The brain is cut into pieces and regenerated, and scientists finally see how it does it

Image credit: Wikimedia Commons, CC BY-SA 3.

Superpowers for you, normal operation for it, why?

Written by | chestnut

Review | clefable

In Aztec mythology in the Americas, there is a dog-headed deity named Xolotyl

The Aztecs revered sacrifice

Back in the real world, the 13th-century Aztecs settled

The name is still used to this day, but not every salamander is called "axolotl", and only the Mexican blunt-mouthed salamander (Ambystoma mexicanum) has received such a special name

Salamanders are amphibians that live in the water as young, and adult salamanders that undergo metamorphosis will land in a completely new form (just like tadpoles turn into frogs).

Not only that, but the Mexican blunt-mouthed salamander also has a strong regenerative ability

In this regard, the Mexican blunt-mouthed salamander is a rare exception

Recently, a research team led by Chinese scientists has drawn the first spatial-temporal map of brain regeneration for the Mexican blunt-mouthed salamander
.

The results of this study, along with three other studies, appeared on the cover
of the journal Science.

Where are the regeneration cheats hidden?

What to do to find the secret of salamander regeneration? If you want to know whether a particular cell or molecule plays a role in the regeneration process of a certain part, the simplest idea may be to do some special treatment for the salamander, to see what kind of changes can make it lose its regenerative ability
.

For example, scientists once thought that the immune system might play an important role
when regenerating after amputation.

Macrophages, as part of the immune system, play a key role in the inflammatory response after injury and may also be related to
tissue repair.

So they injected the Mexican blunt-mouthed salamander with a drug that removed macrophages from its limbs and amputated them
.

It turned out that salamanders without macrophages could not regenerate a new leg, replaced by scar tissue
.

There are also regeneration-related proteins, such as transforming growth factor-β (TGF-β), which were also discovered
through similar experimental ideas.

When such molecules do not work properly, the limb regeneration process of the Mexican blunt salamander is easily blocked
.

In fact, not only the limbs, but also the regeneration after brain damage also depends on many different cells and molecules
.

The researchers even look at which cells are working hard at what time after brain damage occurs: expressing specific genes to make substances
that might help with brain regeneration.

Of the four studies that recently appeared on the cover of Science, three were carefully observed in response to the brain regeneration process of the Mexican blunt-mouthed salamander, specific to individual cells
.

Although each cell carries almost the same genome, the genes expressed are not necessarily the same, one cell expresses some genes, and another cell may express another part of the gene
.

In the salamander's mind, the cells have their own tasks, so how do researchers distinguish between each cell?

mRNA transcribed from DNA (Credit: Wikimedia Commons, CC BY-SA 4.
0)

Middle school biology tells us that to express a gene, we want to transcribe DNA into messenger RNA (mRNA); Then there will be transporter RNA (tRNA) that follows the sequence provided by the mRNA, grabs the corresponding amino acids and arranges them, and combines them into proteins
with the help of other molecules.

MRNAs are different depending on the genes expressed
.

Scientists can use single-cell transcriptomics methods to simultaneously measure the concentrations of many different messenger RNAs, giving them an idea of which cells are actively expressing which genes
.

Brain damage, can you go back to childhood?

Specifically, the researchers looked at the telencephalon of the Mexican blunt salamander, which is the two hemispheres
of the brain.

In one of the science cover studies, Dr.
Wei Xiaoyu and colleagues at the University of BGI performed brain damage treatment on juvenile salamanders, removed part of the left brain, and then observed the process
of brain regeneration.

They divided the process into 7 periods, from 2 days, 5 days, 10 days, 15 days, 20 days, 30 days, all the way to 60 days
after the injury.

By these days, scientists take slices of salamander's telencephalon to see where their repairs go
.

The research team used a technique called stereo-seq to observe which cells are available at different time points, in which regions of the brain, and which specific genes are expressed, in order to draw a spatial-temporal map
of brain regeneration.

Spatial-temporal atlas of brain regeneration, 8 figures from undamaged adolescents and 7 telencephalic slices at different stages after injury (Image source: original paper)

Before that, the scientists first used the telencephalic slice of the Mexican blunt-mouthed salamander without brain injury to confirm 33 different cell types (different genes expressed) and how these types of cells are distributed in the salamander brains of different ages
.

In this way, according to the situation of normal salamanders, it is possible to determine whether the salamander with damage to the brain has completed brain regeneration
.

The researchers found that the brain damage of juvenile salamanders had healed within 30 days, only at that time, the cell types in the damaged area were still different
compared to the undamaged area.

But after 60 days, the levels of the various different cells that the scientists labeled, as well as their location distribution, were no longer significantly different from those of normal juvenile salamanders
.

To achieve such a regenerative effect, I am afraid that many neurons
will be manufactured.

In humans who are also vertebrates, the generation of neurons mainly occurs in the embryonic stage, which lasts for about two years after birth, and the older they are, the more difficult it is to make new neurons
.

And the brain regeneration ability of adolescent Mexican blunt salamander is so strong, is it that after brain damage, some cells in their brains have returned to the state of early development?

