Evidence Mounts that Brains Diverged from One Ancestral Arrangement

Microscopic image of a fruit fly brain showing several neurons specified during development of the deutocerebral-tritocerebral boundary.

Microscopic image of a fruit fly brain showing several neurons specified during development of the deutocerebral-tritocerebral boundary, or DTB, revealed by Green Fluorescent Protein. The circuits arising from the DTB play crucial roles in the regulation of behavior.

Jessika Bridi/Hirth Lab, King’s College London

Humans, mice and flies share the same fundamental genetic mechanisms that regulate the formation and function of brain areas involved in attention and movement control, according to a new study. The findings not only shed light on the deep evolutionary past connecting organisms with seemingly unrelated body plans, but also may help scientists understand the subtle changes that can occur in genes and brain circuits that can lead to mental health disorders such as anxiety and autism spectrum disorders.

Resemblances between the nervous systems of vertebrates and invertebrates have been known since the early 18th century, but only recently have scientists asked whether such similarities are due to corresponding genetic programs that already existed in a common ancestor of vertebrates and invertebrates that lived more than half a billion years ago.

"The crucial question scientists are trying to answer is: Did the brains in the animal kingdom evolve from a common ancestor?" said Nicholas Strausfeld, Regents Professor of Neuroscience at the University of Arizona and a co-author of the study. "Or, did brains evolve independently in different lineages of animals?"

The study provides evidence of underlying gene regulatory networks governing the formation of two corresponding structures in the developing brains of fruit flies and vertebrates including mice and humans. Uncovering previously unknown similarities in how their brains develop during embryogenesis, the study further supports the hypothesis of a basic brain architecture shared across the animal kingdom.

Published in the journal Proceedings of the National Academy of Sciences, the collaborative study between King's College London, University of Arizona, University of Leuven and Leibniz Institute DSMZ has provided strong evidence that the mechanisms that regulate genetic activity required for the formation of important behavior-related brain areas  are the same for insects and mammals.

Schematic comparison showing the brain of a fruit fly on the left and that of a mouse on the right, with homologous boundary in blue.

Schematic views of the developing brains of a fruit fly (left) and mouse (right). Areas shaded in blue show the deutocerebral-tritocerebral boundary in the fly and the midbrain-hindbrain boundary in the mouse. These homologous regions are shown here alongside shared expression patterns of homologous genes, indicated by the color patterns. In both organisms, the boundary gives rise to shared behavioral circuits that process sensory input, auditory and visual responses as well as balance and motor coordination, among others.

Hirth Lab, King’s College London

Most strikingly, the authors demonstrate that when these regulatory mechanisms are inhibited or impaired in insects and mammals, they experience very similar behavioral problems. This indicates that the same building blocks that control the activity of genes are essential to both the formation of brain circuits but also the behavior-related functions they perform. According to the researchers, this provides evidence that these mechanisms likely arose in a common ancestor.

"Our research indicates that the way the brain's circuits are put in place is the same in humans, flies and mice," said senior study author Frank Hirth from the Institute of Psychiatry, Psychology and Neuroscience at King's College London. "The findings indicate that the evolution of their very different brains can be traced back to a single ancestral brain more than a half billion years ago.

Using neuroanatomical observations and developmental genetic experiments, the researchers traced nerve cell lineages in the developing embryos of fruit flies and mice to identify how adult brain structures, along with their functionalities, unfold.

The team focused on those areas of the brain known as the deutocerebral-tritocerebral boundary, or DTB, in flies and the midbrain-hindbrain boundary, or MHB, in vertebrates including humans.

"In both vertebrates and arthropods, this boundary belongs to the anterior part of the brain and separates it from the rest," Strausfeld said. "The anterior part integrates sensory inputs, forms memories, and plans and controls complex actions. The part behind it is essential for controlling balance and autonomic functions like breathing."

Using genomic data, the researchers identified the genes that play a key role in the formation of brain circuits of the DTB in flies and the MHB in mice and men, and ascertained that these circuits play crucial roles in the regulation of behavior. They then ascertained which regions of the genome control when and where these genes are expressed. They found that those genomic regions are very similar in flies, mice and humans, indicating that they share the same fundamental genetic mechanism by which these brain areas develop.

Manipulating the relevant genomic regions in flies resulted in impaired behavior. This corresponds to findings from research on people where mutations in these gene regulatory sequences or the regulated genes themselves have been associated with behavioral disorders, including anxiety and autism spectrum disorders.

The published research builds on previous work led by Hirth showing that the early divisions of the fly's brain into distinctive parts followed by an extended nerve cord correspond to the three front-to-back divisions of the developing mouse brain and its spinal cord. Both in flies and mice, the development of each morphologically corresponding part requires the same set of genes, called homeobox genes, suggesting homologous genetic programs for brain development in invertebrate and vertebrates.

Evidence from soft tissue preservation in fossils of ancient arthropods studied by Strausfeld suggests that overall brain morphologies present in arthropod lineages living today must indeed have originated before the early Cambrian era, more than 520 million years ago.

"This implies that basic neural arrangements can be ancient and yet highly stable over geological time," he said. "You could say the jigsaw puzzle of how the brain evolved still lacks an image on the box, but the pieces currently being added suggest a very early origin of essential circuits that, over an immense span of time, have been maintained, albeit with modification, across the great diversity of brains we see today."

"For many years researchers have been trying to find the mechanistic basis underlying behavior," Hirth said. "We have discovered a crucial part of the jigsaw puzzle by identifying these basic gene regulatory mechanisms required for midbrain circuit formation and function. If we can understand these very small, very basic building blocks, how they form and function, this will help find answers to what happens when things go wrong at a genetic level to cause these disorders."

Funding for this study was provided by the Ministry of Education of Brazil, King’s College London, the Research Foundation Flanders, the US National Science Foundation, the UK Medical Research Council, the UK Biotechnology and Biological Sciences Research Council and the UK Motor Neuron Disease Association.

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