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This article comes from the official account of Wechat: ID:fanpu2019, author: Wangxiang

Mice have brains the size of our thumb tips, but a new study has found that mice, like humans, are imaginative. They use their imagination to place themselves in a previously explored space, or to move distant objects to a specific location. Researchers believe that this result will be of great use in both clinical and basic research in the future.

"Imagination is very important to human society. Almost all inventions have happened twice, the first in imagination and the second in reality." Lai Chongxi told "return to Park".

As a postdoctoral fellow at Howard Hughes Institute of Medicine (HHMI), he should have been extremely excited. Because he just published a paper in the November 2 issue of Science magazine as the first author, uncovering a cognitive subversive secret: like humans, mice have imagination. They use their imagination to place themselves in a previously explored space, or to move distant objects to a specific location.

The ability to imagine away from the current location on the paper publication page is the basis for remembering past events and imagining possible future scenarios.

"now, we have found that animals can do the same, and we have found a way to study it." Albert K. Lee, a former project leader at HHMI's Janelia research park, is now a HHMI researcher at Beth Israel Deaconess Medical Center.

James W. Phillips, a former special adviser on business, energy and industrial strategy to the British prime minister, did not hesitate to speak highly of the study. "this is one of the most impressive work I have ever seen in neuroscience. I think this technology has amazing potential to be the focus of meta-science institutional experiments." He was a classmate of Lai Chongxi when he was studying as a doctoral student at Cambridge University in England.

Lai Chongxi himself is slightly calm. "this study took a long time and took a total of almost eight years, but now the results come out, but I feel less excited." But he thanked the "boss" for his support and patience. After all, "if some bosses can't wait, the research may be cut off." The two "bosses" are also correspondent authors of the paper, one is Albert Lee, and the other is Timothy D. Harris, HHMI's project leader and senior researcher.

Stereotype: mice have no imagination. The brains of mice are indeed much smaller than ours, about the size of our thumb tips. Even in the last century, many scientists still thought that the mouse brain was a simple stimulus-response system.

In the early 20th century, behaviorism occupied a prominent position in the fields of psychology and biology. The core idea of this theory is that the learning and behavior of biological individuals are mainly driven by the response to reward and punishment. Behaviorists believe that individuals adjust their behavior by responding to stimuli in the environment and adjusting their behavior according to the consequences of those stimuli (reward or punishment). In other words, behaviorist theory emphasizes the relationship between external stimulus and response, which is the main mechanism of behavior formation.

Edward Tolman (Edward Tolman), a professor at the University of California, Berkeley, disagrees. He published Cognitive maps in rats and men in 1948 and put forward a concept called "cognitive map", which holds that when people and animals explore the environment, they will form a psychological representation of the outside world in the brain, and these representations construct psychological models to guide their behavior.

In other words, even if there is no reward and punishment mechanism, the organism's brain still stores information about the environment and models it.

In 1971, American scientist John John O'Keefe found evidence for Tolman's theory at the level of brain cell activity. He found a special type of nerve cell in the "hippocampal" area of the mouse brain that represents spatial location.

The process of the experiment is like this. He implanted an electrode recorder into the hippocampus of the mouse brain and let the mouse walk freely in a strange room. When the mouse walked to a particular location, the frequency of discharge of the cells in the brain that encoded that location increased. O'Keefe named these cells "Place cell". Different location cells correspond to a particular location, and they form a map of the environment in the brain. For this discovery, O'Keefe won the 2014 Nobel Prize in Physiology and Medicine.

After severe damage to the human hippocampus, the ability to recall the past and imagine the future is lost at the same time, and many case studies of similar patients have confirmed the same situation. One of the most famous papers was published by Demis Hassabis (Demis Hassabis) and his mentor in 2007. Then Hassabis turned to industry and founded the artificial intelligence company DeepMind, which led the current AI revolution.

In other words, there is a proper term for this kind of human ability to psychologically project self into the past and relive past events, as well as the ability to project self into the future and experience future events in advance-psychological time travel (mental time trave). This is a specific type of imagination, which is closely related to the memory of time, place, people, events and so on.

So, will the mouse have a psychological time journey?

