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.
一項針對老鼠的研究顯示，當長期記憶形成時，某些腦細胞會經歷一股強烈的電活動，以至於將它們的 DNA 斷裂。接著，一種炎症反應會啟動，修復這種損傷並有助於鞏固記憶。

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.
這項研究結果於 3 月 27 日發表在《自然》雜誌上，麻省理工學院的神經生物學家蔡麗蕙表示這是「非常令人興奮」的發現，她並未參與這項研究。她說，這些結果有助於我們對於記憶形成的「風險業務」有更完整的了解。通常，DNA 雙螺旋分子的兩股斷裂與包括癌症在內的疾病有關。但在這個案例中，DNA 損傷和修復循環提供了一種解釋，即記憶可能是如何形成並持續存在的。

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.
這也暗示了一個令人心動的可能性：這個循環在患有神經退行性疾病如阿茲海默症的人身上可能存在故障，導致神經元的 DNA 累積錯誤，紐約市阿爾伯特愛因斯坦醫學院的神經科學家、研究合著者 Jelena Radulovic 表示。

Inflammatory response 發炎反應

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.
這不是第一次將 DNA 損傷與記憶聯繫起來。2021 年，蔡教授及其同事們顯示，雙股 DNA 斷裂在大腦中普遍存在，並與學習有關。

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.
為了更好地了解 DNA 斷裂在記憶形成中的作用，Radulovic 和她的同事訓練老鼠將一個小電擊與新環境聯繫起來，這樣當動物再次進入該環境時，它們會“記住”這個經歷並表現出恐懼的跡象，例如停止移動。然後，研究人員檢查了與記憶密切相關的腦區域——海馬迴中神經元的基因活性。他們發現，在訓練後四天，一些負責炎症的基因在一組神經元中活躍。訓練後三週，這些相同的基因活性明顯減少。

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.
團隊找出了發炎的原因：一種叫做 TLR9 的蛋白質，它會觸發對細胞內漂浮的 DNA 碎片的免疫反應。研究人員發現，這種發炎反應類似於免疫細胞在抵禦侵略性病原體的基因物質時所使用的反應。然而，在這種情況下，神經細胞對的不是入侵者的 DNA，而是它們自己的 DNA。

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.
TLR9 在一部分海馬神經元中表現最活躍，這些神經元的 DNA 斷裂難以修復。在這些細胞中，DNA 修復機制會在一個稱為中心體的細胞器中積聚，中心體通常與細胞分裂和分化有關。然而，成熟的神經元不會分裂，Radulovic 表示，因此看到中心體參與 DNA 修復是令人驚訝的。她想知道記憶是否通過一種類似免疫細胞對遇到的外來物質進行調節的機制形成。換句話說，在損傷和修復的循環中，神經元可能會將觸發 DNA 斷裂的記憶形成事件的信息編碼下來，她說。

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.
都柏林三一學院的記憶痕跡神經科學家湯瑪斯·萊恩表示，這項研究提供了「迄今為止最好的證據，證明 DNA 修復對於記憶至關重要」。但他質疑神經元是否編碼了與記憶痕跡不同的東西，相反，他認為 DNA 損傷和修復可能是記憶痕跡形成的結果。「形成記憶痕跡是一個高影響力的事件；之後你必須做很多後勤工作，」他說。

Tsai hopes that future research will address how the double-stranded DNA breaks happen and whether they occur in other brain regions, too.
蔡希望未來的研究能夠探討雙股 DNA 斷裂是如何發生的，以及它們是否也發生在其他腦區。

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.
在都柏林三一學院與瑞安共事的神經科學家克拉拉·奧爾特加·德·聖路易斯表示，這些結果引起了對細胞內記憶形成和持久性機制的迫切關注。她說：“我們對神經元之間的連接和神經可塑性了解很多，但對神經元內部發生的事情了解得遠遠不夠。”