Three hearts; blue blood; no skeleton; arms like tongues. These are just some of the extraterrestrial characteristics of octopuses, squid and cuttlefish, members of the cephalopod family. The crazy list continues. Cephalopod skin can taste chemicalsfeel the light and quickly change color and texture. In many species, arms covered in suckers can even regenerate.
These invertebrates have evolved independently of the vertebrate lineage for over 600 million years. Their last common ancestor was probably a worm-like creature with a rudimentary nervous system and light-sensitive, eye-shaped cells. Despite this evolutionary gap, vertebrates and these highly specialized molluscs share uncanny similarities. Their eyes, for example. “It’s strange how similar they are,” says Cristopher Niell, a neuroscientist at the University of Oregon in Eugene. “The convergent evolution of the eye still blows my mind.”
Now a similarity prompts a boom in cephalopod neuroscience. About 400 million years ago, cuttlefish, squid and octopuses separated from the only other living cephalopods: nautiluses. They then lost their protective shell and developed brains that were particularly large among invertebrates. These brains give soft-bodied cephalopods great intelligence. Cuttlefish, squid and octopuses have excellent memories, use tools and are good problem solvers; they have a sense of time and are capable of delayed gratification.
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Cephalopods are the only nonvertebrate animals with large, intelligent brains, says Cliff Ragsdale, a comparative neuroscientist at the University of Chicago in Illinois. And this represents a unique opportunity. Neuroscientists have gained a wealth of knowledge about how the vertebrate brain works, but are increasingly turning to cephalopods to better understand ways to build an extensive and efficient nervous system.
“This is incredibly exciting for those of us who want to understand the rules of how the brain works,” says Carrie Albertin, a cephalopod researcher at Harvard University in Cambridge, Massachusetts. “It’s very clearly a complex brain that drives elaborate behaviors.”
But a set of ethical challenges accompany study of these powerful brains. Vertebrates used in scientific research enjoy strong legal protections, but this is not always the case for invertebrates. Even the best efforts to provide gold standard care are limited: there are limited options for pain relief for cephalopods, for example.
Nevertheless, over the past decade and, especially, in recent years, neuroscientists have reshaped the tools of modern neuroscience and molecular genetics – developed primarily in mice and other animal models – for use in these enigmatic invertebrates. “There are so many biological questions that have not been explored with a modern cellular and molecular approach,” says Ragsdale.
Build a Brain
A rudimentary examination of the cephalopod nervous system reveals that there are several ways to build a large, intelligent brain. For starters, cephalopod brains are donut-shaped organs built around the esophagus. Additionally, a large number of cephalopod neurons – more than half in the case of octopuses – are located in the eight nerve cords, or mini-brains, that control the arms.
Even systems that perform recognizable functions are mystifying. Although octopus eyes resemble those of vertebrates, the brain’s visual system does not. “It’s hard to express how different it is,” Niell says. “We just have no idea how it works.”
“When you look at the nerve cord of the octopus arm, it’s just – we call it horrible gray spaghetti,” says Robyn Crook, a cephalopod neurobiologist at San Francisco State University in California. “Everything is tiny. There are no packages. There are no big and small cells. It’s just horribly disorganized. And yet, obviously, it makes sense.”
In addition to being different, these neurons also communicate in several surprisingly different ways. For example, in a December preprint, William Schafer, a neurobiologist at the MRC Molecular Biology Laboratory in Cambridge, UK, and his postdoctoral researcher Amy Courtney showed that the octopus’ visual system contains a dopamine receptor that functions differently from that of vertebrates. The octopus receptor is an ion channel opened directly by dopamine, allowing ions to flow, while the vertebrate receptor is activated when dopamine binds to its surface, triggering biochemical signaling inside neurons.
The overarching question is whether these differences are merely superficial and, therefore, cephalopod brains operate on the same principles as those of vertebrates.
It could be that, once mapped, neural circuits will turn out to be organized in comparable ways in cephalopods and mammals, says Gilles Laurent, a systems neuroscientist at the Max Planck Institute for Brain Research in Frankfurt, Germany. “But you might have to be even more abstract than that and understand what calculation is being done” before finding parallels, he says.
Whether or not cephalopod brains function like those of vertebrates, studying them should be a win-win situation. “Either that will tell us that all brains share these fundamental principles,” says Tessa Montague, a cuttlefish neurobiologist at Columbia University in New York, “or, if they actually do things differently, then that’s pretty amazing too, because it tells you that there are different ways to build a complex, functioning brain.”