In fact, under a microscope, the brain tissues of rodents and primates are so similar that they can only be distinguished by trained eyes.

Moreover, neuroscientists have previously decoded signals from rodent brains and found that they are not simply responses to sensory or movement instructions. For example, when the mouse is in a certain position, the corresponding location of the cell becomes active. Scientists can determine the location of location cells by recording their activity.

However, for most people, just knowing where they are does not meet the standard of "imagination", because the connotation of imagination goes beyond the immediate situation. And until 2010, primate researchers still claimed that mice lacked "cognition".

No one has a definite answer.

Lai Chongxi wants to develop an animal model to study systematically: if mice can not go to a specific location, but only by imagining that they go to a specific location, they can also activate the corresponding location cells. then this kind of behavior is very close to the journey of human psychological time.

Reading "thinking" in August 2014, Lai Chongxi entered Cambridge University to study for a doctorate in neuroscience. At that time, he had already begun to conceive and design the experiment in his mind.

One day in 2015, when his classmate Phillips and Lai Chongxi were chatting by the lake, he heard the early ideas of the project for the first time. He immediately thought that Lai Chongxi was the smartest and most creative neuroscientist of his generation in the UK. Years later, he wrote, "when he first described it to me, I felt like something from the distant future, a huge conceptual leap that required technological progress and discovery, coupled with a deep understanding of the concept."

The main difficulty with this experiment is that you can't tell mice what to think or do. You have to give them some hints, such as rewarding them for a particular action. This kind of behavior training is not only a science but also an art.

At the same time, it is difficult to know what the mouse is thinking. Lai Chongxi came up with an ingenious experimental design: if mice can really think and imagine, then when they are induced to think about going to a particular place, they should be able to record their corresponding location cells become active in a predictable way.

To explore whether mice can do this, they used brain-computer interface (BMI) technology, which surgically implanted electrodes into the brains of mice, allowing them to travel through the meta-universe through spatial imagination. In this experiment, the mice were placed on a spherical treadmill in a 360-degree immersive virtual reality (VR) and showed a goal in the virtual world to run toward that goal.

When a mouse runs on a treadmill, its movements change on a 360-degree screen, and its position in the VR environment updates synchronously on the screen-just as a mouse moves in a real world. When the mice reach the target position, they will be rewarded (water). New goals are then generated in the VR environment, repeating the above process. Mice can learn this task in a week.

In the initial stage, the team recorded the activity of the location cells. They then used artificial intelligence to decode the activities of biological neural networks to calculate where the mice thought they were in the virtual reality task.

Next, they went on a task named after the movie "Jumper". The team disconnected the treadmill, which meant that the mice could not reach their goal by running. This forces them to use brain activity to move around in a VR environment. When the mouse's brain activity is decoded to be in the target area, it will move to that location, and once it moves to the target location, they will be rewarded.

The idea transitions in the movie Jump showed that the mice could indeed navigate to the target site only through brain activity. Fundamentally, when rats use mental navigation, they first have to think about where they need to go to get rewards. This kind of thinking process is often experienced by human beings. For example, if a friend invites you to a familiar restaurant, you may imagine the place you want to pass along the way before you go out.

However, the Jumper test also revealed a problem, which is that it is difficult to keep the mice motionless. Humans have the same experience. When your environment starts to float, you can't help but want to follow the environment, and it's hard to stop this impulse. Even if it is stopped, the brain will produce some signals and make noise.

To solve this problem, Chongxi designed the second mission "Jedi" (refers to the Jedi Knight, which is a tribute to the movie Star Wars). In the experiment, the mice themselves were stationary, but only brain activity had to be used to "move" objects on the screen to specific targets in the VR environment. It's like sitting in an office and imagining picking up the cup next to the coffee machine and filling the coffee. The team then changed the location of the target and asked the animals to produce patterns of activity related to the new location. The mice finished the task again.

The team found that mice can precisely and flexibly control their hippocampal activity, which is likely to be similar to that of humans. One surprising finding is that these animals can also maintain this hippocampal activity, keeping their minds in a specific position for a few seconds-a time range similar to that in which humans review past events or imagine new situations.

