Mapping millions of cells in the mouse brain

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Building a map of the complex human brain and its roughly 100 billion individual neurons is no easy task. As a precursor to this monumental challenge, the researchers started with something smaller and easier – the mouse brain – to understand different types of cells and how they are connected, and also to hone technological approaches. to do it.

Now, a new article describes the minute genomic details of the mouse brain at unprecedented resolution and how several types of genomic techniques were combined to enable this analysis, led by graduate student A. Sina Booeshaghi (MS ’19) .

The study was carried out mainly in the laboratory of Lior pachter (BS ’94), Bren Professor of Computational Biology and Computing and Mathematical Sciences, and is part of a collaboration called Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative – Cell Census Network (BICCN), funded by the National Institutes of Health . This study and several other articles from the BICCN collaboration appear in the journal Nature October 6.

In this new group of papers, 13 teams focused on the mouse’s primary motor cortex, the region of the mouse brain that controls movement.

Booeshaghi’s team analyzed genomic data from brain cells collected by collaborators at the Allen Institute, a nonprofit bioscience research organization based in Seattle, Washington. By combining three different experimental techniques, each with their own strengths and weaknesses, the team was able to perform detailed characterizations of gene expression in brain cells in the cortex of mice. Combining techniques, says Pachter, leverages the strength of individual techniques in a way that achieves more than the sum of their parts.

The study reached a granular level of detail by examining what are known as isoforms of genes. To understand isoforms, it is necessary to understand the expression of the individual RNA transcripts that make up the genes; gene expression is the process by which the DNA of a gene is transcribed into RNA, and then the RNA is read by molecular machinery to create proteins. In higher eukaryotes like humans, this flow of information includes a process called splicing, in which RNA is cut up and some of its pieces are glued together before being transformed into protein. This cut-and-paste process produces many “flavors” of transcripts of the same gene: isoforms. Isoforms can translate into proteins with different functions.

By examining these isoforms, Booeshaghi and colleagues determined that the variants are a crucial aspect contributing to the functional differences between brain cells. Examination of isoforms is particularly important in the brain; the splicing process is very active in the brain tissue and many neurological diseases result from disruptions in splicing.

The article is titled “Isoform cell type specificity in the mouse primary motor cortex”. In addition to Booeshaghi and Pachter, other co-authors are Zizhen Yao, Cindy van Velthoven, Kimberly Smith, Bosiljka Tasic, and Hongkui Zeng from the Allen Institute for Brain Science. Funding was provided by the National Institutes of Health Brain Initiative. Lior Pachter is a member of the faculty affiliated with the Tianqiao and Chrissy Chen Neuroscience Institute at Caltech.

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