Cerebellum: Folding into shape

A new computational tool provides insights into the structure of the cerebellum in mammals.
  1. Héloïse de Vareilles  Is a corresponding author
  1. Department of Psychiatry, University of Cambridge, United Kingdom

During development, the brains of most mammals (including humans) will fold into a unique pattern of grooves and ridges. Understanding how these wrinkles emerge can provide important insights into how the brain works. Most research in this area has focused on the structure of the cerebrum, the two large lobes that make up most of the brain. However, much less is known about the structure of the cerebellum – the ‘little brain’ that sits beneath the cerebrum.

The anatomical properties of the cerebrum – such as the number of folds it contains, its thickness and surface area – have been shown to vary between mammalian species and to influence cognitive processes in humans (Mota and Herculano-Houzel, 2015, Cachia et al., 2021). Unlike the cerebrum, which is folded in some mammals (such as humans) but flat in others (such as mice), the cerebellum always has a wrinkled appearance. The structure of the cerebellum is also more uniform across different species (including some invertebrates), and this has led to the assumption that its folds have less of an influence on cognition than the folds of the cerebrum. However, recent work suggests that the cerebellum may have a bigger role in cognition than previously thought (Buckner, 2013).

In 2020, Ken Ashwell of the University of New South Wales compared the volumes of the cerebellum and cerebrum in monotremes, marsupials and eutherian mammals (Ashwell, 2020). However, the study did not dive into the detailed anatomy of the cerebellum, as its small size and highly folded configuration are difficult to examine using conventional methods. Now, in eLife, Roberto Toro from the Institut Pasteur and colleagues – including Katja Heuer as first author – report a new approach for investigating the shape of the cerebellum in mammals (Heuer et al., 2023).

The team developed a computational method that can measure the surface area of the cerebellum, the shape of its individual folds, and the thickness of its most superficial layer (Figure 1A). The approach, which is freely available, was validated by ensuring that it could produce results that fitted with previously reported data. It was then applied to histological slices extracted from the cerebellums of 56 different mammals, including slices examined in the Ashwell study (Figure 1B).

Comparing the structure of the cerebellum in mammalian species.

(A) Heuer et al. created a computational model that can automatically identify grooves in the cerebellum and measure various metrics (shown in red), including the width (bottom left) and perimeter (bottom right) of individual folds. (B) The model was applied to histological slices extracted from the cerebellums of 56 mammals. The results of this analysis are shown for five species (which are displayed on the same scale). Heuer et al. estimated that most mammals are descended from a species that had a cerebellum similar to that of the rock hyrax (bottom right).

Image credit: Adapted from Figure 1 and Figure 3 of the manuscript by Heuer et al., 2023

Heuer et al. – who are based at various institutes in France, the United Kingdom and Germany – found that the different folding metrics detected by their model could be split in to two groups: ones that varied a lot between species (such as surface area), and ones that did not vary as much (such as the width of individual folds). While body size varied by 11 orders of magnitude within the sample, the surface area of the cerebellum varied much less (by around 2.5 orders of magnitude), and the width between two folds only varied by 0.5 orders of magnitude. This suggests that larger mammals have larger cerebellums, but the size of their folds are relatively thin in comparison.

The folding metrics measured also scaled within species. For instance, bigger cerebellums had a higher number of folds than smaller ones an effect which has also been observed in the cerebrum (Germanaud et al., 2012). Species with larger cerebrums also appeared to have relatively smaller cerebellums.

Heuer et al. then set out to find which computational model of evolution was able to recreate the anatomies of the cerebellums found in the different mammalian species. They found that a stabilising model – that is, when animals that are straying away from their common ancestor randomly evolve back to these initial properties – worked best. Using this model, Heuer et al. estimated that the organism most mammals descended from probably had a cerebellum similar to the one found in an animal known as the rock hyrax (Figure 1B).

These observations, along with other results reported by Heuer et al., provide food for thought about the mechanics of brain folding. Although the composition of cells within the cerebellum differ from those in the cerebrum, Heuer et al. propose that these parts of the brain fold in the same way, with the most superficial layer expanding more than the layer immediately below. This process, along with neurons in the cerebellum developing in a certain way, may lead to specific patterns of grooves and ridges forming in the cerebellums of different species. In the future, the new tool created by Heuer et al. could be used to see if these observations occur in the cerebellums of other species (including non-mammals), and to look in to the ‘folds within folds’ that appear in larger cerebellums in more detail.


