Von Economo neurons (VENs) of the cerebral cortex are hypothesized to be centrally involved in the evolution of circuitry underlying self-awareness and social cognition (Nimchinsky et al., 1999
; Allman et al., 2001
). VENs were initially identified as morphologically distinct from pyramidal neurons by their thin, elongated cell body and long, prominent dendrites projecting from apical and basal poles (Allman et al., 2005
; Nimchinsky et al., 1995
; von Economo, 1926
). They are located predominantly in layer V of anterior cingulate (ACC) and fronto-insular cortex (FI), regions that are involved in the integration of interoception, emotion, and cognition. The relevance of this small population of neurons to social cognition is highlighted by the fact that VENs in FI are selectively and profoundly depleted in the behavioral variant of frontotemporal dementia, a neurodegenerative disease characterized by severe deficits in the patient's ability to recognize the emotional impact of their actions on others (Seeley et al., 2006
). In addition, VENs have arisen several times among phylogenetically divergent species that share both large brain size and complex social organization, suggesting that they contribute to specializations of neural circuits that relay socially relevant information over long distances across the brain. Based on their morphology in Nissl-stained sections, high densities of VENs have been identified in ACC and FI of hominoid primates (Allman et al., 2005
; Nimchinsky et al., 1995
), cetaceans (Butti et al., 2009
; Hof and Van der Gucht, 2007
) and elephants (Hakeem et al., 2009
Understanding the VENs’ distinctive relationship to other cortical neuron types will shed light on their neurobiological function and contribution to cognitive adaptations. Watson et al. (2006)
showed that in humans VENs have both fewer and shorter dendritic branches, as well as fewer dendritic spines, as compared to neighboring pyramidal neurons. These findings suggest that VENs are designed to perform relatively simple integrative functions within a narrow cortical column before conveying output to other brain regions for further processing. Additionally, VENs have significantly larger cell bodies than pyramidal neurons and express intense immunostaining against nonphosphorylated neurofilament protein (Nimchinsky et al., 1995
), indicating that they carry large axons involved in the rapid conduction of information.
To further characterize the VENs, it is important to consider their biochemical phenotype. Allman et al. (2010)
and Tetreault et al. (2010)
reviewed a variety of proteins that are selectively expressed by VENs in humans and have a restricted distribution in layer V of ACC and FI. Among these proteins, activating transcription factor 3 (ATF3), the interleukin-4 receptor alpha chain (IL4Rα), and neuromedin B (NMB) displayed some of the most intense staining in VENs.
ATF3 is a member of the mammalian activation transcription factor/cAMP responsive element-binding (CREB) protein family of transcription factors and its variants either activate or repress gene transcription from promoters of ATF binding elements. ATF3 has been shown to be involved in stress responses of the body (Chen et al., 1996
; Hai et al., 1989
) and the control of pain sensitivity in spinal cord neurons (Latremolier et al., 2008
). The activity of ACC is closely related to the perceived unpleasantness of pain (Rainville et al., 1998
), and thus the expression of ATF3 in the VENs might be related to the regulation of pain sensitivity in this structure as well.
IL4Rα is a type I cytokine receptor which binds interleukin-4 and interleukin-13 to regulate the production of immunoglobin E (IgE), thus playing a crucial role in allergic reactions, particularly asthma (Wenzel et al., 2007
). In the brain, IL4Rα plays an important role in inflammatory reactions and has been implicated in the pathology of schizophrenia (Nawa et al., 2000
; 2006; Watanabe et al., 2008
). Anterior cingulate cortex is involved in the regulation of the severity of asthmatic responses to allergens in human subjects (Rosenkranz and Davidson, 2009
) and IL4Rα expression in the VENs may participate in this process.
NMB is a peptide that is involved in the release of digestive enzymes in the stomach, in smooth muscle contractions during intestinal peristalsis, in the mounting of immune responses to potentially damaging ingested substances, and in the control of appetite by the brain (Jensen et al., 2008
). NMB participates in the local control of the intestinal tract, but also functions at higher levels of gut control, first in the hypothalamus where the digestive processes are integrated with other homeostatic systems of the body, and second in the insular and related cortices, where gut feelings and the control of the gut interact with circuitry activated in awareness, motivation and conscious decision-making (Allman et al., 2010
). The high level of expression of proteins that are involved in immune response and digestion by VENs suggests their role in monitoring of a “body-loop” that incorporates visceral states and emotions in the awareness of self and others (Damasio, 1994
; Allman et al, 2010
In the present study, we examined whether ATF3, IL4Rα, and NMB display selective distributions among the various neuron types in layer V of the ACC of hominoid primates (i.e., humans and apes) to test the hypothesis that these proteins serve a special role in the biochemical function of VENs.