Duplication of modules in brain evolution

I enjoyed this new paper in Science that specifically set out to understand how modules in the brain might have arisen during evolution. They studied the cerebellar nuclei (CN in the excerpts below). The cerebellum is the oddly-wrinkled blob at the bottom and back of the human brain and it’s a feature of all vertebrate brains. According to the accompanying commentary, the surface of the cerebellum (where the famous Purkinje cells live) has been far better studied than the groups of cells inside the cerebellum–these are the cerebellar nuclei and they turn out to be modular, not just in individual brains, but across hundreds of millions of years of evolution.

From commentary by Mary E. Hatten (link at bottom):

The work by Kebschull et al. also addresses the critical question of how new brain areas arise during evolution. In the cerebellum, the number of CN increases from one in jawless fish to two in amniotes and three in mammals. Among the three mammalian CN, the medial nucleus is phylogenetically the oldest and the lateral nucleus is the youngest. Using single-cell RNA sequencing (scRNA-seq) to cluster CN neuron types in chicken, mice, and humans, the authors show that new nuclei evolve by duplicating a subset of neurons, or subnuclei, across the three CN. Thus, each of the CN contain stereotyped subnuclei that are duplicated during evolution.

Here is the structured abstract of the paper:

The brains of extant animals have evolved over hundreds of millions of years from simple circuits. Cell types diversified, connections elaborated, and new brain regions emerged. Models for brain region evolution range from duplication of existing regions to splitting of previously multifunctional regions and de novo assembly from existing cell types. These models, however, have not been demonstrated in vertebrate brains at cell-type resolution.

We investigated brain region evolution using the cerebellar nuclei as a model system. The cerebellum is a major hindbrain structure in jawed vertebrates, comprising the cerebellar cortex and cerebellar nuclei. It is thought to act as a feedforward model for motor control and cognitive processes. The cerebellar cortex receives and processes inputs and sends outputs to the cerebellar nuclei, which route the results of cerebellar computations to the rest of the brain. Whereas the cerebellar cortex is well conserved across vertebrates, the cerebellar nuclei vary in number, with none in jawless vertebrates, one pair in cartilaginous fishes and amphibians, two pairs in reptiles and birds, and three pairs in mammals. This pattern suggests that extant cerebellar nuclei evolved from a single ancestral nucleus. Cerebellar nuclei thus provide a good model to interrogate brain region evolution.

We characterized the cerebellar nuclei in mice, chickens, and humans using whole-brain and spinal cord projection mapping in cleared samples, single-nucleus RNA sequencing (snRNAseq), and spatially resolved transcript amplicon readout mapping (STARmap) analysis. We first compared the projection patterns of the three cerebellar nuclei of mice. Our data reveal broad projections of all nuclei, which in common target regions are shifted relative to each other. To understand the transcriptomic differences that underlie these shifting projections, we produced a cell-type atlas of the mouse cerebellar nuclei using snRNAseq. We discovered three region-invariant inhibitory cell classes and 15 region-specific excitatory cell types. Excitatory cell types fall into two classes with distinct gene expression and electrophysiological properties. Members of each class are present in every nucleus and are putative sister cell types. STARmap analysis in mice revealed that the organizational unit of the cerebellar nuclei is cytoarchitectonically distinguishable subnuclei, each of which contains the three inhibitory and two excitatory classes.

To test whether this archetypal subnucleus is also the evolutionary unit of the cerebellar nuclei, we performed snRNAseq and STARmap on the chicken cerebellar nuclei. We identified four subnuclei, three of which had direct orthologs in mice. Each chicken subnucleus contained the same cell-type set of three inhibitory and two excitatory classes already identified in mice, confirming our hypothesis.

Cerebellar nuclei vary in size across vertebrates. In particular, the human lateral nucleus is markedly expanded. To understand this expansion, we performed snRNAseq in humans. We found that the medial and interposed nuclei maintained the archetypal cerebellar nuclei composition. However, the lateral nucleus expanded one excitatory cell class at the expense of the other. Conditional tracing in the mouse lateral nucleus revealed that the cell class expanded in humans preferentially accesses lateral frontal cortices via specific intermediate thalamic nuclei.

We identified a conserved cell-type set that forms an archetypal cerebellar nucleus as the unit of cerebellar nuclei organization and evolution. We propose that this archetypal nucleus was repeatedly duplicated during evolution, accompanied primarily by transcriptomic divergence of excitatory neurons and shifts in their projection patterns. Our data support a model of duplication-and-divergence of entire cell-type sets for brain region evolution.


The paper seems to be a collaboration among a group of all-stars at Stanford:


Wow this is really interesting.

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