It’s possible that I shall make an ass of myself. But in that case one can always get out of it with a little dialectic. I have, of course, so worded my proposition as to be right either way (K.Marx, Letter to F.Engels on the Indian Mutiny)
Credit: (Credit: the Octopus Research Group, The Hebrew University)
How do octopuses remember what they learn? A new study reveals a surprising “molecular switch” in the octopus brain that helps preserve memories by keeping connections between nerve cells strengthened over time, without the need to produce new proteins. The discovery sheds new light on one of nature’s greatest mysteries: how creatures with vastly different brains evolved remarkably sophisticated learning and memory abilities.
How does an octopus remember what it has learned? A new study led by Dr. Ana Luiza Turchetti-Maia, Dr. Tal Shomrat and Prof. Binyamin (Benny) Hochner from the Hebrew University and Ruppin Academic Center has uncovered a previously unknown molecular mechanism that may help explain how these remarkably intelligent animals form and maintain memories.
The findings, published in Journal of Neuroscience, reveal that the octopus brain uses a unique “molecular switch" to maintain strengthened connections between nerve cells. The discovery offers new insights into how sophisticated learning and memory mechanisms evolved independently in animals whose evolutionary lineage diverged from ours hundreds of millions of years ago.
Octopuses are renowned for their remarkable cognitive abilities, including problem-solving, exploration, and learning from experience. Despite their evolutionary distance from humans, they possess sophisticated learning and memory systems.
The research focused on a brain region called the vertical lobe, which, like the hippocampus in vertebrates, plays a central role in learning and memory. Like the hippocampus, the octopus vertical lobe can strengthen connections between neurons in response to brief, strong stimulation through a process known as long-term potentiation (LTP), widely considered one of the fundamental cellular mechanisms underlying learning and memory.
However, the researchers discovered that octopuses maintain these strengthened connections through a surprisingly different molecular process.
At the heart of the discovery is nitric oxide (NO), a tiny gaseous molecule that acts as a messenger between nerve cells. The team found that NO plays a dual role: it mediates strengthening of synaptic connections by facilitating neurotransmitter release and, helps maintain this strengthening by persistently activating nitric oxide synthase (NOS), the enzyme responsible for its own production.
This creates a self-sustaining positive feedback loop — effectively a molecular switch that once turns ON helps keep synaptic connections strengthened over time.
Remarkably, the researchers found that unlike many well-studied forms of memory-related plasticity in vertebrates, in the octopus, this process can maintain long-term potentiation without requiring the production of new proteins, challenging conventional expectations about the molecular processes that sustain long-lasting changes in neural connections.
“What makes this discovery so exciting is that octopuses have evolved a fundamentally different molecular solution to a challenge shared by all learning system: how to turn brief experience into a long-lasting change in neural connections,,” explains Prof. Benny Hochner. “It is a remarkable example of how evolution can give rise to similar principles of learning and memory through very different biological mechanisms”
Beyond revealing another fascinating aspect of octopus intelligence, the discovery highlights how studying animals with independently evolved nervous systems can deepen our understanding of the biological foundations of learning and memory.
A novel nitric oxide (NO)-dependent ‘molecular switch’ mediates LTP in the Octopus vulgaris brain through persistent activation of nitric oxide synthase (NOS).
Californian two-spot octopus (Octopus bimaculoides). Embryo at the final stage before hatching. The species is named after the two prominent blue eyespots that can help deter predators.
Octopuses, squid and cuttlefish, collectively known as coleoid cephalopods, have evolved exceptionally large and elaborately structured nervous systems capable of complex behaviours such as problem-solving and rapid camouflage. A new study by scientists at The University of Vienna suggests that the origins of this complexity may lie not just in the genes themselves, but in how the genome is organised in 3D. The researchers found that ancient, extensive reorganisation of the genome altered how DNA is arranged inside the cell. These shifts brought previously distant regions of DNA into contact, changing the way genes are regulated. Understanding this process could change how we think about how new traits emerge during evolution. The findings are currently published in the renowned journal Nature Communications.
The team studied the 3D structure of the genome across octopus, squid and cuttlefish, combining data on DNA structure with gene activity. "The genome isn't just a sequence of genes. It's folded into a complex three-dimensional structure," said lead author Dr Thea Rogers. "Understanding how that structure evolves is becoming increasingly important for understanding how new forms of biological complexity arise."
"Regulatory entanglement" as a consequence of genome reorganisation
In cephalopods, a large-scale burst of genome reorganisation, which occurred hundreds of millions of years ago, dramatically reshuffled the genome and brought previously distant regions of chromosomes into close proximity.
