, Ting JT, Waters J, de Kock CP, Mansvelder HD, Tamas G, Zeng H, Kalmbach B, Lein ES. Morphoelectric and transcriptomic divergence of the layer 1 interneuron repertoire in human versus mouse neocortex. Science. 2023 Oct 13;382(6667):eadf0805. PubMed.
5. Jorstad NL, Song JH, Exposito-Alonso D, Suresh H, Castro-Pacheco N, Krienen FM, Yanny AM, Close J, Gelfand E, Long B, Seeman SC, Travaglini KJ, Basu S, Beaudin M, Bertagnolli D, Crow M, Ding SL, Eggermont J, Glandon A, Goldy J, Kiick K, Kroes T, McMillen D, Pham T, Rimorin C, Siletti K, Somasundaram S, Tieu M, Torkelson A, Feng G, Hopkins WD, Höllt T, Keene CD, Linnarsson S, McCarroll SA, Lelieveldt BP, Sherwood CC, Smith K, Walsh CA, Dobin A, Gillis J, Lein ES, Hodge RD, Bakken TE. Comparative transcriptomics reveals human-specific cortical features. Science. 2023 Oct 13;382(6667):eade9516. PubMed.
6. Kim CN, Shin D, Wang A, Nowakowski TJ. Spatiotemporal molecular dynamics of the developing human thalamus. bioRxiv. 2023 Aug 22; PubMed.
7. Ament SA, Cortes-Gutierrez M, Herb BR, Mocci E, Colantuoni C, McCarthy MM. A single-cell genomic atlas for maturation of the human cerebellum during early childhood. Sci Transl Med. 2023 Oct 12;:eade1283. PubMed.
8. Rózsa M, Tóth M, Oláh G, Baka J, Lákovics R, Barzó P, Tamás G. Temporal disparity of action potentials triggered in axon initial segments and distal axons in the neocortex. Sci Adv. 2023 Oct 13;9(41):eade4511. Epub 2023 Oct 12 PubMed.
9. Wilbers R, Metodieva VD, Duverdin S, Heyer DB, Galakhova AA, Mertens EJ, Versluis TD, Baayen JC, Idema S, Noske DP, Verburg N, Willemse RB, de Witt Hamer PC, Kole MH, de Kock CP, Mansvelder HD, Goriounova NA. Human voltage-gated Na+ and K+ channel properties underlie sustained fast AP signaling. Sci Adv. 2023 Oct 13;9(41):eade3300. Epub 2023 Oct 12 PubMed.
10. Wilbers R, Galakhova AA, Driessens SL, Heistek TS, Metodieva VD, Hagemann J, Heyer DB, Mertens EJ, Deng S, Idema S, de Witt Hamer PC, Noske DP, van Schie P, Kommers I, Luan G, Li T, Shu Y, de Kock CP, Mansvelder HD, Goriounova NA. Structural and functional specializations of human fast-spiking neurons support fast cortical signaling. Sci Adv. 2023 Oct 13;9(41):eadf0708. Epub 2023 Oct 12 PubMed.
11. Costantini I, Morgan L, Yang J, Balbastre Y, Varadarajan D, Pesce L, Scardigli M, Mazzamuto G, Gavryusev V, Castelli FM, Roffilli M, Silvestri L, Laffey J, Raia S, Varghese M, Wicinski B, Chang S, Chen IA, Wang H, Cordero D, Vera M, Nolan J, Nestor K, Mora J, Iglesias JE, Garcia Pallares E, Evancic K, Augustinack JC, Fogarty M, Dalca AV, Frosch MP, Magnain C, Frost R, van der Kouwe A, Chen SC, Boas DA, Pavone FS, Fischl B, Hof PR. A cellular resolution atlas of Broca's area. Sci Adv. 2023 Oct 13;9(41):eadg3844. Epub 2023 Oct 12 PubMed.
12. Chiou KL, Huang X, Bohlen MO, Tremblay S, DeCasien AR, O'Day DR, Spurrell CH, Gogate AA, Zintel TM, Cayo Biobank Research Unit, Andrews MG, Martínez MI, Starita LM, Montague MJ, Platt ML, Shendure J, Snyder-Mackler N. A single-cell multi-omic atlas spanning the adult rhesus macaque brain. Sci Adv. 2023 Oct 13;9(41):eadh1914. Epub 2023 Oct 12 PubMed.
13. Zhu K, Bendl J, Rahman S, Vicari JM, Coleman C, Clarence T, Latouche O, Tsankova NM, Li A, Brennand KJ, Lee D, Yuan GC, Fullard JF, Roussos P. Multi-omic profiling of the developing human cerebral cortex at the single-cell level. Sci Adv. 2023 Oct 13;9(41):eadg3754. Epub 2023 Oct 12 PubMed.
14. Krienen FM, Levandowski KM, Zaniewski H, Del Rosario RC, Schroeder ME, Goldman M, Wienisch M, Lutservitz A, Beja-Glasser VF, Chen C, Zhang Q, Chan KY, Li KX, Sharma J, McCormack D, Shin TW, Harrahill A, Nyase E, Mudhar G, Mauermann A, Wysoker A, Nemesh J, Kashin S, Vergara J, Chelini G, Dimidschstein J, Berretta S, Deverman BE, Boyden E, McCarroll SA, Feng G. A marmoset brain cell census reveals regional specialization of cellular identities. Sci Adv. 2023 Oct 13;9(41):eadk3986. Epub 2023 Oct 12 PubMed.