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Diversity and Evolution of the Cerebrum Explored by Medaka (Oryzias latipes)

Ryohei Nakamura, Assistant Professor, Department of Biological Sciences

Yasuko Isoe (Research Fellow, Harvard University)

The cerebrum plays an important role in movement, perception, and memory.
The human cerebrum is divided into several brain regions.
The functions of each brain region are gradually being elucidated.
The human cerebrum is divided into several areas (brain regions), and the functions of each brain region are gradually being elucidated.
However, when we look at the cerebrum of vertebrates other than mammals
There are large interspecies differences in the morphology and the number and location of regions.
How did the various forms of the vertebrate cerebrum evolve?
What are the functions of the brain regions in each species?
We aimed to elucidate these mysteries by analyzing the cerebral structure and the properties of individual brain regions in the medaka fish.

In humans, the cerebrum contains several regions, including the cerebral cortex, which occupies most of the brain, and the hippocampus, which is important for memory and plays an important role in intelligence. On the other hand, the cerebrum of vertebrates other than mammals has a roughly conserved composition of regions compared to that of other species, but the morphology and location of each region and the number of compartments within each region differ among species, and the functions of each region and the mechanisms by which they are formed are still unclear. In particular, there are many unknowns about the cerebrum of fishes, which diverged early in the process of vertebrate evolution. Among fish, the ^{zebrafishNote 1} has been widely used as a model animal for molecular biology because of its well-developed methods for studying gene and protein functions, but the zebrafish cerebrum lacks distinct anatomical compartments, making it difficult to study it in relation to the human brain and other organs. On the other hand, the cerebrum of cichlids and mahseer has clear anatomical compartments, but it has not been established as a model animal for molecular biology, making detailed studies at the molecular level difficult. Therefore, we focused our attention on the medaka fish. The killifish is a well-established model animal for molecular biology and has distinct anatomical compartments in the cerebrum.

In this study, we first analyzed the anatomy of the cerebrum of adult killifish. We genetically engineered only a few neural stem cells (cells that will differentiate into neurons in the future) to express fluorescent proteins during the egg stage, and examined the location of clones of these neural stem cells in the cerebrum after brain development. We found that the dorsal part of the medaka's cerebrum formed a single brain region without clones mingling with each other. Next, we analyzed the chromatin ^{structureNote 2} of the chromosomes of each clone in order to understand the nature of each clone. The reason is that the individuality of each neuron is determined by the combination of genes expressed by the cell, and the expression status of each gene is highly dependent on the structure of the chromatin. The analysis revealed that the chromatin structure differed greatly from clone to clone. In particular, we found that the dorsal region of the medaka cerebrum, called Dd, has a unique chromatin structure, and that the expression regulation of genes that control synapses, which are responsible for neuronal signal transduction, differs significantly from other brain regions. In fact, they confirmed that synaptic density is high in this Dd region.

Zebrafish have been used worldwide for brain research in fish. In this study, we were able to clarify the specificity of the dorsal region of the cerebrum because we used medaka fish, for which the anatomical compartments of the cerebrum are easy to understand. In the future, we aim to elucidate the function of each region of the killifish cerebrum to elucidate the evolution of cerebral diversity and the origin of human intelligence.

These results suggest that each region of the killifish cerebrum is composed of clones with unique chromatin structures, and that there are regions, especially dorsal regions, where specialized information processing takes place. Zebrafish have been used worldwide to study the brain in fish. In this study, we were able to clarify the specificity of the dorsal region of the cerebrum because we used medaka fish, for which the anatomical compartments of the cerebrum are easy to understand. In the future, we aim to elucidate the function of each region of the killifish cerebrum and to clarify the evolution of cerebral diversity and part of the origin of human intelligence.

The results of this study were published in Y. Isoe et al. eLife, 12:e85093 (2023).

Note 1: Zebrafish
The zebrafish (Danio rerio), a tropical fish with a distinctive striped pattern, is about 3 cm long and has transparent eggs. Because it is easy to keep and breed in the laboratory and to observe its behavior and development, it has been used frequently in embryological, genetic, and behavioral studies around the world.

Note 2: Chromatin structure
DNA is the genetic code. The DNA is wrapped around a cylindrical protein (histone) and folded into a structure called chromatin. In order for a gene to be expressed, the DNA-decoding protein must bind to the DNA, which causes the folded chromatin to open, exposing the DNA. In this study, we analyzed the open/closed structure of chromatin.

(Press release, July 25, 2023)

The Rigaku-bu News, November 2023

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