Summary: What did the very first complex vertebrate brain look like? To answer this fundamental evolutionary question, scientists have constructed the world’s first three-dimensional, single-cell transcriptomic atlas of an entire lamprey brain. The lamprey, a jawless, eel-like fish whose primitive body plan has remained virtually unchanged for roughly 360 million years, serves as an invaluable evolutionary time traveler.
The study built a high-resolution, single-cell map revealing the exact spatial location and genetic activity of every individual cell in the lamprey brain. By comparing this primitive structural architecture to modern mammalian models, the team discovered that despite diverging over 450 million years ago, the lamprey shares strikingly conserved gene-expression patterns with mammals across many core brain regions. This demonstrates that the common ancestor of all vertebrates did not possess a simple, unorganized nerve cluster, but rather a highly complex, molecularly organized master brain.
Key Facts
- The 3D Single-Cell Map: Researchers engineered the first-ever comprehensive three-dimensional cellular blueprint of a jawless vertebrate brain, charting both precise cell locations and real-time active gene expression.
- Deep Evolutionary Homology: The mapping reveals that core frontostriatal and subcortical networks in lampreys mirror the molecular and genetic expression profiles of modern mice, pushing the origin of a highly complex vertebrate brain back 450 million years.
- “Moonlighting” Neurons: The atlas uncovered versatile cell populations called anamniote-enriched neurons (AENs) that can simultaneously transmit both excitatory and inhibitory chemical signals.
- The Duplication Divergence: While these “moonlighting” AEN cells remain common in primitive species like lampreys and zebrafish, they are rare in amniotes (reptiles, birds, and mammals), which instead utilize dedicated “specialist” neurons following ancient whole-genome duplications.
- Giant Müller Cells: The research highlighted lineage-specific innovations, including the lamprey’s unique midbrain configurations and its oversized neural “Müller cells,” contrasting with the mammals’ later development of a multi-layered neocortex.
- Primitive Cerebellum Roots: The study identified a diffuse, primitive “cerebellum-like region” in the lamprey, proving that the basic coordination hubs of the vertebrate brain began taking shape long before the evolution of jaws.
Source: Chinese Academy of Science
What did the very first complex vertebrate brain look like? To find out, scientists turned to an unlikely time traveler: the lamprey, a jawless, eel-like fish whose body plan has barely changed in roughly 360 million years.
In a study published in Science on June 18, a team of researchers led by SU Bing from the Kunming Institute of Zoology of the Chinese Academy of Sciences, along with collaborators from BGI-Research and Liaoning Normal University, built the first three-dimensional, single-cell atlas of an entire lamprey brain, which is essentially a high-resolution map showing the location of every cell and which genes are active in each cell.
The researchers found that although lampreys diverged from jawed vertebrates about 450 million years ago, their brains share strikingly similar gene-expression patterns with the mouse across many regions. This finding suggests that the common ancestor of all vertebrates likely already had a well-organized, molecularly complex brain.
However, the researchers showed that each lineage also evolved its own innovations: the lamprey has unique midbrain neurons and oversized “Müller cells,” while mammals went on to build a more elaborate, layered cortex.
Moreover, the atlas hints at how neuronal types became more specialized over the course of evolution. The lamprey has a versatile cell type called the anamniote-enriched neuron (AEN) that carries both excitatory and inhibitory signals at once—a process described as “moonlighting.”
Comparing living species across the vertebrate tree, the researchers found these “moonlighting” cells to be common in lampreys and zebrafish but rare in amniotes, which instead rely on “specialist” neurons with dedicated functions. The researchers suggest this contrast is linked to an ancient whole-genome duplication.
In addition, the researchers revealed that even the cerebellum, the brain’s coordination hub, shows early roots: lamprey cells resembling cerebellar neurons point to a diffuse, primitive “cerebellum-like region.”
Overall, the study helps reconstruct the evolutionary blueprint of the ancestral vertebrate brain and provides new insights into how vertebrate brains became increasingly complex over time.
Key Questions Answered:
A: The lamprey occupies a uniquely critical position on the evolutionary tree of life. Having split away from jawed vertebrates approximately 450 million years ago, its physical body plan and lifestyle have remained practically frozen for the last 360 million years. Because it never developed the newer features seen in modern fish, reptiles, or mammals, studying the lamprey’s anatomy is like opening a living molecular capsule. It gives scientists a direct look at the baseline structural blueprint from which all complex human brain regions eventually evolved.
