How The Axolotl Rebuilds Its Brain, Step By Step

The process of brain regeneration in axolotls was explored in detail in a 2013 study published in Neural Development. What researchers found was a highly coordinated sequence of events that resembles a replay of embryonic development.

When part of the axolotl’s telencephalon (the major region of the forebrain involved in sensory processing and behavior) is injured or removed, the first thing that happens is surprisingly mundane: the wound closes. Cells surrounding the damaged area seal the opening to stabilize the tissue. Crucially, though, this happens without the formation of any dense scar tissue typical of mammalian brains.

This difference matters enormously. In humans, glial scars form very quickly after injury. Although this helps contain damage, it also creates a biochemical barrier that effectively blocks any new neural growth. But axolotls largely avoid this response. Instead of walling off the injury, their brains remain permissive to rebuilding.

After this, specialized cells lining the brain’s ventricles (called ependymoglial cells) are activated. These cells function somewhat like dormant neural stem cells, and in a healthy brain, they’d remain dormant. After injury, however, they begin dividing rapidly, which marks the beginning of reconstruction.

At this point, the newly produced cells migrate toward the injury site, where many begin transforming into immature neurons. Over weeks, these immature cells differentiate into the specific neuron types needed to replace what was lost. What’s most fascinating about this step is that it isn’t random. Rather, the regenerating tissue appears to follow spatial and molecular instructions embedded within the surrounding brain.

This means that the axolotl does not simply grow “more brain.” Somehow, it regrows the precise brain tissue needed, in the exact right location its needed in. And as this regeneration process continues over weeks, axons (the long projections neurons use to communicate) start extending into the surrounding tissue. These neural circuits gradually reconnect until, eventually, the regenerated region becomes structurally similar to the original one.

It’s worth noting that there’s still much that scientists don’t fully understand about this process. But one thing that researchers know for sure is that the axolotl’s regenerative strategy is a remarkably precise form of biological reconstruction.

How Is It Possible For The Axolotl To Regrow Its Brain?

Most would assume that the axolotl’s regenerative abilities are incompatible with vertebrate biology. After all, the human brain can barely replace even a small population of damaged neurons. Severe injuries to the spinal cord or cerebral cortex also usually result in permanent impairment. So how is it possible that a salamander can regenerate complex neural tissue without losing control of its body in the process?

In part, the answer is the axolotl’s nervous system itself. Compared to mammals, the axolotl brain is much less densely specialized and metabolically demanding. Many of its most essential behaviors (i.e., swimming, feeding, orienting toward stimuli, etc.) rely heavily on older, evolutionarily conserved neural circuits that are distributed throughout the brainstem and spinal cord. That means damage to parts of the forebrain, although serious, won’t necessarily incapacitate the entire animal.

This is why axolotls can survive the intermediate stages of regeneration. The brain isn’t “offline” while rebuilding occurs, which means that undamaged regions can continue to carry out vital functions while the injured area slowly reconstructs itself over weeks or months.

On top of this, their relatively slow metabolism also helps. Axolotls are aquatic salamanders with lower energy demands than mammals, and they also lead relatively sedentary lives. This makes a lengthy repair process biologically feasible, in a way that likely wouldn’t be for a highly active warm-blooded animal.

But beyond anatomy, the more profound difference relates to their cellular plasticity. Specifically, axolotl cells have an unusual ability to revert into a more flexible, developmental state after injury. Mature cells near damaged tissue can essentially “rewind” aspects of their identity, which allows them to proliferate and generate new structures.

This kind of flexibility is tightly restricted in mammals — for good reason, too. The uncontrolled proliferation of mature cells is incredibly risky, as it can lead to either cancer or total disruption of stable neural circuitry. But while human brains prioritize stability, axolotl brains prioritize regenerative potential.

This trade-off is a likely explanation for why regeneration is so rare among vertebrates with large, complex brains. A highly plastic nervous system is incredibly useful after injury, but it would also make long-term circuit stability much harder to maintain. And yet the axolotl somehow balances both. It can reactivate developmental programs without the need to descend into disorganized growth.

Why Did The Axolotl Evolve Such Extreme Regeneration?

The instinctive assumption is that axolotls evolved regeneration because they needed it. But according to a 2009 review published in Nature Reviews Neuroscience, the story may be more complicated. Rather than representing a bizarre evolutionary innovation unique to salamanders, regeneration may actually reflect an ancient trait that many vertebrates once possessed more broadly.

But over evolutionary time, mammals have obviously lost the vast majority of this regenerative capacity. Instead, evolution opted for faster wound sealing, stronger immune responses and more stable neural systems in mammals. This is likely because surviving injury would have mattered more than perfectly reconstructing tissue months later.

Salamanders, on the other hand, have retained far more of this ancestral regenerative toolkit. Their ecology may have reinforced this retention, since small amphibians are especially vulnerable to predation and environmental injury. Limbs, tails and nervous tissue can be damaged surprisingly easily in aquatic habitats filled with predators, debris, and competition. For an animal living close to the edge of survival, the ability to recover from catastrophic injury could dramatically improve reproductive success.

The axolotl’s strange life history has most probably also enabled this unique ability. Unlike many amphibians, axolotls remain in a juvenile-like aquatic state throughout adulthood, a phenomenon known as “neoteny.” Intriguingly, juvenile tissues in many vertebrates tend to be more regenerative than adult tissues. Thus, by retaining aspects of its developmental state for life, the axolotl may preserve cellular programs that would otherwise be “switched off” after maturation.

The strange irony is that axolotl’s regenerative abilities feel futuristic — almost science-fictional — yet they may actually represent something ancient. It’s far from a superpower; it’s simply a biological inheritance that most mammals gradually abandoned. This raises an unsettling possibility for our own species. Somewhere deep within vertebrate evolution, our capacity for dramatic neural repair would most likely have been more common than it is today.

The axolotl is one of evolution’s greatest biological mysteries. Take my fun Evolution IQ Test to see how much you really know about the forces that shaped life on Earth.