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大腦神經學：一般研究 – 開欄文
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我對大腦神經學的興趣始自上一世紀80年代。
我最早的求知動機在於回答：「行為是否需要準則」和(如果需要)「行為準則是什麼」這兩個問題。後來逐漸領悟到：這兩個問題其實是「決策判定」的問題。做為工程師，我自然了解「決策」的基礎在「知識」。從而，我的讀書範圍從倫理學和社會學擴充到「認識論」。1982前後我讀了第一本介紹「認知科學」的書。自此，大腦神經學成為我主要的閱讀對象。從2000年以後，我立論的基本假設都包含我對它的粗淺了解。《唯物人文觀》(2006)則是我第一次嘗試整合我對大腦神經學與人文/社會科學兩個領域的了解。
最近我起了整合本城市討論/報導過各個重要議題的念頭；大腦神經學自然在列。等我完成手頭兩篇討論「文化」的文章後，我會開始討論「意識」。
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大腦處理資訊的基本原則 ---- Brandon Robert Munn
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這篇文章報導的不只是大腦神經學研究結果，作者歸納出來的原則也適用於企業和政治。一個社會要蓬勃發展，每一位成員都要有一定程度的能力和自由發揮的空間。前者來自教育和具備基本經濟能力，後者建立在合理和開放的社會組織。
How do brains coordinate activity? From fruit flies to monkeys, we discovered this universal principle
Brandon Robert Munn, 11/06/24
The brain is a marvel of efficiency, honed by thousands of years of evolution so it can adapt and thrive in a rapidly changing world. Yet, despite decades of research, the mystery of how the brain achieves this has remained elusive.
Our new research, published in the journal Cell, reveals how neurons – the cells responsible for your childhood memories, thoughts and emotions – coordinate their activity.
It’s a bit like being a worker in a high-performing business. Balancing individual skills with teamwork is key to success, but how do you achieve the balance?
As it turns out, the brain’s secret is surprisingly simple: devote no more than half (and no less than 40%) of each cell’s effort to individual tasks. Where does the rest of the effort go? Towards scalable teamwork.
And here’s the kicker: we found the exact same organisational structure across the brains of five species – from fruit flies and nematodes to zebrafish, mice and monkeys.
These species come from different branches of the tree of life that are separated by more than a billion years of evolution, suggesting we may have uncovered a fundamental principle for optimised information processing. It also offers powerful lessons for any complex system today.
The critical middle ground
Our discovery addresses a long-standing debate about the brain: do neurons act like star players (each highly specialised and efficient) or do they prioritise teamwork (ensuring the whole system works even when some elements falter)?
Answering this question has been challenging. Until recently, neuroscience tools were limited to either recording the activity of a few cells, or of several million.
It would be like trying to understand a massive company by either interviewing a handful of employees or by only receiving high-level department summaries. The critical middle ground was missing.
However, with advances in calcium imaging, we can now record signals from tens of thousands of cells simultaneously. Calcium imaging is a method that lets us watch neural activity in real time by using fluorescent sensors that light up according to calcium levels in the cell.
An example of calcium imaging shows neuron activity in a zebrafish brain. (請至原網頁觀看此視頻)
Applying insights from my physics training to analyse large-scale datasets, we found that brain activity unfolds according to a fractal hierarchy. Cells work together to build larger, coordinated networks, creating an organisation with each scale mirroring those above and below.
This structure answered the debate: the brain actually does both. It balances individuality and teamwork, and does so in a clever way. Roughly half of the effort goes to “personal” performance as neurons collaborate within increasingly larger networks.
The Sierpiński triangle is an example of a fractal, where the same pattern repeats at infinite scales. Beojan Stanislaus/Wikimedia Commons, CC BY-SA (請至原網頁查看圖片)
The brain can rapidly adapt to change
To test whether the brain’s structure had unique advantages, we ran computational simulations, revealing that this fractal hierarchy optimises information flow across the brain.
It allows the brain to do something crucial: adapt to change. It ensures the brain operates efficiently, accomplishing tasks with minimal resources while staying resilient by maintaining function even when neurons misfire.
Whether you are navigating unfamiliar terrain or reacting to a sudden threat, your brain processes and acts on new information rapidly. Neurons continuously adjust their coordination, keeping the brain stable enough for deep thought, yet agile enough to respond to new challenges.
The multiscale organisation we found allows different strategies – or “neural codes” – to function at different scales. For instance, we found that zebrafish movement relies on many neurons working in unison. This resilient design ensures swimming continues smoothly, even in fast-changing environments.
By contrast, mouse vision adapts at the cellular scale, permitting the precision required to extract fine details from a scene. Here, if a few neurons miss key pieces of information, the entire perception can shift – like when an optical illusion tricks your brain.
Evolutionary tree of species analysed in our study, each displaying a fractal neural organisation that balances efficiency and resilience. (MYA: million years ago; BYA: billion years ago) Brandon Munn (請至原網頁查看圖片)
Our findings reveal that this fractal coordination of neuron activity occurs across a vast evolutionary span: from vertebrates, whose last common ancestor lived 450 million years ago, to invertebrates, dating back a billion years.
This suggests brains have evolved to balance efficiency with resilience, allowing for optimised information processing and adaptability to new behavioural demands. The evolutionary persistence hints that we’ve uncovered a fundamental design principle.
A fundamental principle?
These are exciting times, as physics and neuroscience continue interacting to uncover the universal laws of the brain, crafted over aeons of natural selection. Future work will be needed to see how these principles might play out in the human brain.
Our findings also hint at something bigger: this simple rule of individual focus and scalable teamwork might not just be a solution for the brain.
When elements are organised into tiered networks, resources can be shared efficiently, and the system becomes robust against disruptions.
The best businesses operate in the same way — when a new challenge arises, individuals can react without waiting for instructions from their manager, allowing them to solve the problem while remaining supported by the organisation rapidly.
It may be a universal principle to achieve resilience and efficiency in complex systems. It appears basketball legend Michael Jordan was right when he said: “talent wins games, but teamwork and intelligence win championships”.
Brandon Robert Munn is a Postdoctoral research fellow, University of Sydney.
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老鼠開小車之情緒/大腦神經/行為三體互動 -- Kelly Lambert
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請至原網頁參看相關照片及視頻。
索引：
accumbens：依伏神經核
appetitive：此處：誘動性的，具激勵性的；促進食慾的
Froot Loop：穀物圈早餐麥片品牌名稱
spur：此處：鼓勵，激勵，鞭策；促進，加速；尖物，馬刺；(用馬刺)策(馬)
Neuroscientists taught rats to drive tiny cars. They took them out on 'joy rides.'
Scientists taught rats to drive to a certain destination, but the rodents took a detour, suggesting they enjoy both the journey and the rewarding destination.