To answer this question, we must also compare
the spatio-temporal map regenerated after brain injury with the normally developed spatio-temporal map.

The researchers divided the development process of the Mexican blunt-mouthed salamander into 6 stages: the first eating after incubation, the completion of forelimb growth, the completion of hindlimb growth, the adolescent stage, the adult stage, and finally the metamorphosis stage
.

The first three stages are considered early stages
of development.

Spatial-temporal atlas of brain development, St.
44 is the first eating after incubation, St.
54 is the completion of forelimb growth, St.
57 is the completion of hindlimb growth, Juv.
is adolescence, Adult is adulthood, Meta.
is metamorphosis (Source: original paper)

At different stages of development, the scientists focused on the salamander's neural stem cells, known as ependymal glial cells (EGCs): the state of these cells that may represent the salamander's ability to
make new neurons.

The team found that during the normal early development of salamanders, there are few different subtypes of neural stem cells in the ventricular region, or only one subtype (dEGC).


After entering adolescence, the original subtype disappeared, and three different subtypes (wntEGC, sfrpEGC, ribEGC) were specialized, each occupying a different area — which may mean that each subtype of neural stem cells has a different function
.

In adolescent salamanders with brain damage, a new neural stem cell subtype reaEGC appeared
in the wound at the beginning of the injury (2-15 days).

So, is it the neural stem cells of the reaEGC subtype that help the salamander regenerate neurons?

To confirm this hypothesis, the scientists looked more closely at the salamander terminal brain
15 days after the injury.

In the direction of starting from the wound to the tail side, the researchers made 4 consecutive slices
.

Among them, the fourth slice shows a particular phenomenon: between the neural stem cell reaEGC subtype and immature neurons, there is a cell population that is different from both, and they express both genes expressed by reaEGC cells and some genes
expressed by immature neurons.

Therefore, scientists believe that those immature neurons are transformed from neural stem cell reaEGC, and the reason why there is a special cell population in them is likely to be because there is an intermediate state in the conversion process - those cells perform both neural stem cell tasks and neuronal tasks
.

As for whether the regeneration process of salamander brain is similar to the early development process, the researchers compared
the salamander terminal brain slice of brain damage in adolescence with the section of the telencephalon of the young salamander when the growth of the hind limbs of the young salamander is completed.

The results showed that 15 days after the brain injury, the spatial structure of the distribution of cells in the salamander terminal brain (fourth slice) was highly similar to
that of normal young salamanders.

This also means that brain regeneration triggered by brain injury is likely to reproduce the process
of neuronal development.

As you may recall above, in the early developmental stages of salamanders, there is only one subtype of neural stem cells in the ventricular region, dEGC
.

Scientists have found that the new subtype of neural stem cells related to brain regeneration, reaEGC, which appears after the brain damage of young salamanders, expresses genes that are closest to
the expression profile of dEGC.

The commonalities have made researchers feel that the process of neuron generation is similar
, whether it is when salamanders develop early or when adolescents regenerate after brain injury.

They have reason to believe that the neural stem cells of the Mexican blunt salamander returned to their early developmental state
under the induction of brain damage.

The brain regeneration process that starts from this is a bit like a "restart"
of the developmental process.

But it may be about to go extinct

With this map of space-time, human beings have a more complete understanding
of the superpower of regeneration of the brain of the Mexican blunt salamander.

However, this "not getting old" creature has attracted the attention of scientists and is not a recent thing
.

One day in the mid-19th century, the French zoologist Auguste Duméril received several salamanders sent from Mexico
.

Half a year later, he was surprised to find that the salamanders had bred offspring
.

The reason why he was surprised was because he knew that the salamanders were adults, and if you only look at the appearance, they are no different from
when they were children.

Dumerier knew that this salamander was different from
the salamander he had known before.

At first, scientists didn't understand why such strange life
existed.

However, as people learn more and more about the environment in which Mexican blunt-mouthed salamanders live, they also begin to understand their fate
in evolution.

Usually, most of the salamanders that can pervert and go ashore can enjoy some advantages
from land life.

While the Mexican blunt-mouthed salamander lives in high-altitude waters, the surrounding land (such as mountains or hills) may not be well suited for their survival
.

In addition, the lakes inhabited by the Mexican blunt-mouthed salamander may have been short of predators for a long time, providing a relatively stable environment that allows them to spend their lives in the water
.

Today, however, this amazing animal has been classified as critically endangered by the International Union for Conservation of Nature (IUCN
).

With increasing water pollution near Mexico City, coupled with the threat of invasive species and other factors, the number of blunt-mouthed salamanders in Mexico is less than 1,000, and the natural habitat is only Lake Hodgmirco
.

The only natural habitat of the Mexican blunt salamander today, Lake Hodgmirko (Credit: Wikimedia Commons, CC BY-SA 4.
0)

Although the regenerative ability is good, it does not effectively help this salamander adapt to environmental degradation
.

If they can't find a new shelter, perhaps one day, the Mexican blunt-mouthed
salamander will only exist in the laboratory.

There is not much time left for humanity
.

Cover source: popcap

Original paper:

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