Von Economo Neurons – Primate-Specific or Commonplace in the Mammalian Brain?

Abstract

The pioneering work by von Economo in 1925 on the cytoarchitectonics of the cerebral cortex revealed a specialized and unique cell type in the adult human fronto-insular (FI) and anterior cingulate cortex (ACC). In modern studies, these neurons are termed von Economo neurons (VENs). In his work, von Economo described them as stick, rod or corkscrew cells because of their extremely elongated and relatively thin cell body clearly distinguishable from common oval or spindle-shaped infragranular principal neurons. Before von Economo, in 1899 Cajal depicted the unique somato-dendritic morphology of such cells with extremely elongated soma in the FI. However, although VENs are increasingly investigated, Cajal’s observation is still mainly being neglected. On Golgi staining in humans, VENs have a thick and long basal trunk with horizontally oriented terminal branching (basilar skirt) from where the axon arises. They are clearly distinguishable from a spectrum of modified pyramidal neurons found in infragranular layers, including oval or spindle-shaped principal neurons. Spindle-shaped cells with highly elongated cell body were also observed in the ACC of great apes, but despite similarities in soma shape, their dendritic and axonal morphology has still not been described in sufficient detail. Studies identifying VENs in non-human species are predominantly done on Nissl or anti-NeuN staining. In most of these studies, the dendritic and axonal morphology of the analyzed cells was not demonstrated and many of the cells found on Nissl or anti-NeuN staining had a cell body shape characteristic for common oval or spindle-shaped cells. Here we present an extensive literature overview on VENs, which demonstrates that human VENs are specialized elongated principal cells with unique somato-dendritic morphology found abundantly in the FI and ACC of the human brain. More research is needed to properly evaluate the presence of such specialized cells in other primates and non-primate species.

Spindle-Shaped Neurons in the Human Posteromedial (Precuneus) Cortex

“…These findings would accompany the distinction made when classifying VENs, bipolar ovoid and rhomboid-shaped cell bodies or, if one considers the various results for putative VENs in cortical layer V, the identification of human VENs with a cell body shape with some variability between stick-like or rod and spindle shapes, for example. There is also some similarity between the cell body shape (used as the morphological parameter in this case) of a layer V "VEN" included in the original study of von Economo and Koskinas (shown in the bottom left of Figure 4 in Banovac et al, 2021) and the "bipolar" neuron (not considered a "VEN") shown in Figure 10A (leftmost neuron) from Banovac et al (2019). A parallel discussion could be done on VENs shapes and markers in the macaque monkey (e.g., see Figures 2A and D-G, and Figures S1 E , F , and F in Evrard et al, 2012).…”

“…that von Economo and Koskinas identified "VENs" in humans using the Nissl staining (see Figures 4 and 5 in Banovac et al, 2021). That is, it was the cell body shape, its relative size compared to adjacent cells, and the aspect of two main primary dendrites of these neurons located in the layer V of restricted brain areas that led to the identification of "VENs as VENs."…”

“…As mentioned in Cobos and Seeley (2015), "human VENs may be a heterogeneous population comprising projection neurons with diverse targets including the contralateral cortex." These are possibilities that deserve further development and interpretation with the available morphological data (Watson et al, 2006;Banovac et al, 2019Banovac et al, , 2021Correa-Júnior et al, 2020).…”

“…The description of the tuft aspect of the descending dendritic branches, from where the axon is observed (Banovac et al, 2019(Banovac et al, , 2021, is an important morphological feature evidenced in the original Golgi study of VENs, and the efforts to look for these specific cells in the human brain are impressive (Banovac et al, 2021). Notwithstanding, additional images for the descending dendrites in putative VENs have been reported.…”

Genetic Mechanisms Underlying the Evolution of Connectivity in the Human Cortex

“…These projection neurons have a unique somato-dendritic morphology and are primarily found in layer 5 of the frontoinsular and anterior cingulate cortex. While the presence of these neurons only in these two brain regions may be unique to great apes or even humans, many questions about the connectivity, function, or even clear criteria for their identification is still lacking (Hodge et al, 2020;Banovac et al, 2021). These differences in cell type composition could directly impact the basic circuit motifs of neuronal circuits in the human brain.…”