Kelly Lambert, 11/16/24
We crafted our first rodent car from a plastic cereal container. After trial and error, my colleagues and I found that rats could learn to drive forward by grasping a small wire that acted like a gas pedal. Before long, they were steering with surprising precision to reach a Froot Loop treat.
As expected, rats housed in enriched environments — complete with toys, space and companions – learned to drive faster than those in standard cages. This finding supported the idea that complex environments enhance neuroplasticity: the brain's ability to change across the lifespan in response to environmental demands.
After we published our research, the story of driving rats went viral in the media. The project continues in my lab with new, improved rat-operated vehicles, or ROVs, designed by robotics professor John McManus and his students. These upgraded electrical ROVs — featuring rat-proof wiring, indestructible tires and ergonomic driving levers — are akin to a rodent version of Tesla's Cybertruck.
As a neuroscientist who advocates for housing and testing laboratory animals in natural habitats, I've found it amusing to see how far we've strayed from my lab practices with this project. Rats typically prefer dirt, sticks and rocks over plastic objects. Now, we had them driving cars.
But humans didn't evolve to drive either. Although our ancient ancestors didn't have cars, they had flexible brains that enabled them to acquire new skills — fire, language, stone tools and agriculture. And some time after the invention of the wheel, humans made cars.
Although cars made for rats are far from anything they would encounter in the wild, we believed that driving represented an interesting way to study how rodents acquire new skills. Unexpectedly, we found that the rats had an intense motivation for their driving training, often jumping into the car and revving the "lever engine" before their vehicle hit the road. Why was that?
Some rats training to drive press a lever before their car is placed on the track, as if they're eagerly anticipating the ride ahead.
The new destination of joy
Concepts from introductory psychology textbooks took on a new, hands-on dimension in our rodent driving laboratory. Building on foundational learning approaches such as operant conditioning, which reinforces targeted behavior through strategic incentives, we trained the rats step-by-step in their driver's ed programs.
Initially, they learned basic movements, such as climbing into the car and pressing a lever. But with practice, these simple actions evolved into more complex behaviors, such as steering the car toward a specific destination.
The rats also taught me something profound one morning during the pandemic.
It was the summer of 2020, a period marked by emotional isolation for almost everyone on the planet, even laboratory rats. When I walked into the lab, I noticed something unusual: The three driving-trained rats eagerly ran to the side of the cage, jumping up like my dog does when asked if he wants to take a walk.
Had the rats always done this and I just hadn't noticed? Were they just eager for a Froot Loop, or anticipating the drive itself? Whatever the case, they appeared to be feeling something positive — perhaps excitement and anticipation.
Behaviors associated with positive experiences are associated with joy in humans, but what about rats? Was I seeing something akin to joy in a rat? Maybe so, considering that neuroscience research is increasingly suggesting that joy and positive emotions play a critical role in the health of both human and nonhuman animals.
With that, my team and I shifted focus from topics such as how chronic stress influences brains to how positive events — and anticipation for these events — shape neural functions.
Working with postdoctoral fellow Kitty Hartvigsen, I designed a new protocol that used waiting periods to ramp up anticipation before a positive event. Bringing Pavlovian conditioning into the mix, rats had to wait 15 minutes after a Lego block was placed in their cage before they received a Froot Loop. They also had to wait in their transport cage for a few minutes before entering Rat Park, their play area. We also added challenges, such as making them shell sunflower seeds before eating.
This became our Wait For It research program. We dubbed this new line of study UPERs — unpredictable positive experience responses — where rats were trained to wait for rewards. In contrast, control rats received their rewards immediately. After about a month of training, we expose the rats to different tests to determine how waiting for positive experiences affects how they learn and behave. We're currently peering into their brains to map the neural footprint of extended positive experiences.
Preliminary results suggest that rats required to wait for their rewards show signs of shifting from a pessimistic cognitive style to an optimistic one in a test designed to measure rodent optimism. They performed better on cognitive tasks and were bolder in their problem-solving strategies. We linked this program to our lab's broader interest in behaviorceuticals, a term I coined to suggest that experiences can alter brain chemistry similarly to pharmaceuticals.
This research provides further support of how anticipation can reinforce behavior. Previous work with lab rats has shown that rats pressing a bar for cocaine — a stimulant that increases dopamine activation — already experience a surge of dopamine as they anticipate a dose of cocaine.
The tale of rat tails
It wasn't just the effects of anticipation on rat behavior that caught our attention. One day, a student noticed something strange: One of the rats in the group trained to expect positive experiences had its tail straight up with a crook at the end, resembling the handle of an old-fashioned umbrella.
I had never seen this in my decades of working with rats. Reviewing the video footage, we found that the rats trained to anticipate positive experiences were more likely to hold their tails high than untrained rats. But what, exactly, did this mean?
Curious, I posted a picture of the behavior on social media. Fellow neuroscientists identified this as a gentler form of what's called Straub tail, typically seen in rats given the opioid morphine. This S-shaped curl is also linked to dopamine. When dopamine is blocked, the Straub tail behavior subsides.
Natural forms of opiates and dopamine — key players in brain pathways that diminish pain and enhance reward — seem to be telltale ingredients of the elevated tails in our anticipation training program. Observing tail posture in rats adds a new layer to our understanding of rat emotional expression, reminding us that emotions are expressed throughout the entire body.
While we can't directly ask rats whether they like to drive, we devised a behavioral test to assess their motivation to drive. This time, instead of only giving rats the option of driving to the Froot Loop Tree, they could also make a shorter journey on foot — or paw, in this case.
Surprisingly, two of the three rats chose to take the less efficient path of turning away from the reward and running to the car to drive to their Froot Loop destination. This response suggests that the rats enjoy both the journey and the rewarding destination.
Rat lessons on enjoying the journey
We're not the only team investigating positive emotions in animals.
Neuroscientist Jaak Panksepp famously tickled rats, demonstrating their capacity for joy.
Research has also shown that desirable low-stress rat environments retune their brains' reward circuits, such as the nucleus accumbens. When animals are housed in their favored environments, the area of the nucleus accumbens that responds to appetitive experiences expands. Alternatively, when rats are housed in stressful contexts, the fear-generating zones of their nucleus accumbens expand. It is as if the brain is a piano the environment can tune.
Neuroscientist Curt Richter also made the case for rats having hope. In a study that wouldn't be permitted today, rats swam in glass cylinders filled with water, eventually drowning from exhaustion if they weren't rescued. Lab rats frequently handled by humans swam for hours to days. Wild rats gave up after just a few minutes. If the wild rats were briefly rescued, however, their survival time extended dramatically, sometimes by days. It seemed that being rescued gave the rats hope and spurred them on.
The driving rats project has opened new and unexpected doors in my behavioral neuroscience research lab. While it's vital to study negative emotions such as fear and stress, positive experiences also shape the brain in significant ways.
