The "magic elves" that belong only to humans? They are hidden in your brain and mine

Produced by: Science Popularization China

Author: Ma Junjie, Qi Ruicheng (Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences)

Producer: China Science Expo

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Human intelligence far exceeds that of other species and has created a brilliant modern civilization.

You must be wondering, what exactly is different about us compared to other animals, especially chimpanzees, our closest relatives?

Chimpanzee eating

(Photo source: veer photo gallery)

The answer lies in the human brain. The brain is the repository of our higher cognitive functions, and its complexity is comparable to that of the universe. If you want to understand its mysteries, you need to understand it comprehensively.

One of the main research directions of my research team (Wang Guangzhong's team at the Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences) is to use data to understand the brain. We have been trying to explain how the brain works by analyzing and integrating big data at the whole brain level.

Figure: The relevant research results were published online in the international academic journal Molecular Psychiatry on September 3, 2024. The paper is titled "Human-unique brain cell clusters are associated with learning disorders and human episodic memory activity"

(Image source: Molecular Psychiatry website)

Recently, we have made progress in identifying brain cell populations that are specific to humans compared to primates and have found that human-specific cell populations are closely related to learning dysfunction, memory activity, and brain diseases.

So why do we study human-specific brain cells? How do we determine their functions?

Finding brain cells that are unique to humans is difficult, but it’s still a task

If you imagine the brain as a magic box full of magical power and creativity, then cells are the magic elves that build the human brain. Compared with chimpanzees, humans have more elves in their brains; but compared with larger species such as whales, humans have much fewer magic elves in their brains.

Therefore, scientists have been hoping to conduct further "household surveys" on each elf, classify and study these elves in order to find the magical elves that are unique to humans, and then further study what magic of these elves makes humans so unique.

MRI image of the head

(Photo source: Veer Gallery)

However, the number of brain cells is huge, as daunting as the vast starry sky. Finding specific cells in such a large cell population is like finding specific grains of sand in the vast ocean. The difficulty can be imagined. Each type of cell has a unique morphology, characteristics and functions. It is a daunting challenge to accurately identify human-specific cells from these hundreds of millions of cells. It not only requires advanced technical means, but also requires a lot of time and energy for data analysis. Therefore, identifying specific cells in the human brain and their functions is a difficult challenge.

The Journey of Discovering the Amazing Human Brain Cell Clusters (HUCCs)

As mentioned earlier, the number of brain cells is huge, and searching for specific cells aimlessly is like looking for a needle in a haystack.

What should we do? Fortunately, many senior scientists who are interested in the brain have done a lot of research. With the foundation they laid, we can find some directions to focus on.

In order to better study our brain, scientists have divided the brain into multiple brain regions based on physical structure and function, among which the prefrontal cortex is the most developed in humans.

Human brain structure

(Photo source: Sohu)

From primates to humans, the volume of the prefrontal cortex increases significantly. The proportion of the human prefrontal cortex to the total brain volume is much larger than that of other species. At the same time, the prefrontal cortex is the "center" of the brain, responsible for high-level cognitive activities such as memory, judgment, and decision-making.

So we hope to understand the cellular and molecular basis of human higher-level cognitive functions by exploring cells in the prefrontal cortex to reveal the differences between humans and other primates such as chimpanzees, rhesus monkeys, and marmosets.

So, after selecting the target, what method is used to conduct a "household survey" on the cells?

Using single-nucleus sequencing technology, a tool that can conduct a "household survey" of cells, we can efficiently detect the magic carried by different cell elves - gene expression. We have performed single-nucleus sequencing analysis on cells in the prefrontal cortex of humans, chimpanzees, rhesus monkeys and marmosets, and classified cells based on the similarity of gene expression. Cell elves with similar magic skills are divided into the same "family", and the magic that only circulates in this family (specific expression genes) is used as the iconic magic of this cell family.

By comparing gene expression differences, we found 2,717 genes that were only detected to be highly expressed in humans. Generally speaking, the higher the expression of a gene, the more important its function. We then used an analysis tool to identify cells with high gene expression, which we defined as human -unique brain cell clusters (HUCCs) .

Of all the cells in the human prefrontal cortex, about 10% are HUCCs. Among them, there are 11 excitatory neuron subpopulations and 9 non-neuronal cell subpopulations. We believe that it is these HUCCs with unique "magic skills" that, to a certain extent, give humans unique characteristics that distinguish them from other species. The remaining 90% of cells exist in both humans and primates and have similar gene expressions.

The research is not yet finished.

In brain science, there is a concept called "human accelerated evolution region". It refers to the DNA region in the human genome that evolves faster than other primates, often located near the enhancer region to enhance gene expression.

We further analyzed two human prefrontal cortex enhancer-regulated gene datasets and found that there was a high overlap with the human-specific highly expressed genes we identified, and that the expression levels of genes regulated by human-specific enhancers in HUCCs were significantly higher than those in cell populations conserved between species.