A classic model
Neuroscience already owes a debt of gratitude to cephalopods. In 1929, John Zachary Young, a zoology graduate, was working during the summer at the zoological station in Naples, Italy, when he discovered a group of nerve cells in squid that give rise to nerve fibers up to a millimeter wide. Young immediately realized that physiologists could implant electrodes into these fibers. This discovery allowed scientists to decipher the fundamental principles of how neurons fire electrical impulses.
But Young was primarily intrigued by cognition. With his colleague Brian Boycott, he discovered behavioral evidence of short- and long-term memory in octopuses, just as other scientists of the time had documented in humans.
Yet despite Young’s famous work, octopuses never became a widespread model for the study of cognition. One reason for this, Ragsdale said, was that studying cephalopod brains presented a huge technical headache. Boycott, for example, tried and failed for 17 years to make stable neuronal recordings in living animals, eventually becoming so frustrated that he left the field.
Even outside of the brain, it’s not easy to work with cephalopods, says Graziano Fiorito, a cephalopod researcher at the Zoological Station. Octopuses don’t breed in captivity, for example, meaning researchers must rely on wild-caught animals. Gradually, other model species became more attractive. “You can keep tons of zebrafish in an octopus tank,” says Fiorito. From the 1970s, the sea slug Aplysia and other animals with simpler brains offered models of memory that were easier to understand at the neuronal level.
Some cephalopod research continued at specialized facilities, such as the Marine Biological Laboratory in Woods Hole, Massachusetts. And some neuroscientists have even moved from conventional model organisms to studying octopuses.
Their work showed that having a body very different from that of vertebrates results in clear neuronal differences. Cephalopods do not have bones to generate contraction, force or stiffness in their arms. As a result, their motor system operates under extremely different constraints than a vertebrate’s, says Benny Hochner, a neuroscientist at the Hebrew University of Jerusalem who has studied octopus movement and memory since the 1990s. These differences lead to fundamentally distinct mechanisms for planning and executing movement.
For the record, however, there are striking parallels between cephalopods and vertebrates. For example, it has been shown that certain areas of the brain of octopuses use a form of synaptic reinforcement – believed to be at the origin of the formation of new memories – similar to the process observed in mammals. But this is achieved through distinct molecular mechanisms. “I see a beautiful convergence, achieved in completely different ways,” says Hochner.
For this discovery, Hochner’s team relied on a method directly from mammalian neuroscience: studying neurophysiology in brain slices kept alive for hours. Neuroscientists are now seeking to adapt technologies on a large scale, co-opting a multitude of precision tools commonly used in mammalian biology.
One of the first items in the modern cephalopod toolbox was the genome sequence of an octopus, published in 2015 by Albertin, Ragsdale and their colleagues. As a standalone study, the work provided some interesting insights. For example, two large gene families that had evolved to play crucial roles in patterning the nervous system in vertebrates were found to have developed similarly in the octopus, although through distinct mechanisms. But, Ragsdale says, the study also sent a sociological signal. “I think when we released the genome, it made a lot of people who were interested in these creatures say, ‘Well, it’s safe to go in the water now.’ The octopus had entered the era of molecular biology.
Since then, researchers with a wide variety of interests have joined this field. Many wonder how a process they have studied in mice and other cephalopod model organisms works.
Ivan Soltesz, a neuroscientist at Stanford University in Palo Alto, California, has studied how mammals navigate using a group of neurons located in the hippocampus. These “placement cells” are triggered when the animal is in a specific location. His questions about octopuses were simple. “How do they navigate? Do they have location cells?”
Laurent used mammals, fish and flies to understand how the environment is represented in brain areas that process sensory information and extends these studies by focusing on cuttlefish camouflage. Cephalopods control the color and pattern of their skin directly through neural activity and can change color to match their environment, providing a readout of brain activity evoked by perception. Or as Montague, who also works on cuttlefish camouflage, says: “No other animal can tell you what it sees except a human. »
In 2023, Laurent’s team showed that in just a few seconds, cuttlefish find an optimal fit with their environment by traveling through a succession of approximate environments. He is currently working on how they evaluate the quality of each match to create a feedback loop that improves their disguise.
