BRAIN Initiative: The First Comprehensive Atlas of Brain Cells as Proposed by Neuroscientists 

Even with the discovery of many distinct groups of cells in the brain by other scientists, this particular discovery of all the cell kinds in the primary motor cortex is a breakthrough to help us comprehend how these cells work to control our bodily functions and thought processes, and how their functions are affected in instances of physical and psychological impairments.Human Brain

What has been happening?

Recent investigation has shown that the primary motor cortex, a region of the brain tasked with controlling our movements both to and away from a stimulus is comprised of up to 116 distinct groups of cells. These cells function simultaneously to help bring about distinct kinds of movements.

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The investigation studies, up to 17 of them in all are the culmination of five years of work put in by a large group of investigators. Their work which appeared online in the journal Nature on October 6th was backed by the National Institute of Health’s Brain Research through Advancing Innovative Neurotechnologies (BRAIN).

The aim of the investigation was to establish the identity of the numerous groups of cells in a given part of the brain. This was the preliminaries in an extended project of creating an atlas of the brain to facilitate our understanding of the brain’s neural connections and how they control our bodily functions and thought processes and to also understand how physical and psychological impairments disrupt the normal functioning of the brain.

Cellular neuroscientist Helen Bateup, an associate professor of molecular and cell biology at the University of California, Berkeley, and a co-author of the flagship paper that synthesizes the results of other papers suggested that in order to understand an extremely intricate machine such as the brain, we must first break it down and familiarize ourselves with the parts.

She further added that the beginning of any manual on how the brain functions should have a detailed description of the brain’s cellular components, their size, their locations, and the things they interlink with.

What are the findings?

Previously, dozens of cell kinds have been identified by individual investigators on the basis of the cell’s properties:  form, size, excitability, and the kinds of genes expressed in them. But the new investigation identifies up to five times more cell kinds. These new-found cell kinds also include sub kinds of many other famously known kinds of cell. An illustration of this is cells that release particular neurotransmitters like Glutamate or GABA. These cells have numerous sub kinds and these sub kinds can only be differentiated from each other by their electrical firing process and by their gene expression.

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Even though most of the investigation in the papers are focused on the motor cortex, more investigation is still being carried out by the BRAIN initiative cell census network (BICCN) which was created in 2017, to establish the identity of all the distinct kinds of cell in the brain which comprises of more than 160 million single cells made up of neurons and supporting glia.

It is useful to note that the BRAIN initiative was initiated in 2013 by Barack Obama who was the president then. Bateup further added that after identification and definition of the distinct parts of the brain, we could level up and try to figure out how the distinct parts of the brain work collectively, how they create a functional circuit, and how they elicit our perception of things, our conduct, and other intricate functions.

Bateup also collaborated with former UC Berkeley professor, John Ngai, and UC Berkeley colleague, Dirk Hockemeyer to experiment on mice using CRISPR-cas9. In these mice, a particular cell kind is marked with a fluorescent marker which allows for monitoring of the cellular connections in the entirety of the brain.

Bateup mentioned that the Berkeley group created two kinds of knock-in reporter mice which brought to light new devices for explaining the communication between the freshly discovered groups of cells, which they did for the Flagship journal paper.

Ngai, the former leader of UC Berkeley’s BRAIN Initiative efforts before he was taken to manage the entire nationwide initiative mentioned that the drawbacks to the development of working brain disorder treatments are our deficit knowledge about the cells and cellular connections that are altered by distinct diseases which makes establishing the precise location that needs the treatment almost impossible. He also added that elaborate information about the characteristics of the distinct brain cells will progress the development of neurologic disease treatments.

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It should be noted that Ngai is also one of the Flagship paper’s 13 corresponding authors, which comprises over 250 co-authors.

The trio of Bateup, Hockemeyer, and Ngai also worked together on an earlier project to study and profile the entirety of the active genes in single dopamine-producing cells in the midbrain of a mouse that has structures resembling that of human brains.