As animals — human or otherwise — navigate the unpredictability of life, anticipating positive experiences helps drive a persistence to keep searching for life's rewards. In a world of immediate gratification, these rats offer insights into the neural principles guiding everyday behavior. Rather than pushing buttons for instant rewards, they remind us that planning, anticipating and enjoying the ride may be key to a healthy brain. That's a lesson my lab rats have taught me well.
Dr. Kelly Lambert received her undergraduate degree from Samford University in Birmingham AL (majoring in psychology and biology) in 1984 and her M.S. and Ph.D. in the field of Biopsychology from the University of Georgia in 1988. After spending 28 years at Randolph-Macon College in Ashland VA where she served as the Macon and Joan Brock Professor and Chair of the Psychology Department, Co-Director of Undergraduate Research, and Director of the Behavioral Neuroscience Major, she recently joined the faculty at the University of Richmond as Professor of Behavioral Neuroscience. She enjoys teaching courses such as Behavioral Neuroscience, Clinical Neuroscience, Comparative Animal Behavior, Neuroplasticity and Psychobiology of Stress. Dr. Lambert has won several teaching awards including the 2008 Virginia Professor of the Year.
Related Readings:
'A direct relationship between your sense of sight and recovery rate': Biologist Kathy Resilience is a skill that can be cultivated, a psychologist explains
Scientists breed most human-like mice yet
These 3 neurons may underlie the drive to eat food
Willis on why looking at nature can speed up healing
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奇妙的大腦 -- Kerri Smith
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本文附大量示意圖和資訊視頻等輔助說明，請務必上原網頁觀看。
What's so special about the human brain?
Torrents of data from cell atlases, brain organoids and other methods are finally delivering answers to an age-old question.
Kerri Smith, Infographics by Nik Spencer, Illustrations by Phil Wheeler, 11/2024
There must be something about the human brain that’s different from the brains of other animals — something that enables humans to plan, imagine the future, solve crossword puzzles, tell sarcastic jokes and do the many other things that together make our species unique. And something that explains why humans get devastating conditions that other animals don’t — such as bipolar disorder and schizophrenia.
So, what is that something?
In the past few years, new methods for studying the human brain — and those of other species — have started to reveal key differences in greater detail than ever before.
Researchers can now snoop on what happens inside millions of brain cells by cataloguing the genes, RNA and proteins they produce. And by studying brain tissue, scientists are learning key lessons about how the organ develops and functions.
One is that the differences between human brain cells and those of other species are often subtle. Another is that the human brain develops slowly compared with other animals. But how these features give rise to our cognitive skills is still a mystery — although researchers have plenty of promising leads.
Size matters
If there is one thing that stands out about the human brain compared with those of other primates — and even those of some extinct human relatives — it is its size.
The human brain is up to three times larger in volume than the brains of chimpanzees, gorillas and many extinct human relatives.
Brain size is tightly correlated with body size in most animals. But humans break the mould. Our brains are much larger than expected given our body size.
Here are some animals’ brains ranked according to size.
Researchers often use a ratio called the encephalization quotient (EQ) to get an idea of how much larger or smaller an animal’s brain is compared with what would be expected given its body size. The EQ is 1.0 if the brain to body mass ratio meets expectations.
Here are their brains scaled according to their EQ, with the actual brain sizes represented by dotted lines. The mouse brain is half as big as expected for its body size. The human brain is more than seven times the expected size.
Although evolution has enlarged the human brain, it hasn’t done so uniformly: some brain areas have ballooned more than others.
One particularly enlarged region is the cortex, an area that carries out planning, reasoning, language and many other behaviours that humans excel at.
Other areas, such as the cerebellum — an area at the back of the brain that is densely populated with neurons, and which helps to conduct movement and planning — have expanded too.
The prefrontal cortex has a similar structure in both chimps and humans, although it takes up much more real estate in the human brain than in the chimp brain.
There is also a big difference between the number of neurons in the human brain compared with those of other animals. The human brain has about 1,000 times more neurons than the mouse brain, for instance, and 13.5 times more than the macaque1..
But brain size and neuron number aren’t everything; some animals whose brains look and develop differently to mammals — such as ravens and other members of the crow family — can learn or remember impressively. “Brain size alone can’t explain human cognition,” says Chet Sherwood, an anthropologist and neuroscientist at The George Washington University in Washington DC.
Special recipe
Looking at brain cells closely has shown some interesting patterns. Over the past five years, techniques that enable scientists to catalogue the genes expressed in a single cell have been revealing the many different types of cell that make up a brain — at a level of detail much higher than anything achieved before.
Last year, a team based at the Allen Institute for Brain Science in Seattle, Washington, reported the most-comprehensive atlases yet of cell types in both the mouse and human brain. As part of an international effort called the BRAIN Initiative Cell Census Network (BICCN), researchers catalogued the whole mouse brain, finding 5,300 cell types2; the human atlas is unfinished but so far includes more than 3,300 types from 100 locations3; researchers expect to find many more.
Some regions do have distinct cell types — for instance, the human visual cortex contained several types of neuron that were exclusive to that area4. But in general, human-specific cell types are rare.
The overall impression, when comparing the cell types of the human brain with other species, is one of similarity. “I was expecting bigger differences,” says Ed Lein, a neuroscientist at the Allen Institute, who is involved in efforts to catalogue cells in human, mouse and other brains. “The basic cellular architecture is remarkably conserved until you get down to the finer details”, he says.
Most human brain regions differ from primates and mice in the relative proportions of cell types that appear5, and in the ways those cells express their genes: it's not the ingredients that are different, but the recipe.
Take these two comparable regions of the human and mouse cortex, which both process auditory information. The mouse area contains a higher proportion of excitatory neurons, which propagate signals, relative to inhibitory neurons, which dampen activity. The human region had a much greater proportion of non-neuronal cells, such as astrocytes, oligodendrocytes and microglia. These cells support neurons and also help to prune and refine their connections during development. The ratio of these cells to neurons was five times that of mice.
The upshot of the differences still isn’t clear, but the atlases provide a way to study these cells and the genes they express, to better understand their function.
The same cell types can also look different in different species. This is the same type of neuron — a pyramidal cell — from the cortex of a mouse, chimp and human. The mouse brain has fewer of these cells and they are less well connected compared with the human brain6.
Even compared with the chimp, the human neurons are longer and make more connections with each other. The cortical layers they live in are thicker than those of the chimp.
Source: Ref. 6
Making connections
No neuron is an island, and the networks they form could be a huge part of what gives various brains their different functions and specialisms.
One study compared 1.6 million connections between more than 2,000 total brain cells in mouse, macaque and human brain samples taken from the cortex. The human wiring diagram, or ‘connectome’, had 2.5 times more interneurons — a class of cells that dampen neural activity and control excitation, shown here in two colours — than did the mouse, and those cells made ten times more connections between themselves7..
A specialized group of interneurons with a preference for connecting to others of the same type (bipolar neurons, in green) were rare in mice but have expanded to be more than half the population in humans. A second class of interneurons, called multipolar neurons, did not expand to the same extent.