The researchers found that when regions of DNA are brought into contact, they can begin to interact and influence each other's activity. Over time, these interactions can become embedded, forming increasingly interconnected regulatory networks.
"Regulatory entanglement" balances innovation and stability in genome evolution
This process, described by the researchers as "regulatory entanglement", may allow genomes to generate new patterns of gene expression while maintaining essential functions.
Not all aspects of genome structure appear to respond to genome reorganisation in the same way. The researchers found that large structural units of the genome, known as chromatin domains, remained largely stable over evolutionary time.
In contrast, finer-scale connections known as chromatin loops were far more dynamic. These loops bring distant regions of DNA into contact. They varied widely across species, tissues and developmental stages, and were often found near genes involved in key cephalopod traits, including those linked to the nervous system. This suggests that these more flexible regions may be particularly affected by large-scale changes in DNA organisation.
3D structure of DNA shapes evolutionary processes actively
Together, these findings challenge the idea that genome architecture is a passive consequence of evolution. Instead, they suggest that the 3D organisation of DNA actively shapes how evolution unfolds. In cephalopods, this may have played a key role in the emergence of their unusually complex nervous systems.
Summary
Scientists at the University of Vienna reconstructed the 3D organisation of the genome in octopus, squid and cuttlefish to investigate how genome architecture evolved following an ancient burst of genome reorganisation.
The study found that this large-scale reorganisation brought previously distant regions of DNA into contact, creating new networks of regulatory interactions that became embedded over evolutionary time.
The researchers describe this process as "regulatory entanglement", whereby new DNA interactions become increasingly interconnected, allowing genomes to generate novel patterns of gene regulation while maintaining essential biological functions.
The researchers found that not all aspects of the 3D genome respond to genome reorganisation in the same way. Large chromatin domains remained remarkably stable, whereas finer-scale chromatin loops were far more dynamic.
The findings challenge the view of genome architecture as a passive consequence of evolution and instead suggest that the 3D organisation of DNA can actively influence evolutionary change.
About the University of Vienna:
For over 650 years the University of Vienna has stood for education, research and innovation. Today, it is ranked among the top 100 and thus the top four per cent of all universities worldwide and is globally connected. With degree programmes covering 188 disciplines, and approximately 11,000 employees, we are one of the largest academic institutions in Europe. Here, people from a broad spectrum of disciplines come together to carry out research at the highest level and develop solutions for current and future challenges. Its students and graduates develop reflected and sustainable solutions to complex challenges using innovative spirit and curiosity.
From color-changing skin to jet-propelled motion, squid and cuttlefish have long fascinated scientists. To understand the origins of their unique characteristics, many attempts have been made to define their evolutionary history. However, the limited fossil record and incomplete genomic information have made it impossible to confidently order the evolution of these enigmatic creatures, until now.
Published in Nature Ecology & Evolution, a new study from the Okinawa Institute of Science and Technology (OIST) combines existing databases with three newly sequenced squid genomes to identify the ‘long fuse’ that led to today’s diversity of squid and cuttlefish, which together make up the decapodiform (ten-limbed) cephalopods.
Dr. Gustavo Sanchez, first author on the study and Staff Scientist in OIST’s Molecular Genetics Unit, says, “Squid and cuttlefish are remarkable creatures, yet their evolution has been notoriously difficult to study. The question of their ancestry has been under investigation for decades, and many research groups have proposed different evolutionaryhypothesesbased on different morphological characteristics and molecular datasets. With our new genomic information, we have been able to resolve some of the mysteries surrounding their origins.”
Demystifying the decapodiformes
Squid and cuttlefish are found in a wide variety of habitats across the globe, from deep seas to shallow coastlines. One of the few characteristics linking most of these diverse creatures is their internal shell. But even this takes a variety of forms, from the smooth, rounded cuttlebones of cuttlefish, the thin, sword-like gladius of oceanic and coastal squid, and the spiral-shaped shell of ram’s horn squids, to a complete loss in shallow water species.
Past attempts to order the evolution of these animals have been limited by a lack of data. Sanchez explains, “Earlier reconstructions of decapodiform evolution were built from datasets with limited resolution and were prone to biased signals, obscuring the true relationships between different species. Whole genome data now provide a cleaner, more consistent picture of how these animals evolved.”
