Biochemical specificity of von Economo neurons in hominoids

Abstract

Objectives: Von Economo neurons (VENs) are defined by their thin, elongated cell body and long dendrites projecting from apical and basal ends. These distinctive neurons are mostly present in anterior cingulate (ACC) and fronto-insular (FI) cortex, with particularly high densities in cetaceans, elephants, and hominoid primates (i.e., humans and apes). This distribution suggests that VENs contribute to specializations of neural circuits in species that share both large brain size and complex social cognition, possibly representing an adaptation to rapidly relay socially-relevant information over long distances across the brain. Recent evidence indicates that unique patterns of protein expression may also characterize VENs, particularly involving molecules that are known to regulate gut and immune function.

Methods: In this study, we used quantitative stereologic methods to examine the expression of three such proteins that are localized in VENs-activating-transcription factor 3 (ATF3), interleukin 4 receptor (IL4Rα), and neuromedin B (NMB). We quantified immunoreactivity against these proteins in different morphological classes of ACC layer V neurons of hominoids.

Results: Among the different neuron types analyzed (pyramidal, VEN, fork, enveloping, and other multipolar), VENs showed the greatest percentage that displayed immunostaining. Additionally, a higher proportion of VENs in humans were immunoreactive to ATF3, IL4Rα, and NMB than in other apes. No other ACC layer V neuron type displayed a significant species difference in the percentage of immunoreactive neurons.

Conclusions: These findings demonstrate that phylogenetic variation exists in the protein expression profile of VENs, suggesting that humans might have evolved biochemical specializations for enhanced interoceptive sensitivity.

Figure 1

Nissl stain illustrating different morphological classes of neurons analyzed in this study found in layer V of anterior cingulate cortex. A) a pyramidal neuron from a gorilla; B) a VEN from a human; C) an enveloping neuron from a human; D) a fork neuron from a bonobo; and C) a neuron that was classified as “other” from a human. Scale bar is 20μm. Each morphological class was counted separately in stereologic analyses.

Figure 2

Immunostaining of ATF3, IL4Rα, and NMB in anterior cingulate cortex of various hominoids. A) IL4Rα immunostaining in a human illustrating several pyramidal neurons and a VEN as indicated by the arrow; B) IL4Rα immunostaining in a human illustrating several VENs (arrow) and a fork neuron (asterisk); C) ATF3 immunostaining of a pyramidal neuron from a human; D) IL4Rα immunostaining of a VEN from a chimpanzee; E) IL4Rα immunostaining of a fork neuron from an orang-utan; F) NMB immunostaining of an enveloping neuron from a siamang. The scale bar in panels A and B is 40μm. The scale bar in panels C-F is 10μm.

Figure 3

Distribution of neuron types according to immunoreactivity in layer V of anterior cingulate cortex across all hominoids. (A) The percentage of immunoreactive neurons for each protein from each morphological type. (B) The percentage of immunoreactive neurons out of the total number of Nissl-stained neurons for each protein and each neuron type. Bar indicates mean; error bars indicate 2 standard errors.

Figure 4

Percentage of immunoreactive VENs out of the total Nissl-stained neuron population in different species. Bar indicates mean; error bars indicate 2 standard errors.