At the same time, Japanese researchers have published work showing that octopuses experience rapid changes in skin color when they sleep, suggesting they might be dreaming.
Niell — whose lab studies vision in mice and octopuses — focused on the cephalopod’s optic lobe, which, as an initial structure for visual processing, is roughly similar to a vertebrate’s retina. In 2022, his team analyzed gene expression in individual neurons, identifying six main classes of cells. By examining the location of the cells, the researchers discovered a previously unknown layered organization. They then studied neuronal responses to visual stimuli.
These first characterizations revealed similarities and differences between octopuses and other animals. For example, researchers found a map of visual space in the octopus brain, a feature common to the entire animal kingdom. And octopuses have neurons that respond specifically to certain visual features, such as the orientation of lines or grids, just like mammals.
“There will be some of these shared principles, but there will also likely be some things that are just completely new,” Niell says, “that either offer a different solution to the same problem or solve problems that we’re considering.” The current system is not required to do this. His current work seeks to find where that balance lies.
When Hochner’s team produced a partial connectome – a highly detailed map of all the synaptic connections between neurons – for the octopus’ vertical lobe, they also discovered a mix of familiar and new principles. The researchers found small, simple, and very abundant neurons in the lobe that they believe have a function analogous to that of individual branches of more complex mammalian neurons. Other groups are working on other connectomes of the brain and nerve cords.
Hard graft
Not all techniques used in other animals have been easy to adapt to cephalopods. One method that has proven difficult to achieve is the ability to record from large numbers of individual neurons. In mammals, such alive recordings have been a driving force in the field. These techniques contribute to a major objective of systems neuroscience: understanding how neurons, alone or in populations, respond to stimuli and generate behaviors.
But, as Niell says – and Boycott discovered about 70 years ago – “everything is a little harder in cephalopods”. A major problem is that cephalopods do not have a skull, meaning there is no hard surface on which to attach the electrodes. Additionally, if you leave something sticking out of an octopus’ head, the animal is likely to reach up and remove it. More fundamentally, Soltesz says, the small size of most cephalopod neurons and their intrinsic electrical properties make them more difficult to record than those of vertebrates. But his group and others have now made progress record the average activity of small groups of cells.
There are other particularities. Many species of cephalopods can change color to camouflage themselves. But octopuses are contortionists: Their flexible bodies make it difficult to track changes in pigments and patterns. So Montague and others use cuttlefish because the animals’ flat bodies are easier to imagine.
Researchers are developing tools for multiple species at once – a more difficult approach than focusing on a single species, but one that has advantages. For example, Montague makes genetically modified cuttlefish, and Albertin helped create a CRISPR system to edit the genes of a species of squid that is small and reproduces well in the lab.
Establishing a new animal model is difficult work, and Laurent and Soltesz praise the postdocs who have led many grueling efforts to develop recording methods.
Montague’s biggest concern is the cost of eventually establishing his own lab. “Cephalopods are just incredibly expensive,” she says, “and they require absolute expert care.”
Patchwork protections
Laws regarding the care and welfare of cephalopods vary widely around the world. “Different people work under completely different constraints,” says Courtney. “In Japan and the United States, there are no legal requirements in terms of ethics, whereas in Europe and the United Kingdom, ethics are quite strict.” These stricter requirements reflect legal protections afforded to vertebrates used in research, including adequate anesthesia and pain relief when needed.
Protections were introduced in Europe and the United Kingdom in the 2010s, with Fiorito and others providing guidelines for cephalopod care. But efforts to do so in the United States have failed, leaving labs there and elsewhere with limited legal obligations. (American researchers interviewed for this article say they voluntarily follow European guidelines.)
Crook’s research supports the idea that cephalopods feel pain. But, she says, no painkillers developed for mammals seem to work in cephalopods, and local anesthetics appear to have limited effectiveness. Crook is researching compounds that relieve pain in cephalopods and says others should also step up to contribute to these efforts. Developing an animal model with very little knowledge about how to relieve pain “is an ethical minefield,” she says.
Despite the need for caution, Crook and others are enthusiastic about expanding these animal models and, unlike the incremental progress seen in other model organisms, many technologies are arriving simultaneously. “The fact that everyone is participating at the same time is, I think, fascinating,” says Crook. “It’s a really, really different way to build a field in neuroscience.”
This article is reproduced with permission and has been published for the first time April 29, 2026.