The regulation of the accelerated evolutionary regions of humans on the genome has endowed the human-specific cell elves HUCCs with special talents. These enhancer regions play an important regulatory role in the high expression of genes in neurons, especially excitatory neurons.

Data sampling locations in the human and primate prefrontal cortex

(Image source: Reference 1)

How do HUCCs affect brain function?

These specialized cells play a key role in the brain's cortical thickness and memory encoding.

In the magic box of the brain, excitatory neurons are the magic elves that issue "refueling orders" to strengthen the activities of downstream elves. They stimulate and command the surrounding magic elves (other neurons or cells), making the entire magic box full of vitality and magical changes, and promoting the manifestation of various wonderful thoughts and behaviors.

Many neurons in the brain are busy "commanding" the body

(Photo source: Veer Gallery)

We found that compared with conservative excitatory neurons, genes related to cortical thickness were significantly more highly expressed in excitatory neurons of HUCCs. These genes are also closely related to static brain activity and memory encoding processes. The enhancement of these magics in HUCCs promotes the development of the human cerebral cortex and also enhances human memory and thinking abilities.

Furthermore, by comparing the similarities of magic carried by cellular elves and clustering similar magic together through gene co-expression analysis, we found that magic related to higher-level cognitive functions was significantly enriched in modules of HUCCs, and the main functions of these modules included regulating synaptic density, vascular morphogenesis, and encoding cell adhesion molecules.

The key magic genes in the module include FRMPD4, DLGAP2, FOXP1 and PDZRN3, which are at the core of the functional modules enriched in HUCCs. In addition, scientists have previously found that these genes are involved in cognitive functions and nervous system homeostasis.

As two sides of the same coin, unique HUCCs are also associated with a higher risk of brain disease

The unique magic of HUCCs cell elves not only promotes the evolution of advanced cognitive functions of the human brain, but also brings a higher risk of brain diseases.

We found that some gene regulation in HUCCs is significantly enriched with risk genes that can cause mental illness. The magic associated with learning disabilities is highly expressed in seven HUCCs excitatory neuron subpopulations, which means that once the magic carried by these cells fails, or the health of these cell elves is threatened, it is likely to cause symptoms of learning disabilities in the human brain.

The blood-brain barrier is like a protective membrane of the brain's magic box, mainly composed of endothelial cells, vascular cells, pericytes and other cell elves. These cell elves hold hands to form a tight barrier, and the magic they carry mainly protects the brain from the invasion of harmful substances.

We found that these cell elves are also an important cell subgroup of HUCCs, and changes and damage to the blood-brain barrier are closely related to the occurrence and development of various brain diseases. These magic genes that are significantly highly expressed in HUCCs related to the blood-brain barrier are widely involved in related functions such as cell apoptosis, oxidative stress, and inflammatory response.

Just as a coin has two sides, the specific magic carried by HUCCs, while promoting the evolution of advanced cognitive functions of the human brain, also increases the potential risk of brain diseases.

Discovery is just the beginning, we look forward to more in-depth research

In this way, after a series of studies, we found that human-specific cell elves are regulated by enhancer regions to activate specific magic. These cell elves play an important role in regulating the thickness of the human cerebral cortex and memory encoding, and are also closely related to a variety of brain diseases.

What are the uses of these findings?

On the one hand, just as scientists before us have continuously expanded our understanding of the brain, these new discoveries reveal the key role of specific cell groups in the cognitive function of the human brain, laying a cellular foundation for our understanding of the unique higher neural functions of the human brain and providing a new perspective for our understanding of the complexity and uniqueness of the human brain.

On the other hand, HUCCs have broad application prospects in the diagnosis and treatment of neurological diseases, such as discovering biomarkers for diagnosing the occurrence and development of brain diseases, developing new treatments for learning disabilities, etc., to promote the healthy development of brain function and improve human cognitive ability and quality of life.

Of course, our research has deepened our understanding of HUCCs, but there are still limitations in our research. There is still a lot of unknowns waiting for us to explore in the understanding and research of human higher cognitive functions and brain diseases.

In the future, our research will continue to deepen the functional mechanism of HUCCs and reveal how they interact with other cells. We also hope to study the performance of these cells at the protein level through multi-omics to help develop new treatments for neurological diseases such as learning disabilities and Alzheimer's disease.

References:

1.Ma S, Skarica M, Li Q, Xu C, Risgaard RD, Tebbenkamp ATN, et al. Molecular and cellular evolution of the primate dorsolateral prefrontal cortex. Science.2022;377:eabo7257.PMID: 36007006

2.Ma J, Qi R, Wang J, Berto S, Wang G. Human-unique brain cell clusters are associated with learning disorders and human episodic memory activity. Molecular Psychiatry. 2024. PMID: 3922743