1. Evolutionary Biology
  2. Neuroscience

Pyramidal Neurons: Looking for the origins of axons

Pyramidal neurons with axons that exit from dendrites rather than the cell body itself are relatively common in non-primates, but rare in monkeys and humans.
https://doi.org/10.7554/eLife.79839
Share this article
Cite this article
  1. Kathleen S Rockland
(2022)
Pyramidal Neurons: Looking for the origins of axons
eLife 11:e79839.
https://doi.org/10.7554/eLife.79839
  2. Download BibTeX
  3. Download .RIS
  1. Kathleen S Rockland  Is a corresponding author
  1. Department of Anatomy and Neurobiology School of Medicine, Boston University, United States

Pyramidal neurons are easily recognizable because their soma – the part of the neuron that contains the nucleus – has a characteristic triangular shape (hence their name). On closer examination, however, it becomes clear that the size of the soma can vary, as can the size and shape of the ‘arbor’ formed by the dendrites that carry signals to the soma (DeFelipe and Fariñas, 1992). Moreover, it has been reported that the axons of some pyramidal neurons in the mammalian cortex emerge from dendrites rather than from the base of the soma (Triarhou, 2014; Figure 1).

Figure 1
Download asset Open asset
Axons can emerge from different parts of pyramidal neurons.

(A) The neocortex of an infant macaque monkey that has been stained with dyes that label the dendrites and axons (initial segment only) of pyramidal neurons (shown in green). Branching off the base of the soma are several basal dendrites, and a single apical dendrite protrudes from its apex. Most pyramidal neurons contain an axon (indicated by the white arrow) that exits from the base of the soma (B). In some neurons, however, the axon emerges from a dendrite (C), or initially co-joins with a dendrite as it exits from the soma (D). Scale bars represent 100 micrometers for panel A, and 25 micrometers for the other panels.

Image credit: Adapted from Figure 1 in Wahle et al., 2022

These ‘axon carrying dendrites’ are unusual because the signals dendrites receive are usually processed in the soma before they are sent out via the axon to other neurons (Förster, 2014). These kinds of morphological differences are important because they influence how individual neurons and neuronal groups compute information. Researchers are particularly interested in features that only occur in humans and primates, as these may be associated with cognitive behaviors as well as neurological and psychiatric conditions. Now, in eLife, Petra Wahle from Ruhr University Bochum and co-workers in Germany, Austria and Spain report that the proportion of axon carrying dendrites (AcDs) varies between mammalian species and different areas of the brain (Wahle et al., 2022).

Wahle et al. used a range of histological techniques to compare the morphology and structure of pyramidal neurons in postmortem tissue samples extracted from six cortical areas at different stages of the animals’ development (Figure 2). This revealed that the proportion of pyramidal neurons with an AcD was around 10–20% in non-primate mammals (rat, cat and ferret), but much lower (typically a few percent) in macaque monkeys and humans. Moreover, AcDs were rarely found in the upper layers of the neocortex: these layers are thicker in non-human primates and humans, and are associated with complex behaviors and higher cortical functions.

Figure 2
Download asset Open asset
Axon carrying dendrites in different mammalian species.

Neurons with axon carrying dendrites (AcDs) in the rat visual cortex (A1, A2), the cat visual cortex (B1, B2), the ferret visual cortex (C1, C2), the macaque premotor cortex (D1, D2), and the human auditory cortex (E1, E2). Tissue samples were stained using one or two of the following techniques: biocytin (black and white images), immunofluorescence (multi-color images), or the Golgi method (human auditory cortex only). The site where the axons emerge is indicated by a large white arrow, with smaller black arrows highlighting the direction the axon takes through the neocortex. In most pyramidal neurons, the AcD emerges from the base of the soma. It is very rare for the AcD to emerge from the apical dendrite: an example of this is indicated by the asterisk in panel C2. Fewer than ten examples of apical AcDs were identified in the rat, ferret and macaque tissue samples studied, and none were identified in the human tissue samples. Scale bars represent 25 micrometers for all panels.

Image credit: Adapted from Figure 2 in Wahle et al., 2022.

So, what might be the reason for humans and non-human primates having fewer AcDs? It is thought that AcDs enhance the electrical behavior of pyramidal neurons by allowing signals to bypass the soma and flow directly from the dendrite to the axon. This is supported by prior studies showing that AcDs generate stronger and more frequent electrical spikes, and also require a lower threshold to trigger an action potential (Thome et al., 2014; Kole and Brette, 2018). Wahle et al. propose that humans and non-human primates have fewer AcDs because they already have other cellular specializations that can boost the strength of the electrical signal sent through pyramidal neurons.