Source: Ref. 7; M. Sievers et al. (2024)
The finding was “super surprising”, says study leader Moritz Helmstaedter at the Max Planck Institute for Brain Research in Frankfurt, Germany. He thinks that this expanded network of interneurons might help to solve one major problem in the human brain: neurons operate quickly but thoughts and actions take seconds. Larger networks of interneurons could prolong neuronal activity, allowing the brain to generate more complex thoughts and keep things ‘in mind’ for longer.
The team is now looking at larger segments of the human cortex.
The results of Helmstaedter's connectome study are supported by genetic work. When comparing gene expression across species, many differences turn out to be related to how the connections between neurons — called synapses — connect with and signal to each other.
In a study8 led by researchers at the Allen Institute, a few hundred genes showed expression patterns unique to humans. Often, these specializations were related to circuit function — they were involved in synapse-building or signalling. And they were often seen in non-neuronal cells, such as astrocytes and microglia.
Slow to develop
Some scientists think that there is one key pedal that has been pressed in the human brain that can explain many of the differences between us and other species. The brake.
“Whatever you look at, it’s happening more slowly in humans,” says neuroscientist Madeline Lancaster, who studies human brain development at the MRC Laboratory of Molecular Biology in Cambridge, UK.
The pace of brain development varies a lot across species, but it’s incredibly protracted in humans. The mouse brain, for instance, is fully developed just 5% of the way into the animal’s lifespan.
Macaque and chimp brains are fully developed about one-third of the way into theirs.
Human brains take much longer to grow, mature and refine their connections — about 30 years, or almost half our average lifespan.
Source: Ref. 6
This sluggish pace could help humans to grow more neurons, and foster more diversity and complexity. It also gives the brain more time to be shaped by its environment. Research suggests that, in humans, neural progenitors, the cells that give rise to neurons, spend longer in a limbo state before assuming their final identities9. Human progenitors also have more potential — they can become more than one broad type of neuron, whereas in rodents one type of progenitor tends to develop into just one type of neuron10.
Here is a typical timeline for chimp neurons — they develop from progenitors, they grow axons and dendrites to reach out to other cells, those outgrowths develop synapses to connect to each other and send signals, and finally they develop a layer of myelin, which insulates neurons and helps signals to travel6.
The same process in humans takes longer and results in neurons that grow more dendrites, each with more connections. Axons can be longer than those of chimps because they have further to travel, and the resulting neurons are more complex.
Several gene variants have been linked to this slowdown and elaboration. One is a gene duplication seen only in humans; when mice were engineered to have the same duplication, they grew more synapses and their learning improved11.
Another example is a change in the sequence that codes for a protein called NOTCH, which has been linked to the expansion of the cortex. This change allows human neurons to spend longer proliferating — giving rise to a larger pool of new neurons — than those of non-human primates12,13.
Source: Ref. 6
Although some changes to genes and cells undoubtedly make us who we are, it's too early to leap to any conclusions, says Alex Pollen, a geneticist who studies human brain evolution at the University of California San Francisco. Some changes could just be side effects of other adaptations — for example, an increase in certain types of neuron so that brain regions could still communicate when the brain expanded.
There are downsides, too, to our special abilities. Sherwood says that humans undergo more drastic changes than other primates, such as a shrinkage of the cortex, owing to ageing — in part because we live so much longer. But even the oldest great ape brains don’t seem to change as much as human brains do with age, he says. And some conditions that seem specific to humans could be the price we pay for complexity, says Lancaster. “Even a small defect could have more dramatic consequences,” she says.
There’s plenty more to discover about how our brains make us so talkative, sociable and intelligent. Scientists are interested in how gene variants act on neurons and the brain; how neural activity during development influences growth; and how parts of the brain other than the cortex might have changed to endow humans with our unique skills.
The confluence of technologies has energized researchers to look afresh at a classic question, says Lancaster. “I feel lucky to be doing science at this moment.”
References
1. Herculano-Houzel, S. Front. Hum. Neurosci. 3, 31 (2009).
2. Yao, Z. et al. Nature 624, 317–332 (2023).
3. Siletti, K. et al. Science 382, eadd7046 (2023).
4. Jorstad, N. L. et al. Science 382, eadf6812 (2023).
5. Fang, R. et al. Science 377, 56–62 (2022).
6. Lindhout, F. W. et al. Nature 630, 596–608 (2024).
7. Loomba, S. et al. Science 377, eabo0924 (2022).
8. Jorstad, N. L. et al. Science 382, eade9516 (2023).
9. Otani, T. et al. Cell Stem Cell 18, 467–480 (2016).
10. Delgado, R. N. et al. Nature 601, 397–403 (2022).
11. Schmidt, E. R. E. et al. Nature 599, 640–644 (2021).
12. Fiddes, I. T. et al. Cell 173, 1356–1369 (2018).
13. Suzuki, I. K. et al. Cell 173, 1370–1384 (2018).
Author: Kerri Smith
Illustration: Phil Wheeler
Infographics: Nik Spencer
Design: Wes Fernandes
Subeditor: Joanna Beckett
Editor: Richard Monastersky
© 2024 Springer Nature Limited. All rights reserved.
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用物理學方法研究記憶與思考 - The Physics arXiv Blog
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我在天普大學物理系唸研究所時，統計物理課由格林教授講授。我已經忘了他的大名；只記得他的指導教授就是下文提到的吉卜石博士。
The Hunt For The Laws Of Physics Behind Memory And Thought
The massive networks of neurons in our brains produce complex behaviors, like actions and thought. Now physicists want to understand the laws that govern this emergent phenomena.
The Physics arXiv Blog, 10/01/24
表單的底部
One of the curious features of the laws of physics is that many of them seem to be the result of the bulk behavior of many much smaller components. The atoms and molecules in a gas, for example, move at a huge range of velocities. When constrained in a container, these particles continually strike the surface creating a force.
But it is not necessary to know the velocities of all the particles to determine this force. Instead, their influence averages out into a predictable and measurable bulk property called pressure.
This and other bulk properties like temperature, density and elasticity, are hugely useful because of the laws of physics that govern them. Over one hundred years ago, physicists like Willard Gibbs and others determined the mathematical character of these laws and the statistical shorthand that physicists and engineers now use routinely in everything from laboratory experiments to large scale industrial processes.
The success of so-called statistical physics raises the possibility that other systems that consist of enormous numbers of similar entities might also have their own “laws of physics”. In particular, physicists have long hoped that the bulk properties of neurons might be amenable to this kind of approach.
Neural Physics
The behavior of single neurons is well understood. But put them together into networks and much more significant behaviors emerge, such as sensory perception, memories and thought. The hope is that a statistical or mathematical approach to these systems could reveal the laws of neural physics that describe the bulk behavior of nervous systems and brains.
