Scientists reveal a mysterious new mechanism of the brain: trying to explain how

2024-05-06

The human brain contains approximately 86 billion neurons, a number close to the count of stars in the Milky Way galaxy. From a certain perspective, each person's brain is like a profound and boundless universe.

For Professor Ning Zhou from the ShanghaiTech University, who studies neuroimaging, our brains are both mysterious and romantic.

Recently, she and her team have unearthed a new treasure in this "brain universe": they have discovered a new category of neurons in the hippocampus.

"These cells seem to closely connect the external objective information of an organism with its internal subjective intentions. They not only map spatial information but also synchronously represent the animal's exploratory intentions," said Ning Zhou.

At the same time, the encoding mechanism of these neurons depends on the information input from the lateral entorhinal cortex, providing new ideas for understanding how the brain integrates external environmental information with internal subjective intentions, and also offering a new perspective for understanding the function of place cells in the hippocampus.It is understood that scholars have already discovered that the lesions and functions of the hippocampus are significantly related to the existence of many brain diseases, including Alzheimer's disease, epilepsy, and schizophrenia, among others.

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Understanding the encoding and memory mechanisms of the hippocampus will help in the development of new diagnostic markers for brain diseases, the study of brain-computer interfaces, and the development of new drug targets, etc.

The "Navigation Mystery" of the Brain

In the field of neuroscience, people have always been troubled by such an interesting question: how does the brain determine the position of an organism in space and use this information for navigation?With his remarkable achievements in this field, British scientist Professor John O'Keefe, along with Norwegian scientists Edvard Moser and May-Britt Moser (now divorced), jointly received the Nobel Prize in Physiology or Medicine in 2014.

As early as 1971, Professor John O'Keefe discovered a special type of neuron in the hippocampus while studying rats and named it the "place cell."

When recording electrodes are implanted into the hippocampus of rats to track the activity of neurons, it can be observed that each place cell is activated only when the rat passes through a specific area.

In other words, each place cell corresponds to a specific area in space, and they constitute an indexing mechanism for the animal brain to map external spatial information.

Interestingly, similar positioning cells also exist in the human brain, and these cells together form the human brain's "cognitive map" of the external world.For many years, scientists have never ceased to explore the mechanisms and functions of place cells formation.

For example, are hippocampal neurons only limited to representing spatial positions? Do they also indicate time, or even more abstract concepts?

Do these neurons merely exist as a mapping of the external world in the brain? Or are they also influenced and regulated by the psychological state of the organism?

Furthermore, do hippocampal neurons have the ability to encode both external objective information and the brain's subjective intentions simultaneously?

It is these questions that continue to inspire people to explore. And the answers to these doubts may help us to further uncover the deep mysteries of cognitive functions in the brain.How does the brain encode information?

For Zhou Ning, she has been studying life sciences since her undergraduate years. Previously, after completing her undergraduate studies at the School of Life Sciences at Peking University, Zhou Ning obtained a Ph.D. in neuroscience from the University of British Columbia (UBC) in Canada.

In 2011, Zhou Ning established her independent research group at China Medical University in Taiwan, China. In 2019, she joined the iHuman Research Institute at the Shanghai University of Science and Technology as an independent principal investigator.

For a long time, she has been committed to conducting basic research related to neurophysiology and pathology through techniques such as fluorescence imaging and electrophysiology.For instance, during her doctoral studies, Ning Zhou often utilized two-photon fluorescence microscopy technology to image and record brain slice tissues that were labeled with fluorescent indicators.

 

She frequently observed the calcium ion fluorescence intensity in living brain slice cells fluctuating with the activity of brain cells, flickering and waxing and waning, akin to the twinkling of stars in the distant sky, which fascinated Ning Zhou immensely.

 

As mentioned earlier, the human brain has approximately 86 billion neurons. The hidden signals behind these intricate neuronal networks within living animals are the key to understanding how the brain encodes information.

 

Therefore, Ning Zhou's research focus gradually honed in on using neuroimaging techniques in living animals to delve deeper into how the brain encodes these complex messages.

 

"Every time I analyze the calcium ion activity in neurons, it feels as if I am decrypting the brain's code, which is both unknown and incredibly exciting," she said.Previous research on the hippocampus has revealed that place cells may adjust according to the animal's foraging motivation or attentional state.

