Cell atlas created of brain region for damaged movement in ALS

A detailed atlas of the different cell types that inhabit the motor cortex, the region of the brain that controls voluntary movement and is damaged in people with amyotrophic lateral sclerosis (ALS), has been created by a global consortium of researchers.

The group’s long-term goal, which involves hundreds of scientists, is to create a cell atlas of the entire brain to better understand the diseases that affect it and to develop more effective treatments.

Their atlas of motor cortex cells is described in a special collection of 17 scientific studies published in the journal Nature.

“Mapping the motor cortex can lead to a better understanding of diseases where the neurons that control our movements are attacked, such as ALS”, Sten Linnarsson, PhD, professor of molecular systems biology at Karolinska Institutet in Sweden and co-author of several of the articles, said in a press release.

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ALS is characterized by the death of motor neurons, the specialized nerve cells that control voluntary movement. These nerve cells send signals from the brain to the spinal cord and then to the muscles.

Primary motor neurons are located in the motor cortex, the region of the brain involved in the planning and execution of voluntary movements. While the motor cortex plays a central role in movement, the process involves millions of neurons in different parts of the brain.

To better understand this process, a detailed analysis of different cell types in the motor cortex of humans, mice, and marmoset monkeys was analyzed by a research consortium as part of the BRAIN Initiative Cell Census Network (BICCN).

Their work was primarily funded by the National Institute of Mental Health in the United States, which is part of the National Institutes of Health (NIH). The NIH launched the BICCN in 2017.

“In order to understand how the brain works and what goes wrong when we have a disease, we need to start by looking at the brain’s most important building blocks, the cells,” Linnarsson said. “Once we have created a catalog of all the cell types that together make up our brains, we can learn more about how they interact with each other in a system. “

In the consortium’s flagship study, “A multimodal cell census and an atlas of the primary motor cortex of mammalsThe scientists first divided the millions of neurons and other types of cells in the motor cortex into different categories. They then used various methods to measure the properties of individual cells.

The researchers looked at the activity of a full set of genes in cells and their location, the three-dimensional shape of cells, their electrical properties, and how they connect to neighboring cells.

This work has revealed an interconnected genetic landscape of cell types that have integrated their gene expression (activity), as well as common points of gene expression that are similar in mouse to marmoset and humans. Examining gene expression at the single cell level provided locations for cell types in the motor cortex to create an atlas, and how specific gene activity dictated characteristics of neurons, such as their physiological and anatomical properties.

A detailed comparison of these species was reported in the study, “Comparative cellular analysis of the motor cortex in humans, marmosets and mice. “

Here, using large-scale gene expression profiling of more than 450,000 individual cells, the team demonstrated that most cells in the motor cortex have retained homologs in all three mammalian species. In addition, only a few genes and regulatory mechanisms were responsible for these similarities.

The differences between species were related to the proportion of cells, their shapes and electrical properties, as well as single active or inactive genes.

Classification based on gene expression has also made it possible to measure the electrical signals, genetic analysis and anatomy of human Betz cells – large motor neurons that communicate with the spinal cord and are damaged in ALS.

These results highlight the molecular mechanisms linked to the diversity of cell types in mammals and describe the genes and regulatory pathways responsible for cell function by type and their changes between species.

“But the project doesn’t end there,” Linnarsson added. “Together, we will continue to map other areas of the brain until we have a complete cell atlas of the entire human brain.”

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