Axolotls can regenerate their brains

The Axolotl (Ambystoma mexicanum) is an aquatic salamander known for its ability to regenerate its spinal cord, heart, and limbs. These amphibians also willingly form new neurons throughout their lives. In 1964 researchers observed that adult axolotls could regenerate parts of their brains even after a large part had been completely removed. However, one study found that axolotl brain regeneration has limited ability to rebuild original tissue structure.

How perfectly can axolotls regenerate their brains after an injury?

As a researcher studying regeneration at the cellular level, I and my colleagues at the Treutlein lab at ETH Zurich and at the Tanaka lab at the Institute of Molecular Pathology in Vienna asked whether axolotls are able to regenerate all the different cell types in to regenerate their brain, including the connections that connect one brain region to another. In our recently published study, we created an atlas of the cells that make up part of the axolotl brain and shed light on both how it regenerates and how the brain evolved across species.

Why look at cells?

Different cell types have different functions. They can specialize in certain roles because they each express different genes. Understanding what types of cells exist in the brain and what they do helps provide the bigger picture of how the brain works. It also allows researchers to make comparisons across 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). This tool allows researchers to count the number of active genes in each cell of a given sample. This provides a “snapshot” of the activities that each cell was doing while collecting.

This tool has been instrumental in understanding the cell types found in animal brains. Scientists have used scRNA-seq in fish, reptiles, mice and even humans. But one important piece of the puzzle of brain development is missing: amphibians.

Mapping the axolotl brain

Our team decided to focus on the axolotl telencephalon. In humans, the telencephalon is the largest division of the brain and contains a region called the neocortex that plays a key role in animal behavior and cognition. Over the course of recent evolution, the neocortex has grown massively in size compared to other brain regions. Similarly, the cell types that make up the overall telencephalon have greatly diversified and increased in complexity over time, making this region an intriguing area of ​​study.

We used scRNA-seq to identify the different types of cells that make up the axolotl tencephalon, including different types of neurons and progenitor cells, or cells that can divide into more of themselves or transform into other cell types. We identified which genes are active when progenitor cells become neurons and found that many pass through an intermediate cell type called neuroblasts, previously unknown to exist in axolotls, before they become mature neurons.

Then we put axolotl regeneration to the test by removing a section of their midbrain. Using a special scRNA-seq method, we were able to capture and sequence all new cells at different stages of regeneration, from one to 12 weeks after injury. Ultimately, we found that all removed cell types were fully restored.

We have observed that brain regeneration occurs in three main phases. The first phase begins with a rapid increase in the number of progenitor cells, and a small proportion of these cells activate a wound healing process. In phase two, progenitor cells begin to differentiate into neuroblasts. Finally, in phase three, the neuroblasts differentiate into the same types of neurons that were originally lost.

Amazingly, we also observed that the severed neural connections between the removed area and other areas of the brain were reconnected. This rewiring indicates that the regenerated area had also regained its original function.

Amphibians and human brains

Adding amphibians to the evolutionary puzzle allows researchers to deduce how the brain and its cell types changed over time, as well as the mechanisms behind regeneration.

When we compared our axolotl data to other species, we found that cells in their telencephalon bear a close resemblance to the mammalian hippocampus, the region of the brain involved in memory formation, and the olfactory cortex, the region of the brain brain involved in smell perception. We even found some similarities in an axolotl cell type with the neocortex, the area of ​​the brain known for perception, reasoning and spatial reasoning in humans. These similarities suggest that these areas of the brain are evolutionarily conserved or comparable throughout evolution, and that the mammalian neocortex may have an ancestral cell type in the amphibian telencephalon.

While our study sheds light on the process of brain regeneration, including the genes involved and how cells ultimately become neurons, we still don’t know what external signals trigger this process. Also, we don’t know if the processes we’ve identified are still accessible to animals that evolved later, like mice or humans.

But we’re not solving the puzzle of brain development alone. The Tosches Lab at Columbia University explored the diversity of cell types in another species of salamander, Pleurodeles waltlwhile the Fei lab at the Guangdong Academy of Medical Sciences in China and collaborators at life sciences company BGI studied how cell types are spatially organized in the axolotl forebrain.

The identification of all cell types in the axolotl brain also helps pave the way for innovative research in regenerative medicine. The brains of mice and humans have largely lost their ability to repair or regenerate themselves. Medical interventions for severe brain injuries currently focus on drug and stem cell therapies to speed or enhance repair. Studying the genes and cell types that allow axolotls to achieve near-perfect regeneration could hold the key to improving the treatment of serious injuries and unlocking the regenerative potential in humans.

This article was republished by The Conversation under a Creative Commons license. Read the original article.