For example, when an animal is searching for food, the hippocampus may activate more place cells to mark the specific location of the food.

Similarly, when changes in the external environment attract the animal's attention to the change signals, the number and activity of place cells may also adjust accordingly.

These studies have raised a question for Zhou Ning: Can the subjective intentions of an organism be encoded by hippocampal neurons when they are neither driven by food nor attracted by external stimuli?

Imagine this: When we go to work or school along familiar roads every day, we pass by a familiar statue at the corner of the street. One day, we suddenly decide to stop and take a close look at it. Will the neural encoding of the hippocampus be different from usual?Do there exist a group of neurons that can simultaneously encode the position of this statue and our willingness to explore? If the answer is affirmative, then these neurons may guide us to where to go and what to do.

 

This question has filled the team of Zhou Ning with passion, especially the doctoral student Zeng Yifan who showed a strong interest in it. After some deep contemplation, they designed an ingenious experiment to explore the aforementioned question.

 

Specifically, they constructed two behavioral boxes with circular tracks, trained mice to run in the same direction, and rewarded them with a milk powder ball at a fixed position after each lap.

 

At the same time, different shapes and colors of objects were placed at three other positions, allowing the mice to stop and observe and explore when they were close to these objects, or choose to ignore the objects and continue running. Under both of these conditions, the paths taken by the mice were highly consistent.

 

A few weeks before the experiment began, they implanted a gradient refractive index lens (Grin Lens) in the head of the mice and labeled the hippocampal neurons with the calcium ion fluorescent indicator GCaMP6f.In this way, when mice engage in various behaviors, the activity of neurons in the hippocampus can be recorded in real-time through a head-mounted micro-microscope.

Micro-microscope technology is a groundbreaking experimental technique that has emerged in the field of neurobiology in recent years. Despite weighing less than 3 grams, it integrates key functional components of traditional microscopes.

This allows for high-speed imaging at the subcellular level of an approximately 0.4 square millimeter brain area and can simultaneously capture data from more than 200 neurons.

Thanks to its lightweight design, mice can carry this microscope while engaging in free activities in a nearly unrestricted natural state, ensuring the naturalness of the mice's movements and behaviors.

In the behavior box designed by the research group, mice can independently choose whether to explore approaching objects.While filming the behavioral performance of mice with a camera, the team used a mini microscope to record the calcium signal activity of neurons in the hippocampus.

By conducting an in-depth analysis of the collected data, they were able to identify very typical place cells, the characteristics of which highly match the traditional place cells previously reported.

What excited the research team was that, in addition to those typical place cells, they discovered a group of unique hippocampal neurons that were only activated when the mouse explored a specific location.

However, when the mouse passed the same place without performing any exploratory behavior, these cells were almost silent.

This special cell function had not been mentioned before, so they named it object exploration-dependent place cells (oePC).Subsequently, they constructed a series of experiments aimed at studying how object-encoding place cells (oePCs) jointly encode exploratory intentions and spatial information, and attempted to explain the underlying mechanisms.

By analyzing the activation timing of oePCs and the behavior of mice exploring objects, they observed that the active period of these cells usually occurs about 0.8 seconds before the animal's exploratory behavior, and occurs when the animal is about 3 centimeters away from the object. This means that the activation of oePCs actually precedes the actual exploratory behavior.

Further research on the location field characteristics of oePCs revealed that when an object is moved from its original position by 0.5 cm, 1 cm, 2 cm, or 4 cm, the activity intensity of oePCs gradually weakens or even disappears with the increase in the distance of movement. This indicates that oePCs have the ability to encode specific locations.

When new objects replace old ones, there is no significant change in the activity pattern of oePCs.

It is puzzling that earlier studies have pointed out that replacing objects in the environment will cause a significant change in the activity of traditional place cells, so why do oePCs not change?At this point, the first thing they had to consider was: whether the new and old objects were too similar for the mice to distinguish between them?

To rule out this possibility, the research team carefully selected a series of complex objects that were distinctly different in terms of shape, color, and other aspects to test the mice. However, even so, the encoding of the oePCs still did not show significant changes.

Further analysis of the traditional place cells with the same location field revealed that these cells indeed produced a significant encoding difference in response to the replacement of the objects.

This comparative result clearly indicates that, unlike traditional place cells, oePCs seem not to encode the features of the objects themselves.

