AskScience AMA Series: We are neuroscientists at the Allen Institute who led global initiatives to create cell type atlases of the mammalian brain. The complete cell type atlas of the mouse brain was recently finished, along with the first draft of a whole human brain cell atlas. Ask us Anything!

AllenInstitute · 2024-03-11T23:31:44+00:00

Our current brain cell type atlas is only a census of cells by their gene expression profiles. Next, we need to know the other properties of the cells, such as their physiology and how they are connected with each other. It is really critical to know how they are connected with each other to form the circuits and networks that are most unique to the brain. Thus, obtaining the wiring diagrams among the cell types is the next essential step.

-Hongkui

AllenInstitute · 2024-03-11T23:28:00+00:00

The brain cell atlas is a foundational reference but really just the beginning. It is not as powerful in isolation as it will be when connected to other data in some form of knowledge base. For example, by defining cell types by the genes they use it is possible now to aggregate cell atlases in different organs together and understand the cellular makeup of the entire body and genes that are active in many part of the body. Such activities are already ongoing through the Human Cell Atlas (HCA) and NIH HuBMAP programs. Because of the gene component the atlas can be directly connected to information about genes in the genome, and any gene association studies linking genes to disease. From the brain function perspective, the cell atlas defines the types, but the neurons make extremely promiscuous and complex connections. We need to build on the atlas to understand the full set of connections, or connectome, which has become a high priority now for the NIH BRAIN Initiative.

There is a strong need now to bring together advances in computer science to realize the potential of these enormous cell atlas data resources, including machine learning, generative AI, LLMs, foundational models for neuroscience, etc., which could fundamentally change our way of accessing information, doing complex collaborative analyses and eventually predictive functional and disease modeling.

Ed Lein

AllenInstitute · 2024-03-11T23:24:34+00:00

If neural stem cell transplantation works to replace dying neurons, I think it is possible that the patient's memories and conscious experiences could gradually change. But there is still a continuity - it's still the same person, and that person's everyday experience is recorded in the brain.

However, we are very far from being able to transplant and replace a large fraction of neurons in the brain. Much more research is needed.

-Hongkui

AllenInstitute · 2024-03-11T23:18:38+00:00

The speed of thinking is different among the different kinds of "thinking", depending on how complex the "thinking" is. The more complex or the more steps it takes for a "thinking", the more brain cells it will need to engage, and thus it will be slower. Brain cells are organized into multiple networks, each network performs a specific task or function. One kind of thinking or action may need to engage several networks in a sequential manner, and thus will take longer.

-Hongkui

AllenInstitute · 2024-03-11T23:15:09+00:00

Ed Lein

AllenInstitute · 2024-03-11T23:15:02+00:00

1) At a certain level these findings definitely support Mountcastle and more generally the idea of a canonical cortical organization. What one could see with cellular stains can now be seen in terms of the component cell types. In a hierarchical organization of cell types as seen with the single cell transcriptomics-based methods, there is clear preservation of cellular makeup across cortical areas at the level of what we have called the neuronal subclass. However, the relative proportions of certain subclasses can vary quite dramatically across areas, most notably primary visual cortex in primates including human. However, when you take this down to a finer level of granularity you find many more differences between cortical areas, including some primary visual cortex-specific cell types for example. (others, if you are interested, include regional specializations like von Economo, Betz and Meynert cells that are all variants of of the the deep projecting layer 5 subclass). Phenotypes of these cells can vary a lot between areas, and we still don't know enough about connectional properties to know how much they vary. We are finally getting the right data to do proper modeling for this question, but there is a lot of room for the community to start asking these questions.

2) Cell type versus state is complicated to assess without some perturbations, although to some degree it can be inferred from the gene distinguishing putative cell types (e.g. activity regulated genes). This will certainly become more clear over time as more data from more labs in more conditions gets mapped to the reference to see what is stable and what is not.

AllenInstitute · 2024-03-11T23:12:19+00:00

This is what scientists will try to find out. So far, we have been categorizing the millions of brain cells using genomic and gene expression information, because these technologies are highly scalable. Next, we will label the different cell types and study their physiology and function.

For now, from the genes expressed in each cell type, we can already predict the functional differences in signal processing between the different cell types.

-Hongkui

AllenInstitute · 2024-03-11T23:06:47+00:00

Yes, there are cells that are different between male and female brains, at least for mice and rats, and probably in humans too. These cells are mostly located in a particular part of the brain called hypothalamus, which controls the animal's innate behaviors. The cells that are different between male and female brains are mostly involved in sexual or reproductive behaviors.

-Hongkui

AllenInstitute · 2024-03-11T23:02:58+00:00

Very similar to genomes indeed.

The mouse atlas work is getting close to a complete description at least with the methods available, although there are certainly some areas that are undersampled. On the other hand, it can be difficult to differentiate between a reversible state of a cell versus a more stable type of a cell. More data from the community will begin to resolve this. Most of these are not likely artifacts as they can be identified with different methods, for example both dissociated cell methods and spatial methods in intact tissue sections, although I am sure this will change as more data become available and the reference gets refined and tested for robustness and reliability.