Because most squid and cuttlefish genomes are large, typically reaching up to twice the size of human genomes, generating and analyzing them requires state-of-the-art sequencing facilities and considerable computational power. Researchers also need fresh DNA for sequencing, which is a challenge when sourcing specimens at sea. “Some lineages are only abundant and highly diverse in tropical reef systems like the Ryukyu Archipelago, while others are enigmatic and known only in the deep sea. We were fortunate to find some key species on our doorstep in Okinawa, and collaborate with colleagues with access to more challenging samples,” says Sanchez.
The paper presents the first-ever evolutionary tree for decapodiformes that is based on sequenced genomes from nearly all decapodiform lineages. This was made possible due to a global collaboration spanning the last five years, with the Aquatic Symbiosis Genomics Project funded by the Wellcome Sanger Institute aiming to sequence some cephalopod genomes among other marine and freshwater species. Sanchez headed the Japanese branch of the cephalopod hub of this project.
“Within the symbiosis project, we’ve been steadily sequencing genomes for several years, but several key gaps remained. In this study, we were able to fill these missing puzzle pieces,” confirms Sanchez.
Co-author Dr. Fernando Á. Fernández-Álvarez of the Spanish Institute of Oceanography was especially enthusiastic to study the enigmatic ram’s horn squid, Spirula spirula, a rarely encountered species whose unusual internal shell has long puzzled biologists. From the moment he had it in hand, he saw its genomic potential. “In the past, the structure of the ram’s horn squid shell made some scientists wrongly conclude it was closely related to cuttlefishes.”, says Fernández-Álvarez. “I believed this genome could help close a key gap and bring clarity to the broader evolutionary questions of cephalopods.”
A long fuse model of evolution
Using a combination of genomic data and recently discovered fossils, the researchers were able to map out an evolutionary timeline and ecological scenario for the origin and diversification of squid and cuttlefish.
“Our analysis shows that these animals originated in the deep ocean, a habitat which still harbors species like the ram’s horn squid,” says Sanchez.
The model shows that the different decapodiform orders first split rapidly around 100 million years ago, putting their origins firmly in the mid-Cretaceous period. However, 66 million years ago, a catastrophic mass extinction event known as the Cretaceous-Paleogene (K-Pg) wiped out three-quarters of the plant and animal species on Earth. This same event famously led to the extinction of dinosaurs and the rise of mammals. So how did squid survive?
The researchers believe that ancient cephalopods were able to find refugia within tiny deep-sea microcosms which harbored an abundance of oxygen. Sanchez explains, “The sea surface would have been a very harsh environment for cephalopods. Around that time, very few suitable oxygen-rich habitats would have been found near the shores. Intense ocean acidification in shallower waters would also likely have degraded their shells, so the fact that some form of this feature has been retained throughout their evolutionary history is evidence of their deeper oceanic origins.”
After the K-Pg event, coral reefs started to rebuild along coastlines. This created more habitable shallow water ecosystems, to which many of the ancient 10-limbed cephalopod lineages migrated.
“Following the initial lineage splits in the Cretaceous, we don’t see much branching for many tens of millions of years. However, in the K-Pg recovery period, we suddenly see rapid diversification, as species adapt and evolve to new and changing ecosystems. This is an example of a ‘long fuse’ model; a period of limited change followed by an explosion of diversity,” says Sanchez.
From gene evolution to gene editing
The team hopes this research can provide a framework for future investigations into the origins of decapodiformes’ unique characteristics.
“Squids and cuttlefish have so many unique features compared to other animal groups, making them an endless source of inspiration for scientists,” says Prof. Daniel Rokhsar, head of the Molecular Genetics Unit. “With these genomes and with a clear picture of their evolutionary relationships, we can make meaningful comparisons to uncover the molecular changes associated with major cephalopod innovations, from the emergence of novel organs and dynamic camouflage to the neural complexity that supports their remarkable behavior.”
Rapid mid-Cretaceous diversification of squid and cuttlefish preceded radiation into coastal niches.
Article Publication Date
30-Mar-2026
COI Statement
DSR is a member of the Scientific Advisory Board and shareholder of Dovetail Genomics. The other authors have declared that no competing interests exist.
Photo of a common cuttlefish (Sepia sp.) by Keishu Asada
Photo of a ram’s horn squid (Spirula spirula) taken by Dr. Victor Tuset
The intricate ram’s horn squid shell is only about the size of a fingernail. Compared to other cephalopod species, the shell structure has not degraded over time. As part of this study, researchers used transcriptomics which revealed genes supporting biomineralization and regeneration of the shell.
Credit
Catherine Hodges/OIST
The researchers employed multiple decapodiformes genomes along with a robust model of evolution and fossil evidence. Their evolutionary tree branches into 4 sections in the Cretaceous period, then sees no further branching until after the K-Pg extinction event, when rapid diversification occurred. Each final line end marks a different species. Of the major orders of decapodiformes, just oegopsida and spirulida remain in the deep ocean habitats of their ancestors.
