Mapping the mouse brain and, by extension, the human brain too

The circuits of the human brain contain over 100 billion neurons, each linked to many other neurons via thousands of synaptic connections, resulting in a three-pound organ that is profoundly more complex than the sum of its countless parts.

In recent years, however, transformative advances in imaging, sequencing, and computational technologies have opened up the possibility of mapping a truly human brain to the resolution of its molecular and cellular components. While this ultimate goal remains to be achieved, researchers have steadily made progress with a smaller, but no less significant effort: an atlas of the mouse brain.

The Mouse Brain Atlas is a multi-year, multi-institutional effort to analyze the underlying form and function of mouse brain genomics, which serves as a model for related human research. Photo credit: Allen Brain Institute

In a special issue of Nature, published online October 7, 2021, researchers at the University of California at San Diego, along with colleagues across the country, describe their progress in collecting papers. Two of the papers, in which scientists from UC San Diego were the lead authors, further refine the organization of cells in key regions of the mouse brain and, more importantly, the organization of transcriptomic factors and elements. , epigenomics and regulators that supply these brain cells. with function and purpose.

“To truly understand how the brain works, and from this knowledge to develop new drugs and therapies to improve human life and health, we need to see and quantify the structure, organization and function of the brain down to individual cell level, “said Bing Ren, PhD, director of the Center for Epigenomics, professor of cellular and molecular medicine at UC San Diego School of Medicine and member of the Ludwig Institute for Cancer Research at UC San Diego .

“Depth and specificity are essential,” agreed Eran A. Mukamel, PhD, director of the Computational Neural DNA Dynamics Lab and associate professor in the Department of Cognitive Sciences at UC San Diego. “We want a complete list of the parts of the brain, including not only the locations and connections of neurons, but also the molecular and epigenetic fingerprints that give them their specialized identity.”

Elements of genetic regulation

Since 2006, there has been a concerted international effort to create a three-dimensional atlas of the brain of mice, which is about the size of a pea and includes around eight to 14 million neurons and glial cells. Although the mouse brain is not a miniature version of the human brain, it has proven to be a powerful model for studying many functions, diseases and mental disorders of the human brain, in part because the genes responsible for building and the functioning of human and rodent organs are 90 percent identical.

In their article, lead author Ren, his colleagues and collaborators at the Center for Epigenomics focused on creating an atlas of regulatory elements of genes in the mouse brain, the most evolving brain region of the brain. which supports high level sensory perception, motor control and cognitive functions. .

Recent investigations of mouse and human brains have revealed that the brain contains hundreds of types of neural cells spread across different regions, but transcriptional regulation programs – the directions responsible for each cell’s unique pattern of gene expression. , and therefore its identity and function – remain unknown. .

Ren’s team probed accessible chromatin – the stuff of chromosomes – in more than 800,000 individual cell nuclei from 45 locations in the brain of adult mice, then used the data to map the state of 491,818 elements. candidate cis-regulatory DNAs in 160 distinct cell types. Cis-regulatory elements are regions of non-coding DNA that regulate the transcription (copy of a segment of DNA into RNA) of neighboring genes.

They found that different types of neurons are located in separate areas of the mouse brain and that the specificity of their spatial distribution and function is correlated, and probably determined, by the unique set of cis DNA elements. -regulators within each type of cell. Indeed, some of the cell-type-specific elements identified by Ren’s team have been shown to be independently sufficient to drive the expression of the reporter gene in specific subclasses of neurons in the mouse brain.

Surprisingly, most of the mouse brain cis-regulatory elements mapped by the researchers have homologous or similar sequences in the human genome that can act as regulatory elements, and therefore could be used to annotate the regulatory elements of the genes involved in the specification. the type of human brain cells.

Ren said the findings provide a basis for a comprehensive analysis of genetic regulatory programs in the brains of mammals, including humans, and may help interpret the non-coding risk variants that contribute to various diseases and neurological traits in the brain. man.

Transcriptomic and epigenomic elements

Each cell or population of cells produces a unique pattern of RNA transcripts – strands of RNA transcribed from DNA that transmit genetic instructions for the proteins that direct and sustain life. It is estimated that millions of chemical reactions occur every second in mammalian cells. This complexity, combined with growing datasets describing the functions of genes, fats, proteins, sugars, and other players in cell biology, has complicated efforts to understand how the brain is organized and functions.

Mukamel and his colleagues have brought together advanced sequencing techniques to focus on the mouse’s primary motor cortex, a region of the brain fundamental for movement. They have generated more than 500,000 transcriptomes and epigenomes – comprehensive lists of all the RNA molecules and DNA modifications that make every mouse brain cell unique.

Using new computer and statistical models, they created a multimodal atlas of 56 types of neuronal cells in the mouse primary motor cortex that details their molecular, genomic and anatomical characteristics.

Mukamel said the study showed that each brain cell has a coordinated pattern of gene expression and epigenetic regulation that can be recognized with high fidelity using different sequencing techniques. Just as an individual has characteristic handwriting, facial features, vocal patterns, and personality traits, the authors found that the RNA and DNA signatures of cell types in the motor cortex differentiate each cell from its neighbors.