In another experimental design, the team cleverly hid the objects behind partitions, so that the mice could only see these objects when they showed initiative in exploration and went through a small door to search.It is interesting to note that they observed that oePCs (object-encoding place cells) were already pre-activated even when the mice were approaching but had not yet directly seen the objects.

When those familiar objects were unexpectedly removed, or when an object was suddenly replaced with food at the same location, the activity of oePCs began to significantly decrease.

This phenomenon indicates that these cells are not encoding changes in environmental signals, nor are they expressing anticipation for potential rewards.

To further study the characteristics of oePCs, the research team designed a series of experiments, including continuous imaging observations over several days, as well as behavioral box environment change tests.

At this point, oePCs showed a pattern similar to that of classic place cells, meaning that the neuronal activity of oePCs exhibits a certain stability in a familiar environment. However, in a new environment, they show the potential for reprogramming.Finally, they began to explore the impact of the input circuit from the lateral entorhinal cortex (LEC) to the hippocampus on the encoding ability of the object-place cells (oePCs).

By expressing the inhibitory chemogenetic protein hM4Di in the LEC and injecting its specific ligand—clozapine-N-oxide (CNO)—into the mice to suppress the activity of LEC neurons.

The experiment found that when the function of the LEC was inhibited, the activity pattern of the oePCs was significantly disrupted. In contrast, in mice expressing the control protein, the oePCs were unaffected.

This finding strongly suggests that the signal for exploring intentions is transmitted to the hippocampal area neurons through the LEC.Do It Yourself "Becoming a Welder"

It is also reported that the self-assembly of the mini microscope - is one of the key events for the successful completion of this project.

Zhou Ning said: "This microscope is based on the open source project of the miniscope from the University of California, Los Angeles. Its structure and principle are not unfamiliar to me. I have previously built a two-photon fluorescence microscope system with my own hands and have accumulated a certain amount of optical technology and practical experience."

However, in the process of assembling the mini microscope, Zhou Ning encountered an unexpected challenge.

Due to the small size and precision structure of this microscope, she needs to perform electronic welding on an interface that is less than one millimeter wide.Here comes the problem: The tip of the soldering iron in the research group is several millimeters in diameter, which means the operating space is extremely limited. A slight mistake could lead to a short circuit, weak solder joints, or even burn out the chip.

For a researcher with a background in biology, such technical requirements are undoubtedly a huge challenge.

To this end, she kept trying various techniques and even considered whether to learn from the assembly line of an electronics manufacturing factory. After multiple trials and failures, Zhou Ning finally mastered the key points of soldering.

"Now in the team, my technology is still considered top-notch, and I am also a skilled worker, so I still need to continue to undertake the daily maintenance work of the micro microscope," she said.

In summary, through various efforts, she and the team finally revealed the existence of a group of new hippocampal neurons (oePC).Recently, a related paper titled "Conjunctive encoding of exploratory intentions and spatial information in the hippocampus" was published in Nature Communications[1].

Zeng Yifan is the first author, and Zhou Ning serves as the corresponding author.

In general, with a series of groundbreaking achievements in the field of hippocampal function research in the scientific community recently, human understanding of this mysterious brain area is gradually deepening.

For example, it has been found that the hippocampal neurons of mice can encode abstract cognitive variables, as well as experiments that achieve autonomous control of virtual objects to designated positions by mice through hippocampal brain-computer interface technology.

Nevertheless, human understanding of the hippocampus is still just the tip of the iceberg.How the hippocampus maps the external world and transforms this information into an individual's subjective consciousness and actions is a key issue in revealing the core mechanisms of cognition and behavior in animals and humans.

Therefore, Ning Zhou hopes to continue to unveil the mysterious functions of the hippocampus, which will not only help humans understand the working mechanisms of the brain but also may provide new ideas and strategies for the treatment of related neurological diseases.

Specifically, she plans to delve into the role of these neurons in brain diseases, especially to investigate whether the reduced environmental exploration behavior in individuals with autism is related to the functional abnormalities of oePC neurons.

In addition, she also hopes to collaborate with other teams in the field of computational neurobiology, using advanced algorithms such as closed-loop control to regulate oePC in real time, thereby precisely studying their impact on animal behavior.

And she hopes to improve the neural network model through cooperation, thereby simulating the complex functions of the hippocampus and further unraveling the secrets of brain operation.

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