A: A “moonlighting” neuron, specifically categorized in this study as an anamniote-enriched neuron (AEN), is a highly versatile cell capable of dual-functioning. Unlike the specialized neurons in our own brains that are strictly hardwired to either excite or inhibit neural activity, these ancestral cells can do both simultaneously. The atlas shows that while these multi-tasking cells are highly abundant in lampreys and zebrafish, they were systematically phased out in mammals. Following an ancient whole-genome duplication event, our ancestors copy-pasted these genes, allowing separate cell lines to evolve into highly focused, dedicated “specialists.”
A: Yes, in an embryonic form. The cerebellum is famously known as the brain’s main coordination, movement, and timing hub. While the lamprey lacks the distinct, tightly packed cabbage-like structure of a modern mammalian cerebellum, the 3D single-cell atlas successfully detected a scattered population of cells that match the precise genetic signatures of cerebellar neurons. This proves that a diffuse, primitive “cerebellum-like region” was already fully functional hundreds of millions of years ago, establishing the deep evolutionary roots of motor control.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this brain mapping and evolutionary neuroscience research news
Author: SU Bing
Source: Kunming Institute of Zoology
Contact: SU Bing – Kunming Institute of Zoology
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Lamprey 3D single-cell transcriptomics reveals ancestral and specialized features of the vertebrate brain” by Haixu Wu, Duoyuan Chen, Jun Li, Tao Zhou, Zhenkun Zhuang, Zhiwei Niu, Zeyu Du, Yongjie Chen, Shunqin Chuan, Chunyan Xu, Xun Liao, Xiaoyu Meng, Jiali Lu, Wenxue Cui, Youning Lin, Fubaoqian Huang, Kuo Liao, Yan Liu, Tao Yang, Jing Chen, Hui Wang, Zhiqiang Dong, Longqi Liu, Xiaodong Fang, Xun Xu, Qingwei Li, Yue Pang, Shiping Liu, Bing Su. Science
DOI:10.1126/science.aea2535
Abstract
Lamprey 3D single-cell transcriptomics reveals ancestral and specialized features of the vertebrate brain
INTRODUCTION
The vertebrate brain is highly complex, comprising distinct regions and diverse cell types that have allowed for remarkable behavioral adaptations over 500 million years of evolution. Understanding how this complexity arose requires systematic cross-species analyses among vertebrate lineages.
The lamprey, a jawless vertebrate that diverged from jawed vertebrates ~450 million years ago, represents one of the most basal living vertebrates. Although its brain retains fundamental structural features, including the telencephalon, diencephalon, mesencephalon, and rhombencephalon, it lacks certain specialized architectures, such as a layered cortex or a fully developed cerebellum. This makes the lamprey an essential model for disentangling ancient ancestral traits from later evolutionary innovations.
RATIONALE
Although single-cell sequencing has categorized brain cells in various species, a comprehensive, three-dimensional (3D) spatial understanding of gene expression in a jawless vertebrate brain has been missing. To uncover the evolutionary blueprint of the vertebrate brain, we combined single-nucleus RNA sequencing (snRNA-seq) with high-resolution spatial transcriptomics to construct a complete, 3D molecular atlas of the adult lamprey brain.
We then performed extensive cross-species comparisons, integrating our lamprey data with newly generated zebrafish data and existing datasets from reptiles, birds, and mammals, especially the spatial transcriptome data of mice. These analyses allowed us to trace the evolutionary trajectories of vertebrate lineages across multiple dimensions, including brain structural organization, cellular composition, spatial distribution, and molecular profiles.
RESULTS
Our 3D atlas identified 209 distinct cell populations distributed across 14 major brain regions in the lamprey. We found a deep evolutionary conservation in the brain’s overall blueprint; structures such as the olfactory bulb, thalamus, and hindbrain share remarkably similar cellular makeups and spatial layouts in both lampreys and mice.
At the same time, we also discovered striking evolutionary divergence, including differences in the layered organization of the forebrain and the presence of distinctive cell groups in the midbrain, highlighting localized evolutionary innovations. Furthermore, we uncovered a fundamental shift in how brain neurons operate.
During vertebrate brain evolution, neurons underwent extensive specialization, driven by genetic shifts that physically reorganized and functionally diversified these cellular populations. Lastly, we identified specialized cerebellar cells in the lamprey, indicating that the basic cellular framework of the cerebellum existed long before the fully developed structure emerged in jawed vertebrates.
CONCLUSION
The common ancestor of all vertebrates already possessed a highly sophisticated brain blueprint featuring distinct anatomical regions and diverse cellular populations. During vertebrate evolution, brain complexity increased not just through the addition of new regions but through the profound specialization and spatial reorganization of ancient cell types.
The transition from broadly functioning, unspecialized ancestral neural networks to the highly precise, segregated circuits of modern mammals highlights the core mechanisms that drove the functional diversification of the vertebrate brain.