The careful quantification and systematic survey of pyramidal neurons from different species and brain regions also yielded three other observations. First, Wahle et al. found that inhibitory interneurons do not follow the same trend as pyramidal cells: primates have similar numbers of AcD interneurons as other mammalian species. Second, humans have an unexpectedly high number of AcDs (8.86–13.23%) in the white matter compartment below the cortex, which largely contains bundles of axons intermixed with a population of scattered neurons. Among other features, these neurons are born early in development and have less distinct axon and dendritic regions compared to neurons at the cortical surface (Suárez-Solá et al., 2009). This weakened polarity may be the reason why a higher proportion of neurons in white matter have AcDs.

Third, consistent with previous work on the hippocampus (Benavides-Piccione et al., 2020), Wahle et al. found that humans had more pyramidal neurons with AcDs in this region of the brain than mice – which is the opposite of what happens in other parts of the cortex. Wahle et al. suggest that this could be because the hippocampus of humans and non-human primates requires extra features to carry out its complex memory-related processes. One way to test this could be to expand the histological analysis to other parts of the brain that are also associated with higher order functions, such as the amygdala.

In a broader context, the work by Wahle et al. adds to an already long list of pyramidal neurons that are morphologically distinct (DeFelipe and Fariñas, 1992). This includes inverted pyramidal neurons where apical dendrites (which usually emerge from the top of the soma) orientate down towards the white matter rather than up towards the surface of the brain (Banovac et al., 2021). An anatomical study in rabbits showed that the axons of inverted neurons can exit from multiple places (the base or side of the cell body, or off the downward-facing dendrite), and can project to a variety of cortical structures (Mendizabal-Zubiaga et al., 2007). This mixed population of standard and inverted pyramidal neurons has also been found in the brains of non-primate mammals and the hippocampus of non-human primates, suggesting that they may lead to different axonal outputs.

Another possibility is that differences in morphology may result from mis-steps during development. Notably, inverted pyramidal neurons are abundant in the cortex of mutant reeler mice, which have disorganized cortical layers owing to disruptions in neuronal migration during development (Landrieu and Goffinet, 1981; Förster, 2014).

Organization of the cytoskeleton (the scaffold of proteins that maintains the cell’s structure) may also play a role in these morphological differences, particularly the location of the initial segment of the axon, which varies across vertebrates and invertebrates (Prokop, 2020). Species variations are becoming increasingly easy to investigate due to the advent of super-resolution microscopy (Xu et al., 2013), and AcDs offer an interesting assay for examining ultrastructural specializations in normal and abnormal brains.

The findings of Wahle et al. highlight how the morphology of pyramidal neurons, and potentially other cells in the brain, does not always follow a uniform pattern and can vary between species. The study also offers several new avenues of research. For instance, the mechanisms involved in the formation and function of AcDs remain to be explored. Furthermore, it is still unclear why in the samples studied by Wahle et al. it is more common for dendrites at the base of the pyramidal soma to have AcDs than the apical dendrite (Figure 2C). In addition, other mechanisms – such as gene expression and metabolism – might play a role in this unusual axon location. AcDs could be an effective assay to identify neurons with distinct roles in the brain (Höfflin et al., 2017).

Answering these questions will require expanding the histological approach used by Wahle et al. to other areas of the brain, especially regions outside the cortex, and examining more species and stages of development. In addition, computer simulations could be used to model the consequences of having different proportions of AcDs. This could provide new insights into how and why cognitive behavior differs so much between species, particularly humans and non-human primates.

References

Article and author information

Author details

  1. Kathleen S Rockland

    Kathleen S Rockland is in the Department of Anatomy and Neurobiology, School of Medicine, Boston University, Boston, United States
    For correspondence
    krock@bu.edu
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6650-8785

Publication history

  1. Version of Record published:

Copyright

© 2022, Rockland

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.

Metrics

  • 2,123
    views
  • 246
    downloads
  • 1
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

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. Kathleen S Rockland
(2022)
Pyramidal Neurons: Looking for the origins of axons
eLife 11:e79839.
https://doi.org/10.7554/eLife.79839

Categories and tags

Research organisms

    1. Related to

    Neocortical pyramidal neurons with axons emerging from dendrites are frequent in non-primates, but rare in monkey and human

    Petra Wahle, Eric Sobierajski ... Gundela Meyer
  2. Further reading

Further reading

    1. Evolutionary Biology
    2. Neuroscience

    Neocortical pyramidal neurons with axons emerging from dendrites are frequent in non-primates, but rare in monkey and human