“It is an old dream of the physics community to provide a statistical mechanics description for these and other emergent phenomena of life,” say Leenoy Meshulam at the University of Washington and William Bialek at Princeton University, who have reviewed progress in this area.
“These aspirations appear in a new light because of developments in our ability to measure the electrical activity of the brain, sampling thousands of individual neurons simultaneously over hours or days.”
The nature of these laws is, of course, fundamentally different to the nature of conventional statistical physics. At the heart of the difference is that neurons link together to form complex networks in which the behavior of one neuron can be closely correlated with the behavior of its neighbors.
It is relatively straightforward to formulate a set of equations that capture this behavior. But it quickly becomes apparent that these equations cannot be easily solved in anything other than trivial circumstances.
Instead, physicists must consider the correlations between all possible pairs of neurons and then use experimental evidence to constrain what correlations are possible.
The problem, of course, is that the number of pairs increases exponentially with the number of neurons. That raises the question of how much more data must be gathered to constrain the model as the number of neurons increases.
One standard system in which this has been well measured is the retina (視網膜). This consists of a network of light sensitive neurons in which activity between neighbors is known to be corelated. So if one neuron is activated there is a strong possibility that its neighbor will be too. (This is the reason for the gently evolving, coral-like patterns in vision that people sometimes notice when they first wake up.)
Experiments in this area began by monitoring the behavior of a handful of neurons, then a few dozen, a few hundred and now approach thousands (but not millions). It turns out that the data helps constrain the model to the point where they give remarkably accurate predictions of neural behavior when asked, for example, to predict how many neurons are active out of any given set of them.
That suggests the system of equations accurately captures the behavior of retinal networks. In other words, “the models really are the solutions to the mathematical problem that we set out to solve,” say Meshulam and Bialek.
Of course, the retina is a highly specialized part of the nervous system so an important question is whether similar techniques can generalize to the higher cognitive tasks that take place in other parts of the brain.
Emergent Behavior
One challenge here is that networks can demonstrate emergent behavior. This is not the result of random correlations or even weak correlations. Instead, the correlations can be remarkably strong and can spread through a network like an avalanche.
Networks that demonstrate this property are said to be in a state of criticality (臨界狀態) and are connected in a special way that allows this behavior. This criticality turns out to be common in nature and suggests networks can tune themselves in a special way to achieve it.
“Self-organized criticality” has been widely studied in the last two decades and there has been some success in describing it mathematically. But exactly how this self-tuning works is the focus of much ongoing research.
Just how powerful these approaches will become is not yet clear. Meshulam and Bialek take heart from the observation that some natural behaviors are amenable to the kind of analysis that physicists are good at. “All the birds in a flock agreeing to fly in the same direction is like the alignment of spins in a magnet,” they say.
The fact that this is merely a metaphor concerns them — metaphors can help understanding but the real behavior of these system is often much more complex and subtle.
But there are reasons to think that mathematical models can go further. “The explosion of data on networks of real neurons offers the opportunity to move beyond metaphor,” they say, adding that the data from millions of neurons should soon help to inform this debate.
“Our experimentalist friends will continue to move the frontier, combining tools from physics and biology to make more and more of the brain accessible in this way,” conclude Meshulam and Bialek. “The outlook for theory is bright.”
Ref: Statistical mechanics for networks of real neurons : arxiv.org/abs/2409.00412
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戀愛腦 -- Jess Thomson
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問題：實驗觀察到的「大腦活動」，是「情緒」引起的，還是「語言」引起的？
Scientists Reveal Where the Brain Feels Love—and Which Type Is Strongest
Jess Thomson, 08/26/24
Love might feel like it comes from the heart, but scientists have figured out where love lives inside the brain.
Researchers used functional magnetic resonance imaging (fMRI) to measure brain activity while people thought about various types of love, finding that the brain lit up in different areas, according to a new paper in the journal Cerebral Cortex.
They discovered that love in different types of relationships results in brain activity of different strengths, but all activated more or less the same brain areas.
Stock image of a couple (main) and a brain (inset). Scientists have measured brain scans regarding different kinds of love. ISTOCK / GETTY IMAGES PLUS (請至原網頁查看照片)
"We now provide a more comprehensive picture of the brain activity associated with different types of love than previous research," study co-author Pärttyli Rinne, a philosopher and researcher at Aalto University in Finland, said in a statement. "The activation pattern of love is generated in social situations in the basal ganglia, the midline of the forehead, the precuneus and the temporoparietal junction at the sides of the back of the head."
Love comes in many forms, from parental love for children to romantic love, friendship love, and even love of animals or nature.
The researchers describe how they measured brain activity in people who had just heard a description of a type of love, such as: "You see your newborn child for the first time. The baby is soft, healthy and hearty — your life's greatest wonder. You feel love for the little one."
They found that the love of a parent generated the most powerful brain activity, followed by romantic love. While the intensity of the brain activity varied between types, they all mostly lit up in the same region of the brain, with some exceptions.
"In parental love, there was activation deep in the brain's reward system in the striatum area while imagining love, and this was not seen for any other kind of love," said Rinne.
They also tested the brain activity associated with friendships, pets, nature, and strangers. The researchers found that love of nature lit up the brain's reward system and not the areas associated with social cognition, while love of people lit up the social areas instead.
Interestingly, the researchers discovered that brain waves when spoken to about animals actually revealed if the person had a pet or not.
"When looking at love for pets and the brain activity associated with it, brain areas associated with sociality statistically reveal whether or not the person is a pet owner. When it comes to the pet owners, these areas are more activated than with non-pet owners," said Rinne.
Understanding the physiology of love may seem cold, however, the scientists hope that their research could be used to better treat attachment disorders, depression or relationship issues.
References
Rinne, P., Lahnakoski, J., Saarimäki, H., Tavast, M., Sams, M., & Henriksson, L. (2024). Six types of loves differentially recruit reward and social cognition brain areas. Cerebral Cortex, 34(8). https://doi.org/10.1093/cercor/bhae331
Jess Thomson is a Newsweek Science Reporter based in London UK. Her focus is reporting on science, technology and healthcare. She has covered weird animal behavior, space news and the impacts of climate change extensively. Jess joined Newsweek in May 2022 and previously worked at Springer Nature. She is a graduate of the University of Oxford. Languages: English.
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記憶和DNA -- Max Kozlov
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如果這篇大腦神經學研究通俗報導中研究者的詮釋成立度很高，此文作者對研究結果報導的可信度也很高，相信此研究能幫助我們進一步了解「記憶」、「意識」、以及和「大腦神經」相關的種種症狀(如作者提及的阿茲海默症)。
我不清楚這篇通俗報導所說的大腦DNA是否具有「可遺傳性」；如果有，或許它也能解釋「似曾相識」現象。甚至可以解釋：「龍生龍，鳳生鳳，老鼠生的兒子只學得會打洞」現象。
索引：
engram：記憶實體，記憶痕跡
hippocampus：海馬迴，大腦內貌似海馬的區塊
inflammation：發炎
organelle：細胞內構成該細胞的次級結構，具有特定功能
pathogens：病原體
plasticity, neural：(大腦神經網路連接的)可塑性
Memories are made by breaking DNA — and fixing it
Nerve cells form long-term memories with the help of an inflammatory response, study in mice finds.
