Olfactory cortex: a vestige of the past dating back millions of years

Image generated using the Dall.E. Generative model Prompt used: ‘Wooden puppet with visible cortex and salamander’.

For this pioneering study, it all began in 2016 with a meeting between three researchers at the Collège de France: Sara Zeppilli and Alexander Fleischmann, both neuroscience specialists, and Anton Crombach, who studies gene regulation and bioinformatics. In 2018, when they finished their studies, Zeppilli and Fleischmann joined Brown University in the United States, while Crombach was recruited by Inria’s Beagle project team.

“Despite the distance, we stayed in touch”, Anton Crombach recalls. “It was Sara who first thought of this olfactory cortex study, and the idea matured gradually during our discussions.” Ten other researchers joined the project when it was launched in 2021. Four years later, the article published in Nature Neuroscience in 2025 is proof of the remarkable impact of their research.

“The first break with convention was the decision to study the olfactory cortex”, Anton Crombach continues. “Very often, neuroscience research on animals focuses on the neocortex, which is specific to mammals, probably because this is particularly large in humans and controls the higher cognitive functions, among others. But this overlooks the importance of smell for many animals, including mice. We were imprisoned in a form of anthropomorphism.” 

This sidestep turned out to be a wise move: by comparing the neural function of the olfactory cortex in mice with their neocortex, the researchers discovered two ‘systems’ that are radically different. 

Neurons in the neocortex are mature and have very distinct profiles; their genes are activated by a range of regulatory genes, which are rarely expressed simultaneously. A kind of task specialisation which has been cleverly developed over millions of years of evolution. 

In the olfactory cortex, on the other hand, the researchers noticed neurons of a less specific profile; their genes are activated mainly by the same range of regulators, but often simultaneously in this case. In other words, the neural function is more primitive and the roles less compartmentalised. The researchers therefore believe it to be more flexible and capable of adapting. 

The olfactory cortex still has ancestral signatures, its identity has remained intact throughout millions of years of evolution", adds Anton Crombach. “Although it has evolved alongside more recent brain structures, such as the neocortex, it retains the molecular traces of a very distant past.

Another result confirms this analysis. The researchers observed that the so-called ‘glutamatergic’ neurons (which receive olfactory signals) are not the same in the olfactory cortex of laboratory mice and those descending from wild mice. The former live in stable, secure conditions, while the latter are confronted with an uncertain, changing world. Again, the olfactory cortex does indeed appear to be more ‘plastic’, more sensitive to the environment. Especially as the glutamatergic neurons of the neocortex are identical in both mice.

The reviewers of our article were struck by these results”, Anton Crombach recalls. “And they made an additional request: to go further in the comparison we had begun between mice and three animals that appeared on Earth millions of years before them, the tortoise, the lizard and the salamander.

The researchers’ observation at the end of this new study: glutamatergic neurons of the olfactory cortex in mice share more molecular similarities with the neurons of these three ‘archaic’ animals than with those of their own neocortex!

Regarding the bioinformatics aspect, which is Anton Crombach’s speciality, a number of challenges had to gradually be met. The first was to handle the massive volumes of data generated in the experiments conducted by his American colleagues. The second was, of course, to interpret all this data.

We knew from the outset that the olfactory cortex was unknown territory. Surprises were to be expected, but I didn’t think it would be to this extent! Some of the results were so disconcerting that at first I had to make sure they were solid and reliable, especially with the machine learning aspects. We were then able to start attributing meaning to them.

The researchers indeed observed that neurons in both parts of the brain (neocortex and olfactory cortex) have similar genetic activity and activate the same functions, but with different regulation methods. 

“It’s a bit like two people playing the same game, but each with their own rules. Gene regulation is my speciality, but I had never seen this before.” Anton Crombach then worked on the visualisation of these results, to present them in the form of easy-to-understand images rather than pages and pages of figures. 

More generally, the Inria researcher played the role of project IT coordinator. “My colleagues have expertise in this field, of course. But when it came to validating a new algorithm or finding out why an existing one didn’t work, they came to me.” Which meant that with the time difference between France and the United States, he was often videoconferencing at night. “That publication in a prestigious magazine made it more than worth the effort. I have no regrets.” 

The researchers can boast of having provided unique insights on a region of the brain that is often ignored, and contributed to knowledge on the evolution of the vertebral cortex. Maria Tosches, the neuroevolution specialist associated with the project, says she is proud to have contributed ‘another piece to this puzzle’. 

As for Anton Crombach and Alexander Fleischmann, they have launched themselves into a new study: modifications of gene expression occurring in the olfactory cortex of mice when they memorise odours. 

Lastly, another research team in Louvain (Belgium) has published work on the comparison between the brains of mice and hens. The results are similar to those observed in this study. Proof that it is not an isolated case, but probably a first among other discoveries of much greater significance.

• Circuits neuronaux et comportement : le système olfactif, interview with Alexander Fleischmann (video), Collège de France, 9/9/2014.
• Evolution of the Cerebral Cortex, lecture by Maria Antonietta Tosches (video), Simons Foundation, 19/3/2025.
• Olfaction : le cerveau a du nez ! The Conversation, 28/6/2016.
• L’incessant dynamisme du cerveau adulte, Institut Pasteur, 30/6/2016.