    Petra Wahle, Eric Sobierajski ... Gundela Meyer
    Research Article Updated

    The canonical view of neuronal function is that inputs are received by dendrites and somata, become integrated in the somatodendritic compartment and upon reaching a sufficient threshold, generate axonal output with axons emerging from the cell body. The latter is not necessarily the case. Instead, axons may originate from dendrites. The terms ‘axon carrying dendrite’ (AcD) and ‘AcD neurons’ have been coined to describe this feature. In rodent hippocampus, AcD cells are shown to be functionally ‘privileged’, since inputs here can circumvent somatic integration and lead to immediate action potential initiation in the axon. Here, we report on the diversity of axon origins in neocortical pyramidal cells of rodent, ungulate, carnivore, and primate. Detection methods were Thy-1-EGFP labeling in mouse, retrograde biocytin tracing in rat, cat, ferret, and macaque, SMI-32/βIV-spectrin immunofluorescence in pig, cat, and macaque, and Golgi staining in macaque and human. We found that in non-primate mammals, 10–21% of pyramidal cells of layers II–VI had an AcD. In marked contrast, in macaque and human, this proportion was lower and was particularly low for supragranular neurons. A comparison of six cortical areas (being sensory, association, and limbic in nature) in three macaques yielded percentages of AcD cells which varied by a factor of 2 between the areas and between the individuals. Unexpectedly, pyramidal cells in the white matter of postnatal cat and aged human cortex exhibit AcDs to much higher percentages. In addition, interneurons assessed in developing cat and adult human cortex had AcDs at type-specific proportions and for some types at much higher percentages than pyramidal cells. Our findings expand the current knowledge regarding the distribution and proportion of AcD cells in neocortex of non-primate taxa, which strikingly differ from primates where these cells are mainly found in deeper layers and white matter.

    1. Evolutionary Biology

    Spatial and temporal distribution of ribosomes in single cells reveals aging differences between old and new daughters of Escherichia coli

    Lin Chao, Chun Kuen Chan ... Ulla Camilla Rang
    Research Article

    Lineages of rod-shaped bacteria such as Escherichia coli exhibit a temporal decline in elongation rate in a manner comparable to cellular or biological aging. The effect results from the production of asymmetrical daughters, one with a lower elongation rate, by the division of a mother cell. The slower daughter compared to the faster daughter, denoted respectively as the old and new daughters, has more aggregates of damaged proteins and fewer expressed gene products. We have examined further the degree of asymmetry by measuring the density of ribosomes between old and new daughters and between their poles. We found that ribosomes were denser in the new daughter and also in the new pole of the daughters. These ribosome patterns match the ones we previously found for expressed gene products. This outcome suggests that the asymmetry is not likely to result from properties unique to the gene expressed in our previous study, but rather from a more fundamental upstream process affecting the distribution of ribosomal abundance. Because damage aggregates and ribosomes are both more abundant at the poles of E. coli cells, we suggest that competition for space between the two could explain the reduced ribosomal density in old daughters. Using published values for aggregate sizes and the relationship between ribosomal number and elongation rates, we show that the aggregate volumes could in principle displace quantitatively the amount of ribosomes needed to reduce the elongation rate of the old daughters.

    1. Evolutionary Biology
    2. Genetics and Genomics

    Systematic genetic characterization of the human PKR kinase domain highlights its functional malleability to escape a poxvirus substrate mimic

    Michael James Chambers, Sophia B Scobell, Meru J Sadhu
    Research Article

    Evolutionary arms races can arise at the contact surfaces between host and viral proteins, producing dynamic spaces in which genetic variants are continually pursued.  However, the sampling of genetic variation must be balanced with the need to maintain protein function. A striking case is given by protein kinase R (PKR), a member of the mammalian innate immune system. PKR detects viral replication within the host cell and halts protein synthesis to prevent viral replication by phosphorylating eIF2α, a component of the translation initiation machinery. PKR is targeted by many viral antagonists, including poxvirus pseudosubstrate antagonists that mimic the natural substrate, eIF2α, and inhibit PKR activity. Remarkably, PKR has several rapidly evolving residues at this interface, suggesting it is engaging in an evolutionary arms race, despite the surface’s critical role in phosphorylating eIF2α. To systematically explore the evolutionary opportunities available at this dynamic interface, we generated and characterized a library of 426 SNP-accessible nonsynonymous variants of human PKR for their ability to escape inhibition by the model pseudosubstrate inhibitor K3, encoded by the vaccinia virus gene K3L. We identified key sites in the PKR kinase domain that harbor K3-resistant variants, as well as critical sites where variation leads to loss of function. We find K3-resistant variants are readily available throughout the interface and are enriched at sites under positive selection. Moreover, variants beneficial against K3 were also beneficial against an enhanced variant of K3, indicating resilience to viral adaptation. Overall, we find that the eIF2α-binding surface of PKR is highly malleable, potentiating its evolutionary ability to combat viral inhibition.