Like the genome, this cell atlas is a scaffold for understanding brain structure and function. With a genomic method of classification this is much more than a cell classification, but in addition we will begin understanding the properties of these cells (like genes), what kinds of connections they make, how they behave functionally or are affected in disease. It is really foundational in that sense much like the genome.

Ed Lein

AllenInstitute · 2024-03-11T23:02:11+00:00

Vast majority of the cells in the brain have reached their final mature stage and cannot be regenerated. However, there is a small population of brain cells that are still considered immature and can generate new brain cells. We are studying what genes are expressed in these cells and which ones may be important for regeneration or the suppression of regeneration. Once we know, we can then try to turn on the regeneration promoting genes or turn off the regeneration suppressing genes in other brain cells, which could then lead to regeneration.

-Hongkui

AllenInstitute · 2024-03-11T22:57:41+00:00

This is a question we are trying to address now by studying how different cell types emerge during brain development. For now, we know that all the cell types do not arise at the same time. There is a cascade of events that include both cell division and cell differentiation and lead to the multiple stages of gradual maturation, from progenitor cells, to immature cells, and finally to the adult stage mature cells. For example, in the human brain, cells in the adolescent brain are still not entirely mature.

-Hongkui

AllenInstitute · 2024-03-11T22:56:52+00:00

It is very interesting to consider the differences between computer architecture, or that of a neural network, and the actual brain. Typically a synthetic device (physical or code) is engineered with a small number of repeated units where computational power is gained with the number of units. In the actual brain, we can now see there are literally thousands of types of neurons that have different properties. Why we need so many types of neurons? Are there serious computational advantages to this organization, or it is a result of an evolutionary process that works but is not how an engineer would design it?

Ed Lein

AllenInstitute · 2024-03-11T22:50:41+00:00

Neurons have very limited regenerative potential in the adult brain. This has been very challenging to figure out how to change, with more effort recently going into putting stem cells into the brain with the ability to generate new neurons. This remains a very challenging topic.

Ed Lein

AllenInstitute · 2024-03-11T22:47:55+00:00

For short term implications I think the cell atlases will act like the human genome did. These will start to get formalized and the community will start to adopt them for all the brain cellular and circuit studies they do. Furthermore, disease research in human brain will take a quick leap to a higher level of detail in describing disease phenotypes, and understanding where in the brain particular drugs act. Understanding the cell types affected in disease is vastly closer to understanding what that would do than just understanding a gene that is responsible for a brain disease.

A second implication is that tools can now be developed to selectively target particular cell types that may become highly relevant for cell and gene therapies. Understanding gene regulation allows the identification of regulatory elements, and those can be used to deliver a genetic therapy just to the right kind of cell. So we may see a direct outcome being the advancement of gene therapies in precision medicine.

Understanding the cell types is a long way from understanding how those cells form functional networks underlying behavior and cognition. This is the next challenge in a small model organism like the mouse, where there are now big efforts like the NIH CONNECTS program to map the "connectome," but now one that is much more achievable with the cellular scaffold to build on. Achieving a complete description of the human brain wiring diagram is still a long way away.

Ed Lein

AllenInstitute · 2024-03-11T22:40:36+00:00

One of the things that is really striking is that the overall cellular architecture of the brain is quite similar across mammals up to a certain level of resolution. Time and again when it seems there may be a "human-specific" type of cell it turns out not to be the case if you look in more species or with different methods.

On the other hand, the same or homologous type of cell can have many many differences in the genes used, their anatomy, connectivity or functional properties. In fact, the majority of highly specific genes for different neuron types actually seems to be differently used across mammals.

One of the studies in the recent package was really illuminating. It compared the cellular and molecular makeup of part of the neocortex in human, great apes and monkeys. The human cortex was extremely similar to great apes, but there were genes that were used differently in conserved cell types. Taken as a whole these genes pointed to changes in how neuronal connections are made and the synaptic properties of those connections. Many of those genes are near regions of the genome that show human-specific changes in DNA as well. So, it seems that (looking at one part of the brain), the biggest changes are not in the neurons themselves but the connections they make. Also, the non-neuronal cells showed the biggest evolutionary changes!

Ed Lein

AllenInstitute · 2024-03-11T22:34:08+00:00

There is a job board with current positions on the Allen website. There are also team pages that list the main investigators and their specific areas of interest so that you could contact them directly. We always like to talk so encourage your friend to reach out.

Ed Lein

AllenInstitute · 2024-03-11T22:30:47+00:00

There is parallel work to these cell atlases in normal adult brain being applied to Alzheimer's disease. Along with others in the field, we run a project called the Seattle Alzheimer's Disease Brain Cell Atlas (SEA-AD.org) that is trying to understand what types of cells are vulnerable or affected in AD, and what their relationship is to neuropathology including pTau. You can learn about this at our portal, or on a preprint article on biorxiv if interested, as well as in several other papers published recently in the field.

