How much of the way a brain works reflects fundamental principles shared across species—and how much has been shaped by the particular environments and behaviors a species has evolved to navigate?
Answering that question requires looking beyond a single model organism. A team led by Yasuko Isoe, a postdoctoral research associate in the lab of MCB Professor Florian Engert, has developed a platform that lets researchers directly compare brain anatomy, gene expression, and neural activity across different fish species.
Called FishExplorer, the web-based brain atlas provides a common framework for mapping and quantitatively comparing brains across species. In a new study, (PDF), Isoe used the platform to compare zebrafish (Danio rerio), a mainstay of neuroscience research, with medaka (Oryzias latipes), a fish that diverged from zebrafish roughly 250 million years ago.
The comparison revealed differences in the size and gene expression of specific brain regions. The researchers also found that regions of the forebrain in zebrafish and medaka responded differently to social stimuli, pointing to possible evolutionary differences in how the two species process social information.
“Zebrafish have long been a leading model for fish neuroscience, but one species is not enough to understand the diversity and evolution of the brain,” said Isoe, the study’s principal investigator. “By comparing species, we can begin to distinguish fundamental principles that are conserved from those that are species-specific.”
“If you see a similar activity pattern in two species, that suggests you are looking at a conserved, fundamental circuit,” she added. “But if the patterns are different, that may point to something that is species-specific.”
Putting Different Brains on the Same Map
FishExplorer provides a common framework. The researchers extended Z-Brain, an existing zebrafish brain atlas, to incorporate a newly developed medaka brain atlas, or M-Brain. They divided both brains into corresponding regions using anatomical and gene-expression landmarks and developed methods to compare them quantitatively.
One challenge, Isoe said, was determining how to make those comparisons fair.
“When you compare different species, you have to ask what you are measuring against and how you normalize those measurements,” she said. “Developing a strategy that allowed us to make fair quantitative comparisons between species was one of the hardest parts.”
The framework divides each brain into “mutually exclusive and comprehensively exhaustive,” or MECE, regions that together cover the entire brain without gaps or overlaps. This creates a standardized spatial map for comparing features such as brain-region volume and gene expression.
Why Medaka?
Medaka provide an informative counterpart to zebrafish. Although the species diverged roughly 250 million years ago, they retain enough anatomical and behavioral similarities to make comparisons possible while having adapted to different environments.
Medaka tolerate higher salinity and typically inhabit clearer, relatively faster-moving water, while zebrafish are naturally found in slower-moving, murkier environments. Such differences raise questions about how brain regions involved in processing sensory information and controlling behavior may have changed as each species adapted to its surroundings.
For Isoe, who is from Japan, the choice of medaka also had a personal connection. The small fish are a familiar part of Japanese life, commonly found in rivers, streams, and rice fields and introduced to many children at an early age. They are also known for schooling behavior: medaka not only gather together but coordinate their swimming and orient in the same direction.
Isoe remembers the well-known Japanese children’s song Medaka no Gakkō (“Medaka School”), which describes a school of medaka swimming together. The song helped spark her early fascination with the fish and, years later, contributed to her interest in using medaka to investigate the neural basis of social behavior.
“Different species evolved in different environments, with different levels of light, water flow, and other physical conditions,” Isoe said. “Comparing the size and activity of their brain regions gives us a way to ask how those different environments may have shaped the brain.”
Fish are particularly well suited to such comparisons. More than 30,000 teleost species occupy a wide range of ecological niches. Their small size facilitates brain-wide imaging, while the transparency of larvae makes it possible to monitor neural activity throughout the living brain at cellular resolution.
Isoe introduced medaka into the Engert lab, which had previously focused primarily on zebrafish, expanding the kinds of questions researchers could ask about how brains and behavior evolve.
From Brain Size to Social Behavior
To demonstrate FishExplorer’s capabilities, Isoe and colleagues compared the anatomy and gene-expression patterns of zebrafish and medaka brains. They found differences in the relative volumes of several regions in the diencephalon and telencephalon, as well as genes that were expressed differently between corresponding regions.
They then exposed the fish to social stimuli and mapped the resulting neural activity onto the standardized brain atlases. Functionally distinct regions within the telencephalon—the teleost forebrain—showed different patterns of activation in zebrafish and medaka.
The findings suggest that although the species share broadly comparable brain structures, some of those structures may participate differently in processing social information.
“We can ask which brain regions become active in the same situation in different fish,” Isoe said. “If one region is activated in one species but not another, that gives us a clue that the same function may be organized differently across species.”
Building a Community Resource
FishExplorer is designed to extend beyond zebrafish and medaka. Researchers can use the browser-based platform to visualize and analyze brain regions and integrate their own imaging datasets with existing atlas data. They can keep newly uploaded data private during analysis and later share it with the broader research community.
The platform was also designed to grow, with the potential to incorporate additional species, developmental stages, tissue types, and datasets. Bringing more species into a common framework could reveal evolutionary patterns that would be difficult to see by studying one animal at a time.
“To collaborate effectively, we need a platform that allows us to speak the same language,” Isoe said. “Researchers may be working on different species in different labs, but if we can bring their data together in the same framework, we can make direct comparisons.”
For now, medaka and zebrafish provide a proof of principle. The larger goal is a resource that grows with the comparative neuroscience community, giving researchers new ways to investigate how neural circuits have been conserved and modified over evolution.
“I believe comparative neuroscience is essential,” Isoe said. “By studying multiple species, we have a much more powerful way to discover both the fundamental principles of the brain and the diversity that evolution has produced.”
