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Salamanders can regenerate their brains, revealing the secrets of brain evolution and regeneration

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Salamanders can regenerate their brains, revealing the secrets of brain evolution and regeneration

Solving the mystery of axis pivot regeneration can improve the medical treatment of serious injuries. Source: Wikimedia Commons

Axolotl (Ambystoma mexicanum) is an aquatic salamander known for its ability to regenerate the spinal cord, heart and limbs. These amphibians also easily make new neurons throughout their lives. In 1964, researchers observed that adult axons could regenerate parts of the brain even if a large part was completely removed. But one study found that the ability of the axon brain to regenerate and rebuild the original tissue structure was limited.

So, how do salamanders perfectly regenerate their brains after being injured?

As a researcher studying cellular-level regeneration, Ashley Maynard and his colleagues in the Treutlein lab at ETH Zurich and Tanaka's lab at the Vienna Institute of Molecular Pathology wondered if axons were able to regenerate different cell types in the brain, including connections that connect one brain region to another. In their recently published study, they created an atlas of cells that make up part of the axon brain, revealing the way it regenerates and the evolution of the brain across species.

Why look at cells?

Different cell types have different functions. They are able to play certain roles specifically because they each express different genes. Understanding what types of cells are in the brain and what they do can help clarify the overall picture of how the brain works. It also allows researchers to compare the entire evolution and try to find biological trends across species.

One way to understand which cells express which genes is to use a technique called single-cell RNA sequencing (scRNA-seq). The tool allows researchers to calculate the number of active genes within each cell for a particular sample. This provides a "snapshot" of the activities that each cell is doing at the time of collection.

The tool helps to understand the types of cells present in the animal's brain. Scientists have used scRNA-seq in fish, reptiles, mice and even humans.

Single-cell RNA sequencing can provide information about the specific function of each cell in a sample.

Mapping axis sound porter brain

Ashley Maynard's team decided to focus on the brain of the axon. In humans, the largest division of the brain, which contains an area called the neocortex, plays a key role in animal behavior and cognition. In recent evolutionary processes, the neocortex has grown dramatically in size compared to other brain regions. Similarly, the cell types that make up whole brain cells are highly diverse and become complex over time, making the region an interesting area of study.

They used SCRNA-seq to identify the different types of cells that make up axons, including different types of neurons and progenitor cells, or cells that can divide into more of themselves or become other cell types. They identified which genes were active when progenitor cells became neurons, and found that many genes passed through an intermediate cell type called neuroblasts — previously unknown to exist in axons — before becoming mature neurons.

The team then tested axon regeneration by removing a segment of its brain. Using a specialized scRNA-seq method, it is possible to capture and sequence all new cells at different stages of regeneration from 1 to 12 weeks after injury. Eventually, they found that all the deleted cell types had been fully restored.

The team observed that brain regeneration proceeds in three main stages. The first stage begins with a rapid increase in the number of progenitor cells, a small fraction of which activate the wound healing process. In the second stage, progenitor cells begin to differentiate into neuroblasts. Finally, in the third stage, neuroblasts differentiate into the same type of neurons that were initially lost.

Surprisingly, the team also observed that the severed neuronal connections between the excised area and the rest of the brain had been reconnected. This rewiring indicates that the regenerated area has also regained its original function.

Axolotls' regenerative abilities have been a source of fascination among scientists.

Amphibian and human brains

Adding amphibians to evolutionary puzzles could allow researchers to infer how the brain and its cell types change over time, as well as the mechanisms behind regeneration.

When the team compared axon data with other species, they found that the cells in their brains showed strong similarities with the mammalian hippocampus, brain regions involved in memory formation, and the olfactory cortex (in which the brain participates in smell). They even found some similarities between an axon cell type and the neocortex, an area of the brain known for human perception, thought, and spatial reasoning. These similarities suggest that these regions of the brain may have been evolutionarily conserved, or remained comparable over evolution, and that the mammalian neocortex may have ancestral cell types in amphibian brains.

While their study revealed the process of brain regeneration, including which genes are involved and how cells eventually become neurons, the team still doesn't know what external signals trigger the process.

The team won't solve the puzzle of brain evolution alone. The Tosches lab at Columbia University explored the diversity of another salamander Pleurodeles waltl cell types, while collaborators from Fei's lab at Guangdong Medical College in China and BGI, a life sciences company, explored the spatial arrangement of axolot forebrain cell types.

Identifying all cell types in the axon brain also helps pave the way for innovative research in regenerative medicine. The brains of mice and humans have largely lost the ability to repair themselves or regenerate. Medical interventions for severe brain injury currently focus on drugs and stem cell therapies to facilitate or facilitate repair. Examining genes and cell types that allow axonal cells to achieve near-perfect regeneration may be key to improving treatment for severe injuries and unlocking the potential for human regeneration.

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