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Scientists Map the Evolution of Our “Little Brain”

A human brain glowing yellow.
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Expansion of the neocortex

The neocortex is the largest and youngest part of the mammalian brain. Human beings’ higher cognitive abilities have long been attributed to the evolution of the neocortex, but a new study suggests we shouldn’t neglect the role of the “little brain” – the cerebellum.

A collaborative team of scientists has explored and mapped the cellular landscape of the cerebellum. “Although the cerebellum, a structure at the back of the skull, contains about 80% of all neurons in the whole human brain, this was long considered a brain region with a rather simple cellular architecture,” explains Professor Henrik Kaessmann, research group leader in the Center for Molecular Biology at Heidelberg University, and the study’s lead author.

Novel technologies such as single-cell sequencing are enabling scientists to map the heterogeneity of cells within tissues. Recent work analyzing the mammalian brain has implied that the cerebellum’s structure might not be so “simple” after all, a notion that is emphasized by Kaessmann and colleagues’ new study published in Nature.

Tracing the evolution of the cerebellum using single-cell sequencing

“In this study, we generated single-nucleus RNA-sequencing data for ~400,000 cells to trace cerebellum development from early neurogenesis to adulthood in human, mouse and the marsupial opossum,” Kaessmann and colleagues describe.

What is RNA sequencing, and why is it used?

RNA-sequencing is a technique that analyzes the quantity and sequences of RNA within a sample, using next-generation sequencing (NGS) approaches. Applying RNA-seq to single cells can identify which genes are “turned on” or “turned off” in a specific cell, creating a clearer picture of the different types of cells and their encoded functions within a sample.

“We established a consensus classification of the cellular diversity in the developing mammalian cerebellum and validated it by spatial mapping in the fetal human cerebellum,” the researchers add.

Human cerebellum has a higher number of Purkinje cells

The human cerebellum comprises a large number of Purkinje cells. Named after the Czech anatomist Jan Evangelista Purkyně – who described them in the 19th century – these cells are large neurons with complex functions in the cerebellum. In the early stages of fetal development, the human cerebellum has almost double the amount of Purkinje cells than mouse and possum brains.

Kaessman and colleagues observed an increase in a particular subtype of Purkinje cell that is created first during development. “It stands to reason that the expansion of these specific types of Purkinje cells during human evolution supports higher cognitive functions in humans,” explains Dr. Mari Sepp, a postdoctoral student in Kaessmann’s lab.

A need to consider alternative animal models in biomedical research

The researchers compared gene expression profiles across the cerebellum cells from humans, mice and the opossum, identifying specific activity programs that have been conserved across species for ~160 million years of evolution. The data implies that these expression patterns – and the cellular programs that underpin them – are key for determining the cell type identities within the mammalian cerebellum.

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“However, we also identified many orthologous genes that gained or lost expression in cerebellar neural cell types in one of the species, or evolved new expression trajectories during neuronal differentiation, indicating widespread gene repurposing at the cell type level,” Kaessmann and colleagues say.

“At the level of cell types, it happens fairly frequently that genes obtain new activity profiles,” says Dr. Kevin Leiss, a former doctoral student in Kaessmann’s lab. “This means that ancestral genes, present in all mammals, become active in new cell types during evolution, potentially changing the properties of these cells.”

Several of the gene activity profiles that varied between human and mouse cerebellum samples have been linked to childhood brain cancers and neurodevelopmental disorders. Professor Stefan Pfister, director at the Hopp Children’s Cancer Center Heidelberg and co-author of the study, emphasizes the need to consider a wider variety of models when studying human diseases.

Reference: Sepp M, Leiss K, Murat F, et al. Cellular development and evolution of the mammalian cerebellum. Nature. 2023. doi: 10.1038/s41586-023-06884-x

This article is a rework of a press release issued by Heidelberg University. Material has been edited for length and content.