Article and author information

Author details

  1. Héloïse de Vareilles

    Héloïse de Vareilles is in the Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom

    For correspondence
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7782-9701

Publication history

  1. Version of Record published: November 9, 2023 (version 1)


© 2023, de Vareilles

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.


  • 348
    Page views
  • 23
  • 0

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Héloïse de Vareilles
Cerebellum: Folding into shape
eLife 12:e93122.
  1. Further reading

Further reading

    1. Biochemistry and Chemical Biology
    2. Evolutionary Biology
    Piotr Karaś, Klaudia Kochanowicz ... Krzysztof Liberek
    Research Article

    Evolution can tinker with multi-protein machines and replace them with simpler single-protein systems performing equivalent functions in an equally efficient manner. It is unclear how, on a molecular level, such simplification can arise. With ancestral reconstruction and biochemical analysis, we have traced the evolution of bacterial small heat shock proteins (sHsp), which help to refold proteins from aggregates using either two proteins with different functions (IbpA and IbpB) or a secondarily single sHsp that performs both functions in an equally efficient way. Secondarily single sHsp evolved from IbpA, an ancestor specialized in strong substrate binding. Evolution of an intermolecular binding site drove the alteration of substrate binding properties, as well as the formation of higher-order oligomers. Upon two mutations in the α-crystallin domain, secondarily single sHsp interacts with aggregated substrates less tightly. Paradoxically, less efficient binding positively influences the ability of sHsp to stimulate substrate refolding, since the dissociation of sHps from aggregates is required to initiate Hsp70-Hsp100-dependent substrate refolding. After the loss of a partner, IbpA took over its role in facilitating the sHsp dissociation from an aggregate by weakening the interaction with the substrate, which became beneficial for the refolding process. We show that the same two amino acids introduced in modern-day systems define whether the IbpA acts as a single sHsp or obligatorily cooperates with an IbpB partner. Our discoveries illuminate how one sequence has evolved to encode functions previously performed by two distinct proteins.

    1. Evolutionary Biology
    2. Genetics and Genomics
    Carolina A Martinez-Gutierrez, Josef C Uyeda, Frank O Aylward
    Research Article

    Microbial plankton play a central role in marine biogeochemical cycles, but the timing in which abundant lineages diversified into ocean environments remains unclear. Here, we reconstructed the timeline in which major clades of bacteria and archaea colonized the ocean using a high-resolution benchmarked phylogenetic tree that allows for simultaneous and direct comparison of the ages of multiple divergent lineages. Our findings show that the diversification of the most prevalent marine clades spans throughout a period of 2.2 Ga, with most clades colonizing the ocean during the last 800 million years. The oldest clades – SAR202, SAR324, Ca. Marinimicrobia, and Marine Group II – diversified around the time of the Great Oxidation Event, during which oxygen concentration increased but remained at microaerophilic levels throughout the Mid-Proterozoic, consistent with the prevalence of some clades within these groups in oxygen minimum zones today. We found the diversification of the prevalent heterotrophic marine clades SAR11, SAR116, SAR92, SAR86, and Roseobacter as well as the Marine Group I to occur near to the Neoproterozoic Oxygenation Event (0.8–0.4 Ga). The diversification of these clades is concomitant with an overall increase of oxygen and nutrients in the ocean at this time, as well as the diversification of eukaryotic algae, consistent with the previous hypothesis that the diversification of heterotrophic bacteria is linked to the emergence of large eukaryotic phytoplankton. The youngest clades correspond to the widespread phototrophic clades Prochlorococcus, Synechococcus, and Crocosphaera, whose diversification happened after the Phanerozoic Oxidation Event (0.45–0.4 Ga), in which oxygen concentrations had already reached their modern levels in the atmosphere and the ocean. Our work clarifies the timing at which abundant lineages of bacteria and archaea colonized the ocean, thereby providing key insights into the evolutionary history of lineages that comprise the majority of prokaryotic biomass in the modern ocean.