Max Kozlov, 03/27/24
Neurons (shown here in a coloured scanning electron micrograph) mend broken DNA during memory formation. Credit: Ted Kinsman/Science Photo Library (請至原網頁查看圖片)
When a long-term memory forms, some brain cells experience a rush of electrical activity so strong that it snaps their DNA. Then, an inflammatory response kicks in, repairing this damage and helping to cement the memory, a study in mice shows.
The findings, published on 27 March in Nature1, are “extremely exciting”, says Li-Huei Tsai, a neurobiologist at the Massachusetts Institute of Technology in Cambridge who was not involved in the work. They contribute to the picture that forming memories is a “risky business”, she says. Normally, breaks in both strands of the double helix DNA molecule are associated with diseases including cancer. But in this case, the DNA damage-and-repair cycle offers one explanation for how memories might form and last.
It also suggests a tantalizing possibility: this cycle might be faulty in people with neurodegenerative diseases such as Alzheimer’s, causing a build-up of errors in a neuron’s DNA, says study co-author Jelena Radulovic, a neuroscientist at the Albert Einstein College of Medicine in New York City.
Inflammatory response
This isn’t the first time that DNA damage has been associated with memory. In 2021, Tsai and her colleagues showed that double-stranded DNA breaks are widespread in the brain, and linked them with learning2.
To better understand the part these DNA breaks play in memory formation, Radulovic and her colleagues trained mice to associate a small electrical shock with a new environment, so that when the animals were once again put into that environment, they would ‘remember’ the experience and show signs of fear, such as freezing in place. Then the researchers examined gene activity in neurons in a brain area key to memory — the hippocampus. They found that some genes responsible for inflammation were active in a set of neurons four days after training. Three weeks after training, the same genes were much less active.
The team pinpointed the cause of the inflammation: a protein called TLR9, which triggers an immune response to DNA fragments floating around the insides of cells. This inflammatory response is similar to one that immune cells use when they defend against genetic material from invading pathogens, Radulovic says. However, in this case, the nerve cells were responding not to invaders, but to their own DNA, the researchers found.
TLR9 was most active in a subset of hippocampal neurons in which DNA breaks resisted repair. In these cells, DNA repair machinery accumulated in an organelle called the centrosome, which is often associated with cell division and differentiation. However, mature neurons don’t divide, Radulovic says, so it is surprising to see centrosomes participating in DNA repair. She wonders whether memories form through a mechanism that is similar to how immune cells become attuned to foreign substances that they encounter. In other words, during damage-and-repair cycles, neurons might encode information about the memory-formation event that triggered the DNA breaks, she says.
When the researchers deleted the gene encoding the TLR9 protein from mice, the animals had trouble recalling long-term memories about their training: they froze much less often when placed into the environment where they had previously been shocked than did mice that had the gene intact. These findings suggest that “we are using our own DNA as a signalling system” to “retain information over a long time”, Radulovic says.
Fitting in
How the team’s findings fit with other discoveries about memory formation is still unclear. For instance, researchers have shown that a subset of hippocampal neurons known as an engram are key to memory formation3. These cells can be thought of as a physical trace of a single memory, and they express certain genes after a learning event. But the group of neurons in which Radulovic and her colleagues observed the memory-related inflammation are mostly different from the engram neurons, the authors say.
Tomás Ryan, an engram neuroscientist at Trinity College Dublin, says the study provides “the best evidence so far that DNA repair is important for memory”. But he questions whether the neurons encode something distinct from the engram — instead, he says, the DNA damage and repair could be a consequence of engram creation. “Forming an engram is a high-impact event; you have to do a lot of housekeeping after,” he says.
Tsai hopes that future research will address how the double-stranded DNA breaks happen and whether they occur in other brain regions, too.
Clara Ortega de San Luis, a neuroscientist who works with Ryan at Trinity College Dublin, says that these results bring much-needed attention to mechanisms of memory formation and persistence inside cells. “We know a lot about connectivity” between neurons “and neural plasticity, but not nearly as much about what happens inside neurons”, she says.
doi: https://doi.org/10.1038/d41586-024-00930-y
Read the related News & Views: ‘Innate immunity in neurons makes memories persist’.
UPDATES & CORRECTIONS
Correction 27 March 2024: An earlier version of this story indicated that broken DNA accumulated in the centrosome. It is DNA repair machinery that accumulates in that organelle.
References
Jovasevic, V. et al. Nature 628, 145–153 (2024). Article Google Scholar
Stott, R. T., Kritsky, O. & Tsai, L.-H. PLoS ONE 16, e0249691 (2021). Article PubMed Google Scholar
Josselyn, S. A. & Tonegawa, S. Science 367, eaaw4325 (2020).
Article Google Scholar；Download references；Reprints and permissions
相關閱讀：
How to see a memory
Flashes of light show how memories are made
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《停經對女人大腦的影響》讀後
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上一篇文章報導：20%的婦女在停經後，可能導致智力衰退。停經期的症狀和造成阿茲海默病的原因有類似之處。
文章後半段是對保持大腦和智力健康的建議。
1) 補充賀爾蒙
2) 經常運動
3) 健康飲食習慣
作者引用一位醫生的話：在社會習俗洗腦下，大多數中年婦女總是把自己的幸福放在其他人之後。言外之意是：一個人要先把自己照顧好，才有餘力招呼別人。
我一向認為：對精神(心理)和大腦疾病症狀及其原因的研究，除了有利臨床治療外，也能幫助我們了解大腦運作的機制與過程。最終讓人類解開「意識」這個謎團。
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停經對女人大腦的影響-Alisha Haridasani Gupta
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How Menopause Changes the Brain
Neurological changes and menopausal symptoms are linked to dementia for some. Here’s what to know.
Alisha Haridasani Gupta, 11/21/23
Neurological changes and menopausal symptoms are linked to dementia for some. (Sonia Pulido/The New York Times) Ñ FOR EDITORIAL USE ONLY WITH NYT STORY MENOPAUSE BRAIN BY ALISHA HARIDASANI GUPTA FOR NOV. 23, 2023. ALL OTHER USE PROHIBITED. Ñ (NYT) -- 請至原網頁參閱相關圖片
Across the U.S., roughly 6 million adults 65 and older have Alzheimer’s disease. Almost two-thirds of them are women — a discrepancy that researchers have long attributed to genetics and women’s longer life spans, among other reasons. But there is growing consensus that menopause may also be an important risk factor for the development of dementia later in life.
