How the axolotl’s brain helps it regrow its tail

If you cut off the tail of an axolotl (please, don't do that), a strange, almost otherworldly salamander from Mexico, it will grow back. Not just the tail itself, but the muscles, the nerves, and even the spinal cord inside. This feat would be unthinkable for humans, whose spinal cord injuries often result in permanent paralysis. For years, scientists have been studying the axolotl’s regenerative superpowers, hoping to unlock secrets that could someday inspire new treatments for people.

Now, a team of researchers has made a surprising discovery: it’s not just the cells at the injury site that matter. The axolotl’s brain actually plays an active role in helping the tail regrow.

The study, published in npj Regenerative Medicine, comes from scientists at the Marine Biological Laboratory’s Eugene Bell Center for Regenerative Biology in Woods Hole, Massachusetts, and the National Human Genome Research Institute at the National Institutes of Health in Bethesda, Maryland. Dr. Karen Echeverri, S.E. Walker, K. Yu, and S. Burgess found that certain neurons in the axolotl’s brain switch on after a tail injury, and without this brain activity, the tail simply doesn’t regenerate properly.

The axolotl (also known as Ambystoma mexicanum) is sometimes called the “Mexican walking fish,” though it’s not a fish at all. It’s a salamander that stays in its larval stage for life, keeping its feathery gills and wide, perpetual grin. Beyond its quirky looks, the axolotl is a legend in biology labs because it can regrow almost any part of its body: limbs, tail, heart tissue, parts of the brain, and even the spinal cord.

By contrast, mammals, including us, don’t fare so well. If the spinal cord is injured, nerve cells around the damage tend to die. Scar tissue forms, blocking any chance of reconnection. The axolotl, however, avoids scar tissue and instead manages to rewire its nerves, restoring lost functions.

For decades, scientists assumed that regeneration was mostly a local process, with cells at the wound site doing all the work. But hints from past studies suggested something bigger: that the brain and other organs far from the injury might also be involved. This new research takes that idea and runs with it.

Here’s what the researchers found. When an axolotl loses its tail, neurons in a specific part of its brain, the medial pallium, a region roughly equivalent to the hippocampus in mammals, suddenly light up. This “lighting up” isn’t visible to the naked eye, but it can be detected through molecular markers of neuronal activity. The scientists focused on a signaling pathway involving a protein called Erk. Within just 30 minutes of tail amputation, Erk activity in these brain cells shot up. And interestingly, this heightened brain activity lasted more than 40 days after the injury.

In younger axolotls, the response was nearly immediate. In adults, it took a little longer, but the same pattern emerged: the brain joined the regeneration process.

To see if this brain activation was actually necessary, the team did a clever experiment. They injected an Erk-blocking drug directly into the axolotl’s brain before amputating its tail. The results were striking: without Erk activity in the brain, the tail regrew poorly, with fewer nerves reconnecting and a much shorter regenerate. In other words, the brain was essential to regrowth.

The story gets even more interesting. The activated brain neurons turned out to produce a signaling molecule called neurotensin. This neuropeptide is already known in mammals for roles in pain regulation, stress responses, and even appetite. But in axolotls, neurotensin seems to help kick-start regeneration.

When the researchers blocked neurotensin, tail regrowth stalled. The hypothalamus, a region deep in the brain that controls hormone release, failed to boost production of growth hormone-releasing hormone (GHRH), a key player in tissue growth. The usual inflammatory response that helps clear debris and prepare the wound site for rebuilding also fizzled out. In short, neurotensin was a linchpin: without it, regeneration faltered.

This research adds a new dimension to our understanding of regeneration. It shows that in axolotls, the brain communicates with distant injury sites, coordinating the rebuilding process. Instead of thinking of regeneration as a purely local repair job, we might need to think of it as a whole-body response.

This could eventually change how we approach spinal cord injuries or other types of tissue damage in humans. We know our bodies don’t regenerate like axolotls, but we do share many of the same molecular players, like Erk signaling pathways and neuropeptides. If we can figure out how to harness or mimic these brain-to-body signals, we might be able to improve healing or even spark regeneration where it normally doesn’t happen. It’s still early days, what works in a salamander won’t simply copy-paste into people. But the principle is clear: the brain is also part of the body’s repair toolkit.

This study also fits into a growing body of evidence showing that long-distance communication is a hallmark of regeneration. In cockroaches, severing the connection between the brain and an injured limb prevents proper regrowth. In frogs and fish, hormones released far from the wound site influence whether new tissue forms.

What makes the axolotl special is its ability to orchestrate all these signals seamlessly, without scarring. That’s something scientists, and doctors, dream of replicating.

Follow-up discoveries in this direction could lead to a future where a spinal cord injury wouldn't mean paralysis, or where damaged heart tissue after a heart attack could be coaxed to regrow. It might sound like science fiction, but studies like this one keep pushing the boundaries of what we know. Whatever will help us leap in that direction, one thing is clear: the axolotl has much more to teach us.

If you want to learn more, read the original article titled "Neuronal activation in the axolotl brain promotes tail regeneration" on npj Regenerative Medicine at http://dx.doi.org/10.1038/s41536-025-00413-2.