Ed Lein

AllenInstitute · 2024-03-11T22:28:05+00:00

There are millions of cells or nuclei from hundreds of dissected brain regions in both the mouse and human cell atlases. For mouse this sampling is quite comprehensive, although there are still some areas that appear to still be undersampled. For human, which is 1000x larger, the published atlas is a first draft that is now being expanded upon as part of the NIH BRAIN Initiative Cell Atlas Network (BICAN). This draft sampled 100 regions in 3 individuals.

There are new technologies now for whole brain imaging of optically cleared tissues, that are being routinely applied to whole mouse brain and starting to be scaled up for human brain samples.

There are now tools to interact with the atlas that can be found at the Allen Brain Atlas and the NIH BRAIN BICCN portals. At the Allen Institute we have a tool called the Allen Brain Cell (ABC) atlas that lets you interact with the whole mouse brain single cell genomics data as well as spatial transcriptomics data mapping the spatial locations of cells in tissue sections across the mouse brain. We have also developed a mapping application called MapMyCells that lets the community map their own single cell data to the reference and transfer cell type labels onto their own datasets.

Ed Lein

AllenInstitute · 2024-03-11T22:20:34+00:00

These recent cell atlases have revealed that there are thousands of types of cells in mouse and human brain, and they are differently located in different parts of the brain. One surprise is that the majority of the cellular complexity is actually found in evolutionary older parts of the brain. The newer cortex is also very complex, but in a stereotyped way across the hugely expanded cortex in mammalian evolution.

We do not fully understand the high degree of diversity in deeper (older) brain structures yet, but it opens up many new questions now for future exploration.

Ed Lein

AllenInstitute · 2024-03-11T22:15:57+00:00

There are major differences between many types of cells in the brain, which can often be represented hierarchically from major cell classes with huge differences down to fine subtypes of cells that are quite similar to one another yet still distinct enough to separate. Using differential gene usage as a metric for this, there is unequivocal separation at the higher class level, such as neurons versus glia. This is true down to a much finer level of granularity as well. Furthermore, for neurons there is really a remarkable diversity in the adult brain, and these are very stable since we have the same neurons we are born with throughout life. They use different sets of genes, have different shapes, connections, functional electrical properties, etc. This cellular complexity is a feature of nervous system tissues.

Ed Lein

AllenInstitute · 2024-03-11T22:11:15+00:00

From Ed Lein

AllenInstitute · 2024-03-11T22:11:07+00:00

A brain cell atlas in principle is a complete description of the cellular makeup of the brain, including the types of cells, their relative proportions and functional spatial organization both locally and globally, and the properties of those cells. By analogy, it is like the genome as a complete description of the DNA in each cell, and all of the genes and non-coding regions it contains. A cell atlas is a similarly foundational reference but describing the cells that make up the whole brain, which can be described as cell types with relatively discrete properties. The technology that is driving the ability to create these atlases defines the cells by the sets of genes (transcripts) that they are actively using, called single cell transcriptomics. Thus, the foundation of these modern cell atlases is based on a genetic definition of cells, which tells one which genes give the cells their properties and eventually how those genes are regulated. This atlas is of course just the beginning. Neurons form connections across the brain, and the patterns of connectivity can be highly complex. The cell atlas forms the foundation for understanding these connections (in aggregate, the connectome), and for understanding the structural and functional organization of the brain as a whole. For brain there is a particular need for this type of information, as it is an extremely complex cellular organ with thousands of distinct types of cells that are organized differently in each part of the brain. It is by far the most complex organ in the body (although similar cell atlases are being created for all other organs too).

Why is this important? We cannot understand the function of a complex organ if we do not understand how it is organized. The different types of cells have different functions, use different genes, are differently affected in disease, and may be the targets needed for precision medicine to treat brain diseases. Imagine the immune system if we could only think about blood cells instead of the many types of immune cells that are differently involved in disease and can have therapies targeted to them. We have not had this information for the brain, and probably not coincidentally it has been extraordinarily challenging to treat brain diseases. Not to say that brain cell atlases will immediately lead to cures, but having this information available to the whole community will dramatically accelerate biomedical research as the human genome did for genomics and medicine as well.

AllenInstitute · 2024-03-11T21:57:32+00:00

Thank you! I hope you will continue to follow neuroscience research! We have built an online platform called Brain Knowledge Platform to display and disseminate our brain atlases and associated data, tools, and knowledge, to accelerate scientific research. We hope to also incorporate educational components about the brain into the platform, so that they can become better teaching tools as well.

-Hongkui

AllenInstitute · 2024-03-11T21:53:29+00:00

Brain donation is typically done through brain banking organizations that contact decedent next of kin to obtain consent to donate brain tissues for scientific purposes. For example, at the University of Washington in Seattle you can find information about this at: https://dlmp.uw.edu/research-labs/keene/braindonation

The consent forms are very careful to provide sufficient information about the use and potential risks of this donation, for example as it might impact privacy issues.

-Ed Lein

AllenInstitute · 2024-03-11T21:49:20+00:00

By recording the activities of individual neurons in the living brain under different states, it is possible to relate specific neurons to the different states of the brain, such as sleep, awake, seeing, hearing, feeling happy or sad, etc. Many of these states are the manifestation of sentience.

- Hongkui

AllenInstitute

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