Women going through the life phase, which is clinically defined as the end of fertility, face as many changes in the brain as in the ovaries, said Dr. Lisa Mosconi, a neuroscientist and director of the Women’s Brain Initiative at Weill Cornell Medicine. While the vast majority of women will weather these changes without long-term health consequences, about 20% will develop dementia in the decades that follow.
The female brain is rich in estrogen receptors, particularly in regions that control memory, mood, sleep and body temperature, all of which “work beautifully when estrogen is high and consistent,” Mosconi said. Estrogen is also vital for the brain’s ability to defend itself against aging and damage.
The characteristic decline in estrogen during menopause not only alters the functioning in some brain regions, she said, it is also thought to change the brain’s structure; scans show reduced volume in menopausal brains compared to male brains of the same age and to those of pre-menopausal women.
These neurological changes may be responsible for some menopausal symptoms, including hot flashes, mood disruption and a mild, usually temporary decline in memory and cognition.
They also resemble changes in the brain that precede dementia, Mosconi said. “Some of the brain regions that are impacted by menopause are also some of the regions impacted by Alzheimer’s disease,” she said, but the link between the two is not fully understood.
The symptoms of menopause themselves, such as lack of sleep and hot flashes, have been linked to dementia too. A study published last year found that hot flashes were associated with an increased amount of tiny lesions in the brain, which are a sign of declining brain health, said Dr. Pauline Maki, a professor of psychiatry and director of the Women’s Mental Health Research Program at the University of Illinois at Chicago and co-author of the study. A more recent study determined that hot flashes during sleep were associated with an increase in blood-based Alzheimer’s biomarkers that serve as early indicators of the disease.
While this research sounds alarming, most women’s brains and cognitive function stabilize after the menopause transition, Maki said.
“Consider how many women go through menopause — every woman, right? And 80% of them will not get dementia,” she said. “We can’t catastrophize this universal transition.”
Beyond that, there are things you can do to bolster your health and cognition in the face of declining estrogen.
Three Steps to Protect Your Brain
Several studies have found that up to 40% of dementia cases could be prevented, said Dr. Jessica Caldwell, director of the Women’s Alzheimer’s Movement Prevention Center at the Cleveland Clinic in Las Vegas. And a few lifestyle changes in midlife, including quitting smoking, reducing alcohol intake, sleeping better and remaining mentally and socially active, aid in prevention.
But for women in menopause, experts say that three things in particular are likely to have the most impact by addressing both the short-term symptoms as well as the long-term risk of dementia.
Hormone Therapy, Timed Right
For decades, researchers were concerned that the hormone therapy used to treat menopause symptoms was associated with an increased risk of developing dementia in older women. But recent studies, including one published last month that reviewed the findings of over 50 studies, look more closely at the timing of the therapy and suggest a more nuanced picture: Hormone therapy that was started around the time when menopausal symptoms began was associated with a reduced risk of Alzheimer’s disease and dementia. Other studies have found that hormone therapy had no effect on dementia and Alzheimer’s risk, Maki said, but these treatments are effective at addressing hot flashes and night sweats as well as improving quality of life, all of which are “important determinants of brain health,” she said.
Consistent Exercise
Physical inactivity presents a greater risk for neurodegenerative diseases in women than in men, Caldwell said. “We know that physical inactivity is a risk factor for dementia. And women throughout their lives, on average, are twice as likely to be physically inactive than men,” she said.
A 2018 study that followed almost 200 middle-aged women for 44 years found that the greater their fitness level at the start of the study, the lower their risk of developing dementia later in life. And Mosconi found that brain scans of physically active middle-aged women had fewer Alzheimer’s biomarkers compared to their sedentary counterparts.
A Healthy Diet
In recent years, researchers have found that certain diets, like the Mediterranean diet and the fairly similar MIND diet, which prioritize vegetables, fruits, whole grains, lean proteins and healthy fats, are associated with a reduced risk of dementia in both men and women. The Mediterranean diet in particular seems to be a protective tool, even for women with a genetic risk for Alzheimer’s disease, Mosconi said. And there may be a specific added benefit of these plant-rich diets for women: Preliminary research suggests that certain gut bacteria — which are nourished by a plant-rich diet — might help balance estrogen levels in the body.
Many of these lifestyle changes take time that many middle-aged women feel they don’t have, Caldwell said.
“We are expected by society to put ourselves after everybody else, whether that’s kids, parents or spouses, and we need to keep ourselves on the priority list,” she said. “Because if we don’t do these types of health-maintenance behaviors, we will not have the healthy brain aging we want.”
c.2023 The New York Times Company
索引：
dementia：(老年)智力衰退
estrogen：雌激素，又稱女性動情素
nuanced：細緻入微的，精細分類的
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昏過去的原因 ------ Miryam Naddaf
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我今年8月身體微恙。有一天半夜起來如廁時昏了過去；但沒多長就醒過來。走了幾步後又昏了過去；也是沒多長就醒過來。兩次症狀和下文描述的一樣；同樣情況十幾、二十年前也發生過一次。
十月中我到心臟科做了整套檢查，醫生說我的心臟沒有問題。前兩天剛好看到這篇文章，和各位分享。如果碰到類似狀況，應該盡快做檢查；但不必驚慌或自己嚇自己。
What causes fainting? Scientists finally have an answer
Mouse experiments reveal the brain-heart connections that cause us to rapidly lose consciousness — and wake up moments later.
Miryam Naddaf, 11/01/23
Whether as a result of heat, hunger, standing for too long, or merely at the sight of blood or needles, 40% of people faint at least once in their lifetime.
But exactly what causes these brief losses of consciousness — which researchers call ‘syncope’ — has remained a mystery for cardiologists and neuroscientists for a long time.
Now, researchers have discovered a neural pathway, which involves a previously undiscovered group of sensory neurons that connect the heart to the brainstem. The study, published in Nature on 1 November1, shows that activating these neurons made mice became immobile almost immediately while displaying symptoms such as rapid pupil dilation and the classic eye-roll observed during human syncope.
The authors suggest that this neural pathway holds the key to understanding fainting, beyond the long-standing observation that it results from reduced blood flow in the brain. “There is blood flow reduction, but at the same time there are dedicated circuits in the brain which manipulate this,” says study co-author Vineet Augustine, a neuroscientist at the University of California, San Diego.
“The study of these pathways could inspire new treatment approaches for cardiac causes of syncope,” says Kalyanam Shivkumar, a cardiologist at the University of California, Los Angeles.
Novel neurons
The mechanisms that control how and why people faint have long puzzled scientists, partly because researchers tend to focus on studying either the heart or the brain in isolation. But the authors of the study developed novel tools to show how these two systems interact.
Using single-cell RNA sequencing analysis of the nodose ganglia, an area in the vagus nerve (which connects the brain to several organs, including the heart), the team identified a group of sensory neurons that express a type of receptor involved in the contraction of small muscles within blood vessels that causes them to constrict.