And just as our human individuality contributes to the strength and diversity of our communities, Mukamel said, the unique patterns of gene expression and regulation in brain circuitry support a very diverse network of cells with specialized roles and functions. interrelated functions.

By combining epigenomic and transcriptomic data from an unprecedented number of cells, Mukamel said the study demonstrates the potential of single-cell sequencing technologies to comprehensively map brain cell types – a lesson that will help understand the circuitry. more complexes of the human brain.

“An Atlas of the Regulatory Elements of Genes in the Adult Mouse Brain”
Co-authors include: Yang E. Li, Sebastian Preissl, Xiaomeng Hou, Ziyang Zhang, Kai Zhang, Yunjiang Qiu, Olivier Poirion, Bin Li, Joshua Chiou, Naoki Kubo, Rongxin Fang, Xinxin Wang, Jee Yun Han, Yiming Yan , Michael Miller, Samantha Kuan, David Gorkin, Kyle J. Gaulton, and Eran A. Mukamel, all at UC San Diego; Hanqing Liu, Jacinta Lucero, Antonio Pinto-Duarte, Michael Nunn and M. Margarita Behrens, Salk Institute; Xiaoyu Yang and Yin Shen, UCSF; and Joseph R. Ecker, Salk and Howard Hughes Medical Institute.

“A transcriptomic and epigenomic cellular atlas of the mouse primary motor cortex”
Co-authors include: Zizhen Yao, Darren Bertagnolli, Tamara Casper, Kirsten Crichton, Nick Dee, Olivia Fong, Jeff Goldy, Mike Hawrylycz, Matthew Kroll, Kanan Lathia, Delissa McMillen, Thuc Nghi Nguyen, Thanh Pham, Christine Rimorin, Kimberly Smith, Josef Sulc, Michael Tieu, Amy Torkelson, Herman Tung, Bosiljka Tasic, Hongkui Zeng, and Cindy van Velthoven, all at the Allen Institute for Brain Science; Hanqing Liu, Andrew I. Aldridge, Anna Bartlett, Chongyuan Luo, Joseph R. Nery, Sheng-Yong Niu, M. Margarita Behrens, Jacinta D. Lucero, Julia K. Osteen, Antonio Pinto-Duarte and Joseph R. Ecker, all at the Salk Institute; Fangming Xie, Wayne I. Doyle, Rongxin Fang, Xiaomeng Hou, Olivier Poirion, Sebastian Preissl, Xinxin Wang, and Bing Ren, all at UC San Diego; Seth A. Ament, Jonathan Crabtree, Heather Creasy, Michelle Giglio, Victor Felix, Brian R. Herb, Ronna Hertzano, Anup Mahurkar, Joshua Orvis, Héctor Corrada Bravo, Jayaram Kancherla, Owen R. White, all at the University of Maryland ; Koen Van den Berge, Sandrine Dudoit, Elizabeth Purdom, Hector Roux de Bézieux and John Ngai, all at UC Berkeley; Tommaso Biancalani, Elizabeth L. Dougherty, Naeem M. Nadaf, Eeshit Dhaval Vaishnav, Aviv Regev, Charles R. Vanderburg and Evan Z. Macosko, all at the Broad Institute of MIT and Harvard; Yang Eric Li, Ludwig Institute for Cancer Research; Sina Booeshaghi, Valentine Svensson, and Lior Pachter, all at the California Institute of Technology; Carlo Colantuoni, Johns Hopkins University; ; Qiwen Hu and Peter V. Kharchenko, Harvard Medical School; Vasilis Ntranos, UCSF; Davide Risso, University of Padua; Angeline C. Rivkin, Howard Hughes Medical Institute; Kelly Street, Dana-Farber Cancer Institute; Z. Josh Huang, Stephan Fischer, Jesse Gillis, Megan Crow, Cold Spring Harbor; Joshua D. Welch, University of Michigan.

Funding came, in part, from the National Institutes of Health (grant U19MH11483), Howard Hughes Medical Institute, National Institutes of Health BRAIN Initiative (grants U19MH114830, U19MH121282, U19MH114821, R24MH114788, U24MH114827, R24MH114815) National Institute on Deafness and Other Communication Disorders (DC013817), the Hearing Health Foundation and the National Institute of General Medical Sciences (GM114267).

Disclosures: Ren is co-founder and consultant of Arima Genomics Inc. and co-founder of Epigenome Technologies. Gaulton is a consultant to Genentech and a shareholder of Vertex Pharmaceuticals. Ecker is a member of the scientific advisory board of Zymo Research, Inc. Kharchenko sits on the scientific advisory board of Celsius Therapeutics, Inc. Regev is a shareholder and founder of Celsius Therapeutics, a shareholder of Immunitas and a member of the scientific advisory board of Syros Pharmaceuticals, Neogen Therapeutics , Asimov, and Thermo Fisher Scientific.

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