So far, from a scientific point of view, this paper has completed the most convincing demonstration of the cognitive ability of rodents. From the point of view of technological development, this work provides a method of reading abstract signals from deep brain tissue, such as the hippocampus. Although brain-computer interfaces have been developed since the early 1990s, they are limited to the cerebral cortex (especially the motor cortex), which is the first time to read cognitive map activity in an animal's deep brain tissue.

The cycle of discovery and invention, Lai Chongxi, is fascinated by brain function, especially "imagination".

To a large extent, his interest is guided by the book In Search of Memory. The book, written by neuroscientist Eric Kandel, shows not only his personal life and career, but also the development and important discoveries of neuroscience, as well as the nature and significance of memory.

With regard to the role of imagination on human beings, Lai Chongxi praised the view of the British philosopher David Hume: all people may be dominated by imagination, without imagination, there is no social arrangement.

Source: I provide the curiosity about how the brain produces imagination, which drives Lai Chongxi to focus on this for more than 8 years.

Although Lai Chongxi's idea and design are very ingenious, he suffers from the lack of a ready-made hippocampal brain-computer interface tool. "there is no brain-computer interface for this kind of deep organization, so we have to do something new." An invasive brain-computer interface consists of three parts. the first step is an array of cell-sized microelectrodes that are used to read electrical signals from nerve cells. The second step is the tool of on-line analysis of neural activity, which converts the original electrical signals into pulse signals, which complete the neural coding of the outside world and self-thinking in the brain. The third step is the decoder, which converts the pulse signals from a large number of cells into interpretable variables, such as spatial location. Lai Chongxi said that they built an online analysis tool based on field programmable gate array (FPGA) from scratch to output nerve pulse signals, which took four years alone.

O'Keefe, who found the location cell, personally told Lai Chongxi that he wanted to organize engineers to make this tool as early as the 1990s. But it was not until 2016 that some available tools were developed one after another.

"what we have done is the most advanced, accurate and fast of the few online neural recording and analysis tools. It is also the only FPGA chip that can give the decoder access to a single nerve cell, a single nerve pulse information in a millisecond. The breakthrough in technical indicators has opened up many possibilities for scientific research. The brain-computer interface of deep brain tissue is one of them." Lai Chongxi told "return to Park".

In Phillips' view, it is difficult to keep engineering and discovery side by side for a long time in traditional research, but Lai Chongxi's research gives a good case study to realize the "cycle of discovery and invention". When Lai Chongxi started the project, he first focused on technology, hoping to record an order of magnitude more neurons at a time than he started, and decode the meaning of these neurons in milliseconds instead of hours. The number and accuracy of neurons that can be processed at the same time is the key to the quality of decoding. The faster the processing speed of the neural signal, the more sufficient the time budget left to the decoder.

Decoders are as important as online recording and analysis tools. Conventional decoders are very sensitive to noise, which may come from imagination itself or from small changes in the position of microelectrodes in the brain. In order to solve these difficulties, Lai Chongxi uses the most advanced AI algorithm to complete the denoising process. After applying the self-developed FPGA chip to specific experiments, Lai Chongxi set about establishing a mapping relationship with VR, VR programming, animal behavior training, recording and analyzing data, and constantly optimizing AI decoders in the process, which took another four years to be written.

Caleb Kemere, a professor at Rice University, wrote in an opinion column in Science magazine: this finding is an exciting expansion of brain-machine interface (BMI) applications from sensorimotor functions to more cognitive areas, and suggests that hippocampal activity is controlled by will.

In the future, Lai Chongxi hopes to do clinical research based on this result. He thinks all these tool chains can be used on humans. The microelectrode is implanted into the deep brain tissue, and the neural activity analyzed online is decoded by AI, read abstract thinking and denoising, and then manipulate the brain or environment as needed. It is possible to read and write to the brain through such tools in the future.

Lai Chongxi believes that this tool chain is of great use in both clinical and basic research.

reference

[1] https://www.science.org/doi/10.1126/science.adh5206

[2] https://www.biorxiv.org/content/10.1101/2023.04.07.536077v1

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