The profiling methodology they used, is the same one that was used by other BICCN investigators to profile cells in the motor cortex by establishing the identity of the particular messenger RNA molecules and their levels in each cell. This analyzing methodology is called transcriptomics, and it works by utilizing single-cell RNA sequencing (scRNA-seq)

The BICCN used several experimental techniques to characterize the distinct cell kinds in distinct kinds of mammals. One of them was the scRNA-seq technique.

About four of the techniques used were for establishing the identity of the distinct levels of gene expression, and to ascertain the architecture of the genome’s chromatin and the status of its DNA methylation which is known as the epigenome.

There were some other techniques that were employed and these include electrophysiological patch-clamp records, used to distinct cells on the basis of their ability to fire action potentials, grouping the cells by their forms, figuring out the cell connectivity, and examining areas of the brain where the cells are spatially located. A lot of these techniques utilize artificial intelligence and machine learning to differentiate the cell kinds.

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Hockemeyer’s opinion of this is that this was the most all-encompassing description of the cell kinds. He concluded by highlighting the noteworthy overlap and the uniformity found in determining the cell kinds using a distinct methodology.

The best way to categorize the cells into distinct groups and distinct functions based on the observable distinctions in the epigenetic profile of the cells and their expression was determined by a group of statisticians who combined the data of all the distinct experimental methods.

Sandrine Dudoit, a UC Berkeley professor and chair of the department of Statistics mentioned that even though there was an abundance of statistical algorithms for analyzing such data, that it was a challenge to actually determine which cell kinds were truly distinct from one another. She co-authored the flagship paper with biostatistician Elizabeth Purdom, a UC Berkeley associate professor of Statistics and the other key member of the statistical group.

Dudoit mentioned that the idea was not to create a de novo clustering method, but to find ways of maximizing the expertise of the distinct pre-existing methods and to find ways to combine mentioned methods that would assess the stability of the results and their reproducibility.

She also mentioned that irrespective of the algorithm that is used for the investigation, you would get clusters of data and that it was crucial to have confidence in whatever results were gotten.

Bateup again deduced that the methodology used would determine the number of individual cell kinds to be discovered in new studies. These ranged from dozens to 116.

An illustration of one of the findings was that humans had as many as two times the amount of distinct inhibitory neurons and excitatory neurons in a part of the brain, while the mice had up to five times the amount.

Bateup further mentioned that previously, 10 or 20 distinct cell kinds had been defined, but that they had no idea if the cells they had defined by their gene expression patterns were the same as the ones they had defined on the basis of electrophysiological properties or the same as the morphology defined neuronal kinds.

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Hockemeyer then mentioned that the great progress of the BICCN was that they had integrated distinct ways of distinguishing a cell kind into coming up with a consensus taxonomy that takes the totality of the properties of the cell kinds into account and not just based on the physiology, the morphology or the expression of the cell’s genes. In his opinion, the knowledge of the gene a cell kind expresses, its morphology, its physiological properties, and the region it is located enables us to have a much deeper and granular understanding of what the cell kind is and the basic properties it possesses.

Dudoit however warned that upcoming studies could possibly show that the amount of motor cell kinds found in the motor cortex is an overestimate of the actual amount, but she mentioned that in assembling a cell atlas of the whole brain, the current studies are a good way to start.

Dudoit added that there were contrasting opinions among biologists on the amount of resolution to be had for the systems.

She then concluded by pointing out that the results gotten were because of the collaborative effort of distinct groups, communicating and working well with each other.

The UC Berkeley group is composed of other members which include Rebecca Chance and David Stafford, Daniel Krame, Shona Allen, Hector Roux de Bezieux, and Koen Van den Berge.

Bateup is a recognized member of the Helen Lewis Neuroscience institute, and Hockemeyer is a member of the Innovative Genomics Institute. Both institutes are investigators which are funded by the Chan Zuckerberg Biohub.

Final Thoughts

The work of these researchers is truly phenomenal. Their research is on the path of changing our perception of how the brain functions and all of the neuroscience as a whole for the better. We can not wait to see what more they and other determined researchers can come up with.

Read Also: Can Neurons Regenerate? A New Study Says They Can


A multimodal cell census and atlas of the mammalian primary motor cortex




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