Memory is stored through changes in the intensity of synapses between neurons
All along, the scientific community believes that memory storage is achieved by enhancing synaptic connections between neurons. This week, however, neuroscientists at the University of California, Los Angeles, published a distorted paper: They successfully transmitted the memory of an apso to another hare by injecting RNA. If the test is correct, it means that the storage of the memory will be overwritten. However, once the paper was disclosed, it was questioned by a large number of peers. Is this research a breakthrough for the Nobel Prize, or will it be a laughing stock for future generations?
Memory is stored through changes in the intensity of synapses between neurons. This ingrained view has been supported by myriad of evidence. New research from the David Glanzman Laboratory provided very different results. This discovery provides new possibilities for the use of RNA therapy to reshape lost memory one day. If the result is correct, it will shake the entire memory and study area. The study was published this week at eNeuro, an online journal of the Society for Neurosciences.
Many scientists will have reservations about the study. The sea hare is a powerful model organism in the field of neuroscience, but its simple brain and human brain work very differently. Therefore, the test needs to be repeated on animals with more complex brain structures.
Glanzman knew that this study of the importance of weakening synapses was not widely accepted by the industry. "I guess there will be many surprises and suspicions," he said. "I don't think that at the next annual meeting of the Society for Neuroscience, everyone will give me a celebration parade." Even his own colleagues have doubts. "It took me a long time to convince my lab to carry out this research," Glanzman said. "They think it's stupid."
How did this research, which caused great controversy, proceed?
David Glanzman, University of California, Los Angeles
Sea rabbit memory transfer test
In this experiment, Glanzman gave a mild electric shock to the California sea lion (Aplysia californica). After being electrocuted, the Hare learned to close the siphon tube and scorpion when it was slightly touched again, and remained for nearly a minute; while the Hare without electric shock was only recovered for a short time.
California Sea Hare
The researchers extracted RNA from the nervous system of the sea urchins that had been electrocuted and injected them into the undamaged sea rabbits. RNA acts as an intracellular messenger, carrying protein manufacturing instructions from homologous DNA. However, after the RNA was injected, the untouched sea-necked rabbits extended their siphons after being touched. In the control group, sea lions were injected with RNA from non-shocked sea rabbits, and they did not have a long time to retract siphons.
"It's as if we have transplanted memories," Glanzman said.
Glanzman's team further demonstrated that the sensory neurons of the sea rabbit in the petri dish are more excitable after injecting the RNA of the shocked sea rabbit, which is often the result of being shocked. However, the control group did not show this phenomenon.
According to Glanzman, these results indicate that memory may be stored in the nucleus of neurons. RNA is synthesized in the nucleus and acts on the DNA in the nucleus, turning on or off specific genes. He said he believes that the stored process of memory contains these RNA-regulated epigenetic changes.
This view challenges the widely accepted concept that memory is stored by enhancing synaptic connections between neurons. Glanzman believes that synaptic changes during memory formation come from RNA-carrying information.
Challenging traditional views
“This idea is very radical and it really challenges the current field of memory research,†said Cai Lihui, a neuroscientist and director of the MIT Institute of Learning and Memory at PICO. Cai Lihui in a recently-reported important review review of memory formation called Glanzman's research "impressive and interesting," and said that a series of studies support epigenetic mechanisms that play a role in memory formation and memory formation. It should be a complex and multifaceted process. However, she said she did not agree with Glanzman's point of view that synaptic connection is not important in memory storage.
Tomás Ryan, an assistant professor at Trinity College in Dublin, and Glanzman, among the neuroscientists as a minority (some call them rebels), questioned the traditional view that memory strengthens storage through synapses. In 2015, Ryan and MIT's Nobel laureate Susumu Tonegawa published a paper on Science that after the blockade of synapses was reinforced, memories could still be evoked. Ryan said that he is validating the idea that memory stores connect neurons in general by establishing new synaptic connections, rather than strengthening existing connections.
Ryan knew Glanzman and trusted his research. He said he believes the truth of the data in the paper. However, he did not think that the behavior of the sea rabbits or cells could prove that the RNA delivered memories. Ryan said that he couldn't understand how RNA working in minutes and hours can cause almost instantaneous memory recall, and how RNA connects many parts of the brain, such as the auditory and visual systems involved in more complex memories.
But Glanzman is convinced that the role played by RNA eclipses synapses. In 2014, his laboratory found that after a series of experimental procedures, the loss of shock memory in an Aplysia can be restored, but the synaptic connection patterns that disappear with memory are randomly combined during memory recovery, suggesting that memory is not stored in synapses. . The Glanzman team and other researchers also found that the formation of long-term memory can be blocked by stopping epigenetic changes, even if synapses are not formed or strengthened.
"The synapses can come and go, but memory can still exist," Glanzman said. Synapse is nothing more than "a reflection of the information in the nucleus."
Glanzman has studied memory for more than thirty years. He completed a post-doctoral research in Eric Kandel's laboratory, which shared the Nobel Prize in Physiology and Medicine in 2000 for exploring the role of the synapse in memory through the sea rabbit. He said he believed most of his academic career. Synaptic changes are the key to memory storage. But in recent years, a series of his own and other laboratory research made him question the creed.
Half-century dispute test
Part of the reason for doubting Glanzman's research is that it is reminiscent of a disturbing segment of the scientific development. Unconventional psychologist James V. McConnell spent several years at the University of Michigan trying to prove that something outside the brain called what he calls "memory RNA" can convey memory. In the fifties and sixties of the last century, McConnell trained flatworms and then fed the trained flatworms to untrained flatworms. Afterwards, the untrained bugs seem to have inherited the same kind of behavior they had eaten, so McConnell believes that memory has shifted through some form. He also showed in the experiment that the trained flatworms can still remember the training they had received after they were cut off their heads and renewed their new heads.
Flatworm
Although some other laboratories repeated this result, McConnell's research was widely criticized because other laboratories invested a lot of time and money to repeat the experiment, and most of them failed.
Recently, Michael Levin, a development biologist at Tufts University, repeated McConnell's headless flatworm experiment under more closely controlled conditions. He believes that McConnell may be right.
Glanzman said that McConnell's student Al Jacobson unexpectedly realized passing RNA injections between flatworms during an assistant professor at the University of California, Los Angeles. The study was published in Nature in 1966, but perhaps because his research was widely questioned, Jacobson failed to get tenure. In fact, the experiment was repeated on rats in the near future.
Glanzman learned of McConnell's research when he was an undergraduate in psychology at Indiana University, but he never took those results seriously. Now, although he still does not believe that McConnell is completely correct in transferring memory, he believes that McConnell and Jacobson's research is not nonsense.
It is not easy to challenge the status quo in the field of memory research. With countless suspicions, resistances, and even direct ridicule against his peers, Todd Sacktor of the State University of New York has spent more than 25 years chasing a molecule: PKMzeta. He believes that this molecule is crucial for the formation of long-term memory and may be related to the RNA mechanism discovered by Glanzman.
This area is of great importance, because memory is so critical to our self-awareness, and many scientists feel that the working mechanism of memory should have been opened up long ago. "This is the last major biological problem of the 20th century," Sacktor said. "Some of these difficulties make it difficult for neuroscientists to find out."
Difficulties may come partly from excessive attention to synapse enhancement. Ryan mentioned that 12,000 papers discussing synaptic fortification have been published, but there is still no good explanation for how memory is stored. He applauded Glanzman for opening a new tractable path, even if this road seemed radical.
"The reality is that our understanding of memory is so limited," Ryan said. "I'm excited about any new possibilities."
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