Human Brain Cell Atlas Heralds ‘New Era in Brain Science’

Human Brain Cell Atlas Heralds ‘New Era in Brain Science’

Brain map concept art in neuroscience

Researchers from the Salk Institute, in a global collaboration, have produced a detailed atlas of human brain cells by analyzing more than half a million cells. This study, part of the National Institutes of Health’s BRAIN Initiative, represents a pivotal shift in understanding brain cell diversity and function.

The new research, part of the NIH BRAIN Initiative, paves the way toward treating, preventing and treating brain disorders.

Salk Institute researchers, as part of a larger collaboration with research teams around the world, have analyzed more than half a million brain cells from three human brains to compile an atlas of the hundreds of cell types that make up the human brain in unprecedented detail.

The research is published in a special issue of the journal Sciences On October 13, 2023, this was the first time that brain cell subtype identification techniques developed and applied in mice have been applied to human brains.

“This research represents the first tests of whether these methods can work in human brain samples, and we were excited about how well they translated,” says Professor Joseph Ecker, director of the Genetic Analysis Laboratory at Salk and a researcher at the Howard Hughes Medical Institute. “This is truly the beginning of a new era in brain science, where we will be able to better understand how brains develop, age, and are affected by disease.”

BRAIN Initiative and Brain Cell Diversity

The new work is part of the National Institutes of Health Brain research through the Innovative Neurotechnologies Initiative, or the BRAIN Initiative, is an effort launched in 2014 to describe the large number of cells—as characterized by many different techniques—in mammalian brains. SALIC is one of three institutions awarded grants to serve as key players in generating data for the NIH BRAIN Initiative Cellular Census Network, BICCN..

Abstract neuronal diversity

An abstract representation of cell diversity in the brain. Individual nuclei are brightly colored for t-SNE plots used in epigenomics analysis to differentiate between individual brain cell types. Background color layers represent environmental factors local to each brain region that affect cell function. Credit: Michael Nunn

Every cell in the human brain contains the same sequence DNABut in different cell types different genes are transcribed on strands of cells RNA For use as protein diagrams. This ultimate difference in which proteins are found, in which cells – and at what levels – allows for enormous diversity in brain cell types and brain complexity. Knowing which cells rely on which DNA sequences to function is crucial not only to understanding how the brain works, but also how mutations in DNA can cause brain disorders, and how to treat those disorders.

“Once we scale our techniques to a large number of brains, we can begin to address questions that we have not been able to solve in the past,” says Margareta Behrens, a research professor in the Computational Neurobiology Laboratory at Salk and co-director. New Action Investigator.

From mice to men: adapting research techniques

In 2020, Ecker and Behrens led a Salk team that characterized 161 cell types in the mouse brain, based on chemical methylation marks along DNA that determine when genes are turned on or off. This type of DNA regulation, called methylation, is one level of cellular identity.

In the new paper, the researchers used the same tools to identify DNA methylation patterns in more than 500,000 brain cells from 46 regions in the brains of three healthy adult male donors. While mouse brains are very similar from animal to animal, containing about 80 million neurons, human brains vary much more and contain about 80 million neurons. one billion nervous cells.

“It’s a big leap from mice to humans, and it also presents some technical challenges that we’ve had to overcome,” Behrens says. “But we were able to adapt things we discovered in mice and still get high-quality results to human brains.”

Innovative technologies and collaborative efforts

Meanwhile, the researchers also used a second technique, which analyzed the 3D structure of DNA molecules in each cell to obtain additional information about the DNA sequences being actively used. Cells are more likely to access exposed DNA regions than tightly folded DNA fragments.

“This is the first time we’ve looked at these dynamic genomic structures at a whole new level of detail of cell types in the brain, and how these structures might regulate which genes are active in which cell types,” says study co-author Jingtian Zhou. The first author of the new paper is a postdoctoral researcher in Ecker’s lab.