These neurons, called NPY2R VSNs, are distinct from other branches of the vagus nerve that connect to the lungs or the gut. They instead form branches within the lower,muscular parts of the heart, the ventricles, and connect to a distinct area in the brainstem called area postrema.
Using a new technique that combines high-resolution ultrasound imaging with optogenetics — a way of controlling neuron activity using light — the researchers stimulated the NPY2R VSNs in mice while monitoring their heart rate, blood pressure, respiration and eye movements. This approach allowed the team to manipulate specific neurons and visualise the heart in real time. “This was not possible before, because you needed to figure out the identity of these neurons,” says Augustine.
When the NPY2R VSNs were activated, mice that had been freely moving around fainted with a few seconds. While passed out, the mice displayed similar symptoms to humans during syncope, including rapid pupil dilation and eyes rolling back in their sockets, as well as reduced heart rate, blood pressure, breathing rate and blood flow to the brain.
“We now know that there are receptors in the heart that when made to fire, will shut down the heart,” says Jan Gert van Dijk, clinical neurologist at Leiden University Medical Centre in the Netherlands.
In humans, syncope is usually followed by a rapid recovery. “Neurons in the brain are very much like extremely spoiled children. They need oxygen and they need sugar, and they need them now,” says Dijk. “They stop working very quickly if you derive them off oxygen or glucose.”
These nerve cells begin to die after about 2 to 5 minutes without oxygen, but syncope typically lasts only 20 to 40 seconds. “If you add oxygen again, they'll simply resume their work and do so just as quickly,” says Dijk.
Brain activity
To better understand what happens inside the brain during syncope, the researchers recorded the activity of thousands of neurons from various brain regions in mice using electrodes. They found that activity decreased in all areas of the brain except one specific region in the hypothalamus known as PVC.
When the authors inhibited/blocked the activity of PVC, the mice experienced longer fainting episodes, while its stimulation caused the animals to wake up and start moving again. The team suggests that a coordinated neural network that includes NPY2R VSNs and PVC regulates fainting and the rapid recovery that follows.
“Coming from a clinical standpoint, this is all very exciting,” says Richard Sutton, clinical cardiologist at Imperial College London. The discovery of NPY2R VSNs “doesn't answer all questions immediately”, he adds, “but I think it could answer with future research almost everything.”
For “questions that cardiologists have been asking for decades, now you can bring in a neuroscience perspective and really see how the nervous system controls the heart”, says Augustine.
The next big question is studying how these neurons are triggered, says Dijk. “It's been one of the biggest riddles of my entire career.”
doi: https://doi.org/10.1038/d41586-023-03450-3
References
Lovelace, J. W. et al. Nature https://doi.org/10.1038/s41586-023-06680-7 (2023).
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最新的大腦結構圖 -- Gemma Conroy
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This is the largest map of the human brain ever made
Researchers catalogue more than 3,000 different types of cell in our most complex organ.
Gemma Conroy, 10/12/23
Researchers have created the largest atlas of human brain cells so far, revealing more than 3,000 cell types — many of which are new to science. The work, published in a package of 21 papers today in Science, Science Advances and Science Translational Medicine, will aid the study of diseases, cognition and what makes us human, among other things, say the authors.
The enormous cell atlas offers a detailed snapshot of the most complex known organ. “It’s highly significant,” says Anthony Hannan, a neuroscientist at the Florey Institute of Neuroscience and Mental Health in Melbourne, Australia. Researchers have previously mapped the human brain using techniques such as magnetic resonance imaging, but this is the first atlas of the whole human brain at the single-cell level, showing its intricate molecular interactions, adds Hannan. “These types of atlases really are laying the groundwork for a much better understanding of the human brain.”
The research is part of the US National Institutes of Health’s Brain Research through Advancing Innovative Neurotechnologies Initiative — Cell Census Network (BICCN), a collaboration between hundreds of scientists. The programme’s goals include cataloguing brain cell types across humans, non-human primates and mice to improve understanding of the cellular mechanisms behind poorly understood brain disorders. The data from the 21 studies have been made publicly available on the Neuroscience Multi-omic Archive online repository.
Cellular menagerie
Kimberly Siletti, a neuroscientist now at the University Medical Center Utrecht in the Netherlands, and her team laid the cornerstone for the atlas by sequencing the RNA of more than 3 million individual cells from 106 locations covering the entire human brain, using tissue samples from three deceased male donors1. They also included one motor cortex dissection from a female donor that had been used in previous studies. Their analysis documented 461 broad categories of brain cell that included more than 3,000 subtypes. “I was surprised at how many different cell types there were,” says Siletti.
Neurons — cells in the brain and nervous system that send and receive signals — varied widely in different parts of the brain, suggesting different functions and developmental histories. The mix of neurons and other cell types also differed across each region; some cells were only found in specific locations. The brainstem — a relatively under-studied structure connecting the brain to the spinal cord — harboured a particularly high number of neuron types, says study co-author Sten Linnarsson, a molecular systems biologist at the Karolinska Institute in Stockholm, Sweden. “One of the big surprises here is how incredibly complex the brainstem is.”
Other studies drilled into the mechanisms of gene regulation and expression in different cells. Joseph Ecker, a molecular biologist at the Salk Institute for Biological Studies in La Jolla, California, and his colleagues investigated the brain through an epigenetic lens using tissue samples from the same three donors2. They analysed chemical markers that switch genes on or off in more than 500,000 individual cells. The various molecules that acted as switches enabled the team to identify nearly 200 brain cell types. Even the same gene in the same type of cell could have different characteristics across the brain. One gene was turned on with one switch at the front of the brain and with another at the back. “There are remarkable regional differences,” says study co-author Wei Tian, a computational biologist at the Salk Institute.
Pinpointing the switches that activate or block gene expression in brain cells could be useful for diagnosing brain disorders and developing tailored treatments, says Ecker. “That’s another tool that comes out of the toolbox we’re building,” he says.
Disease risk
Improving understanding of how genetic switches might contribute to disease risk was also a focus for Bing Ren, a molecular biologist at the University of California, San Diego, and his team3. They analysed how more than one million brain cells from the three donors access and use genetic information. The researchers uncovered links between certain brain cell types and neuropsychiatric disorders, including bipolar disorder, depression and schizophrenia.
Ren and his colleagues used the cell-type data to predict how the genetic switches influence gene regulation and increase the risk of neurological diseases. For instance, in cells called microglia , which clear away dead or damaged cells, the presence of some genetic switches was strongly linked to risks of Alzheimer's disease. Such findings can be used to test whether particular genes or faulty switches contribute directly to the onset of disease. “This is made possible because we have — for the first time — delineated the genetic switches for hundreds of different cell types,” says Ren.
The next step for the BICCN team is to sequence more cells from all parts of the brain, says Ren. The researchers will also work with more tissue samples to build a picture of how the human brain can vary across populations and age groups. “This is only the beginning,” says Ren.
doi: https://doi.org/10.1038/d41586-023-03192-2
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