In a study now published in iScience, researchers from the University of Vienna (Austria), National Institute of Technology - Wakayama College (NITW; Japan), and Shimane University (Japan) present the largest cephalopod genome sequenced to date. Their analyses show that the vampire squid has retained parts of an ancient, squid-like chromosomal architecture, and thus revealing that modern octopuses evolved from squid-like ancestors.
The vampire squid (Vampyroteuthis sp.) is one of the most enigmatic animals of the deep sea. With its dark body, large eyes that can appear red or blue, and cloak-like webbing between its arms, it earned its dramatic name – although it does not suck blood, but feeds peacefully on organic detritus. "Interestingly, in Japanese, the vampire squid is called "kōmori-dako", which means 'bat-octopus'", says one of three lead PIs of this project, Masa-aki Yoshida, Shimane University. Yet its outward appearance hides an even deeper mystery: despite being classified among octopuses, it also shares characteristics with squids and cuttlefish. To understand this paradox, an international team led by Oleg Simakov from the University of Vienna, together with Davin Setiamarga (NITW) and Masa-aki Yoshida (Shimane University), has now decoded the vampire squid genome.
A glimpse into deep-sea evolution
By sequencing the genome of Vampyroteuthis sp., the researchers have reconstructed a key chapter in cephalopod evolution. "Modern" cephalopods (coleoids) – including squids, octopuses, and cuttlefish – split more than 300 million years ago into two major lineages: the ten-armed Decapodiformes (squids and cuttlefish) and the eight-armed Octopodiformes (octopuses and the vampire squid). Despite its name, the vampire squid has eight arms like an octopus but shares key genomic features with squids and cuttlefish. It occupies an intermediate position between these two lineages – a connection that its genome reveals for the first time at the chromosomal level. Although it belongs to the octopus lineage, it retains elements of a more ancestral, squid-like chromosomal organization, providing new insight into early cephalopod evolution.
An enormous genome with ancient architecture
At over 11 billion base pairs, the genome of the vampire squid is roughly four times larger than the human genome – the largest cephalopod genome ever analyzed. Despite this size, its chromosomes show a surprisingly conserved structure. Because of this, Vampyroteuthis is considered a "genomic living fossil" – a modern representative of an ancient lineage that preserves key features of its evolutionary past. The team found that it has preserved parts of a decapodiform-like karyotype while modern octopuses underwent extensive chromosomal fusions and rearrangements during evolution. This conserved genomic architecture provides new clues to how cephalopod lineages diverged. "The vampire squid sits right at the interface between octopuses and squids," says the senior author Oleg Simakov from the Department of Neurosciences and Developmental Biology at the University of Vienna. "Its genome reveals deep evolutionary secrets on how two strikingly different lineages could emerge from a shared ancestor."
Octopus genomes formed their own evolutionary highway
By comparing the vampire squid with other sequenced species, including the pelagic octopus Argonauta hians, the researchers were able to trace the direction of chromosomal changes over evolutionary time. The genome sequence of Argonauta hians ("paper nautilus"), a "weird" pelagic octopus whose females secondarily obtained a shell-like calcified structure, was also presented for the first time in this study. The analysis suggests that early coleoids had a squid-like chromosomal organization, which later fused and compacted into the modern octopus genome – a process known as fusion-with-mixing. These irreversible rearrangements likely drove key morphological innovations such as the specialization of arms and the loss of external shells. "Although it is classified as an octopus, the vampire squid retains a genetic heritage that predates both lineages," adds second author Emese Tóth, University of Vienna. "It gives us a direct look into the earliest stages of cephalopod evolution."
Revisiting cephalopod evolution
The study provides the clearest genetic evidence yet that the common ancestor of octopuses and squids was more squid-like than previously thought. It highlights that large-scale chromosomal reorganization, rather than the emergence of new genes, was the main driver behind the remarkable diversity of modern cephalopods.
About the University of Vienna:
For over 650 years the University of Vienna has stood for education, research and innovation. Today, it is ranked among the top 100 and thus the top four per cent of all universities worldwide and is globally connected. With degree programmes covering over 180 disciplines, and more than 10,000 employees we are one of the largest academic institutions in Europe. Here, people from a broad spectrum of disciplines come together to carry out research at the highest level and develop solutions for current and future challenges. Its students and graduates develop reflected and sustainable solutions to complex challenges using innovative spirit and curiosity.
