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

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

References

Siletti, K. et al. Science 382, eadd7046 (2023).
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Tian, W. et al. Science 382, eadf5357 (2023).
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Li, Y. E. et al. Science 382, eadf7044 (2023).
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