Other research teams also publish their work in the special issue of Sciences They used cells from the same three human brains to test their cell profiling techniques, including a group at UC San Diego led by Ping Ren — also a co-author on Ecker and Behrens’ study. Ren’s team revealed a link between specific types of brain cells and neuropsychiatric disorders, including schizophrenia and bipolar disorder. Alzheimer’s disease Illness and severe depression. In addition, the team has developed deep learning AI models that predict the risks of these disorders.

scMCode chart

A diagram showing how “bar codes” (“scMCodes”) are used to identify and classify cell types in the brain. The image shows an anatomical cross-section of the brain, an abstraction of the brain with regions represented by colored circles (blue, red, green, and yellow), and a bar code representing the technique used by scientists. Credit: Salk Institute

Other groups in the global collaboration have focused on measuring RNA levels to group cells together into subtypes. Based on DNA studies by Ecker and Behrens’ team, the groups found a high level of correspondence in each brain region between which genes were activated, and which genes were transcribed into RNA.

The way forward: more discoveries await

Because the new Salk research was intended as a pilot study to test the effectiveness of the techniques in human brains, the researchers say they cannot yet draw conclusions about how many cell types they might detect in the human brain or how these types differ among themselves. Mice and humans.

“The possibility of finding unique cell types in humans that we don’t see in mice is really exciting,” says Wei Tian, ​​co-first author of the new paper and a scientist in Ecker’s lab. “We have made amazing progress but there are always more questions to ask.”

In 2022, the NIH Brain Initiative launched the new BRAIN Initiative Cell Atlas Network (BICAN), which will follow BICCN efforts. At Salk, a new Center for the Multiphasic Human Brain Cell Atlas, funded through BICAN, aims to study cells from more than a dozen human brains and ask questions about how the brain changes during development, over the course of people’s lives, and with disease. Ecker says this more detailed work on a larger number of brains will pave the way toward a better understanding of how certain types of brain cells go awry in brain disorders and diseases.

“We want to have a complete understanding of the brain across the lifespan so that we can determine when, how, and in what cell types things go wrong with disease, and perhaps prevent or reverse those harmful changes,” Ecker says.

Reference: “Single-cell DNA methylation and 3D genome architecture in the human brain” by Wei Tian, ​​Jingtian Zhou, Anna Bartlett, Qirui Zeng, Hanqing Liu, Rosa J. Castanon, Mia Kenworthy, Jordan Altschul, Cynthia Valadon, and Andrew. Aldridge, 2005; joseph r. Neary, Huaming Chen, Jiaying Xu, Nicholas D. Johnson, Jacinta Lucero, Julia K. Austin, Nora Emerson, John Rink, Jasper Lee, Yang E. Lee, Kimberly Seletti, Michelle Lim, and Naomi Claffey. , Caroline O. Connor, Anna Marie Yanni, Julie Niehus, Nick Dee, Tamara Kasper, Nadia Shapovalova, Danielle Hirschstein, Song Lin Ding, Rebecca Hodge, Boaz B. Levy, C. Dirk Keane, Sten Lennarsson, Ed Lin, Ping Ren, MS Margaret Behrens, and Joseph R. Iker Sciences.
doi: 10.1126/science.adf5357

Other authors of this paper are Anna Bartlett, Qirui Zeng, Hanqing Liu, Rosa J. Castanon, Mia Kenworthy, Jordan Altschul, Cynthia Valadon, Andrew Aldridge, Joseph R. Neary, Huaming Chen, Jiaying Xu, Nicholas D. Johnson, and Jacinta. Lucero, Julia K. Austin, Nora Emerson, John Rink, Jasper Lee, Michelle Lim, Naomi Claffey and Kaz O’Connor from Salk; Yang Li and Ping Ren of the Ludwig Institute for Cancer Research; Kimberly Seletti and Sten Lennarsson of the Carolingian Institute; Anna Marie Yanni, Julie Niehus, Nick Dee, Tamara Kasper, Nadia Shapovalova, Danielle Hirschstein, Rebecca Hodge, Boaz B. Levy, and Ed Lin of the Allen Institute for Brain Science; and C. Dirk Kane of University of Washington.

The work was supported by grants from the National Institute of Mental Health (U01MH121282, UM1 MH130994, NIMH U01MH114812), National Institutes of Health The BRAIN Initiative (NCI CCSG: P30 014195), the Nancy and Buster Alford Foundation, and the Howard Hughes Medical Institute.

You may also like...

Leave a Reply

Your email address will not be published. Required fields are marked *