Cleared brain from the team’s heterotopic mouse model. Prior to clearing and imaging, the researchers injected a retroviral tracer into the spinal cord to label all neurons projecting to this target. This reveals that both heterotopic and normally positioned neurons project to the spinal cord, enabling them to trigger motor function and receive sensory input. Credit: Sergi Roig-Puiggros & Denis Jabaudon, University of Geneva, Switzerland.

The human brain contains billions of connected neurons that collectively support different mental functions, including the processing of sensory information, the encoding of memories, attention processes, and decision-making. For a long time, neuroscientists have assumed the position of specific neurons in the brain plays a key role in the brain’s connectivity and proper functioning.

Researchers at University of Geneva, INSERM, Ecole Polytechnique Fédérale de Lausanne and other institutes recently gathered evidence that contradicts this long-standing assumption, showing misplaced neurons can still retain their "identity," connect with other neurons and support the processing of sensory information.

Their paper, published in Nature Neuroscience, could reshape the present understanding of developmental disorders and other conditions linked to the rearrangement of neurons or cortical malformations.

"This work emerged from a consortium (HETER-OMICS) focusing on the complexity of cortical heterotopias, trying to better understand their development and their consequences for human health from different standpoints, spanning from molecular biology to clinical diagnosis," Sergi Roig-Puiggros, Postdoctoral Research Associate at University of Geneva and first author of the paper, told Medical Xpress.

"However, when we performed the first single-cell transcriptomics experiment on the heterotopic tissue, unexpectedly, we observed a complete conservation of neuronal types and their identities."

This recent study was primarily conducted in Prof. Denis Jabaudon’s laboratory at the University of Geneva. When they were conducting experiments focusing on brain malformations known as cortical heterotopias, the researchers were surprised to discover that alterations in the brain’s structural organization did not appear to alter neurons or prevent them from connecting with other neurons.

This inspired them to widen the scope of their investigation, to determine if the position of neurons contributes to the brain’s connectivity and function.

"We approached this research project from different viewpoints," explained Roig-Puiggros. "As it emerged from a consortium, and then, we collaborated with several teams within and without the University of Geneva, we were able to leverage different expertise to have a complete view on the subject. Among these, we focused on the molecular characterization of misplaced neurons by using single-nuclei and spatial transcriptomics."

Probing the effects of neuron positions

As part of their study, Roig-Puiggros and his colleagues examined neurons and neural connections in the brains of mice that were missing the Eml1 gene. A lack of this gene causes neurons to develop in abnormal locations, both in mice and human patients.

The researchers tracked neurons that were "misplaced" using various experimental techniques. They also used molecular "tags" to identify the genes expressed by these neurons and traced their connections to other neurons.

To determine whether "misplaced" neurons still functioned normally, the researchers also recorded electrical signals in the brain while the mice were processing sensory information. They specifically looked at the groups of neurons that became active when the animals were exposed to different sensory inputs.

"To interrogate the establishment of circuits, we took advantage of viral tracings, in some cases combined with optogenetics, in order to manipulate neuronal activity in combination of light stimulation," explained Roig-Puiggros. "We also addressed neuronal activity from two perspectives, electrophysiologically–recording neurons’ electrical properties in the presence or not of stimuli– and using calcium imaging to follow tissue activity dynamics upon sensory stimulation."

Finally, Roig-Puiggros and his colleagues used drugs to temporarily silence different parts of the brain while leaving "misplaced neurons" active. When they did this, they observed how the animals behaved and assessed their performance in tasks that require the processing of sensory information.

Misplaced neurons can retain their ‘identity’

Contrary to their original expectations, the researchers observed that the rearrangement of neurons does not impair the brain’s connectivity and functions. This finding could have important implications for the understanding and treatment of developmental disorders linked to brain malformations.

"Previous rodent models showed that cortical delamination has limited impact on cortical function, but our findings take this substantially further," said Roig-Puiggros.

"These findings explain why some patients with brain malformations remain asymptomatic or show minimal phenotypes. Conversely, in cases where symptoms are severe, the malformation provides an informative model for understanding circuit composition and integration, enabling investigation of how our findings relate to patient outcomes."

This recent study also highlights the pervasive effects that a single gene mutation can have on the arrangement of neurons in the brain, while also showing that these effects do not necessarily alter the brain’s functionality. This interesting mechanism could be investigated further from an evolutionary standpoint, as it could potentially explain how species acquire new capabilities through evolution.

"Finally, we show that spatial organization is not critical for neuronal identity acquisition and maturation," said Roig-Puiggros. "This suggests that researchers developing organoids should prioritize maintaining cell-type diversity and fidelity rather than focusing exclusively on reproducing in vivo architecture."

Roig-Puiggros and his colleagues are now planning further studies that build on their recent findings. Specifically, they would like to understand why some patients with brain malformations exhibit significant symptoms even if the identities of misplaced neurons are preserved.

"This may be linked to circuit duplication and specific developmental phenotypes we have observed, which we are currently working to better characterize," added Roig-Puiggros.

Written for you by our author Ingrid Fadelli, edited by Sadie Harley, and fact-checked and reviewed by Robert Egan—this article is the result of careful human work. We rely on readers like you to keep independent science journalism alive. If this reporting matters to you, please consider a donation (especially monthly). You’ll get an ad-free account as a thank-you.

Publication details

Sergi Roig-Puiggros et al, Position-independent emergence of neocortical neuron molecular identity, connectivity and function, Nature Neuroscience (2025). DOI: 10.1038/s41593-025-02142-7.

Journal information: Nature Neuroscience

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Neurology

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