The prevailing concept of neocortical pyramidal cell function proposes that excitatory inputs arrive via the dendrites, are integrated in the somatodendritic compartment, and upon reaching sufficient threshold, the axonal domain generates an action potential. The axon usually originates from the ventral aspect of the soma, starting with a short axon hillock followed by the axon initial segment (AIS), the electrogenic domain generating the action potential (reviewed by Kole and Brette, 2018). Already Ramon y Cajal suggested that impulses may bypass the soma and flow directly to the axon (reviewed by Triarhou, 2014). Axon carrying dendrites (AcDs) are common in cortical inhibitory interneurons (Meyer, 1987; Wahle and Meyer, 1987; Meyer and Wahle, 1988; Höfflin et al., 2017). Furthermore, upright, inverted, and fusiform pyramidal neurons of supra- and infragranular layers display AcDs in Golgi impregnated or dye-injected cortex from rodents, lagomorphs, ungulates, and carnivores (Peters et al., 1968; Smit and Uylings, 1975; van der Loos, 1976; Peters and Kara, 1985; Ferrer et al., 1986a; Ferrer et al., 1986b; Hübener et al., 1990; Reblet et al., 1992; Matsubara et al., 1996; Prieto and Winer, 1999; Mendizabal-Zubiaga et al., 2007; Hamada et al., 2016; Ernst et al., 2018). In mouse hippocampal CA1 pyramidal cells, axons frequently emerge from basal dendrites (Thome et al., 2014). Multiphoton glutamate uncaging and patch clamp recordings revealed that input to the AcD is more efficient in eliciting an action potential than input onto regular dendrites (non-AcDs). AcDs are intrinsically more excitable, generating dendritic spikes with higher probability and greater strength. Synaptic input onto AcDs generates action potentials with lower thresholds compared to non-AcDs, presumably due to the short electrotonic distance between input and the AIS. The anatomical diversity of axon origins plus the diversity of length and position of the AIS substantially impact the electrical behavior of pyramidal neurons (reviewed by Kole and Brette, 2018). This begs the questions, of how frequent AcD pyramidal neurons are among the mammalian species, and whether AcD pyramidal neurons also exist in primates. Our data suggest remarkable differences between phylogenetic orders and position in gray and white matter.

A majority of human gray matter pyramidal neurons have axons arising from the soma. In this aspect, in particular supragranular neurons of primates differ from those of non-primates. We found an interindividual variability of AcD cells at about a factor of 2, and despite our high cells numbers a sampling bias cannot be completely excluded. We could not find areal differences in macaques and in cats. Also, the data of human visual, auditory, temporal, and prefrontal cortex did not argue for areal differences. Basal dendritic trees of layer III pyramidal cells in human visual cortex are largest at birth whereas those in temporal cortical areas continue to increase in complexity during the first postnatal years (for review Elston and Fujita, 2014). This suggested that the sparcity of the AcD phenotype in human in particular in supragranular layers is not dependent on postnatal changes of dendritic complexity. An additional fraction of neurons have axons which share a root with a basal dendrite. Electron microscopy has demonstrated the mixed nature of the shared root which displays a dendritic fine structure but also contains the fasciculated microtubuli characteristic for the axon hillock. The latter is less distinct when the axon emerges from a dendrite in that the dense undercoating typical for the initial segment starts immediately after the point of divergence (Peters et al., 1968). This begs the question of how an axon can emerge from a dendrite? Cortical pyramidal neurons migrate radially upward while their axons emerge from the basal somatic pole and already during soma migration descend into the white matter. After the neurons have reached their laminar destination the leading process transforms into the apical dendrite, and basal dendrites begin to sprout. It remains to be shown if, during basal dendritogenesis, the axon hillock becomes passively displaced from the soma onto an outgrowing dendrite. However, the argument does not explain why the proportion of AcD neurons is much higher in hippocampus although numbers published with intracellular labeling methods recently in rodent CA1 neurons vary from 20 (Benavides-Piccione et al., 2020) to about 50% (Thome et al., 2014).

Furthermore, at this moment it is not clear if the axonal origin is always firmly anchored or can drift along the plasma membrane, for instance, by mechanical influences. It is known that the AIS is a regulated microdomain (Jamann et al., 2018) which undergoes activity-dependent shifts in length and in position. So, could the axon hillock actively ‘translocate’ or become passively displaced from the somatic to a proximal dendritic membrane? Dendrites are dynamic structures and although imaging studies in mouse have reported fairly stable basal dendrites of supragranular pyramidal neurons during development (Trachtenberg et al., 2002), there are also reports on dynamic changes elicited by environmental enrichment, activity, or disease (for review Hickmott and Ethell, 2006; Elston and Fujita, 2014).

Domestic pig and wild boar had similar proportions suggesting that domestication has no influence. Kitten and infant macaque data suggest that adult proportions of AcD neurons are already present at early ages, and the three assessments in infant macaque are within the macaque cluster (Figure 3B). In macaque, ontogenetically older infragranular pyramidal cells display more AcDs than later generated supragranular neurons, and the same was observed in our human material. Neurons of the white matter seem to be a special case. In cat, the inverted pyramidal neurons represent a subset of subplate cells. They reside at strategic positions to monitor incoming inputs and may quickly relay that information to the overlying gray matter via axons ascending into the gray matter including layer IV (Friauf et al., 1990). Given that subcortical afferents and white-to-gray matter projections match in topography (reviewed by Molnár et al., 2020), a synaptic double-hit scenario has been postulated with geniculocortical afferents trying to strengthen synapses onto layer IV spiny stellates, and with excitatory subplate afferents transiently acting as ‘helper synapse’ and instructor for the developing thalamocortical connectivity (reviewed by Molnár et al., 2020). With regard to the functional concept of AcD neurons (Thome et al., 2014; Hamada et al., 2016; Kole and Brette, 2018), our findings suggest that action potential firing abilities bypassing somatic integration and somatic inhibition are advantageous during development of thalamocortical wiring. In adult human white matter, pyramidal interstitial cells may differ from the transient subplate cells of non-primate cortex (Meyer et al., 1992; Suarez-Sola et al., 2009; Sedmak and Judaš, 2021). Yet, a function of quickly relaying incoming afferent information up to the gray matter is also conceivable here, and this might narrow the time window of synaptic integration enabling plasticity or help to activate inhibitory interneurons.

Whether neurons with axons sharing a common root with a dendrite should be regarded as AcD neurons is a matter of debate. From the morphological perspective, we assigned AcD in a very conservative manner. All neurons in which the axon origin was not unequivocally arising from a dendrite or seemed to share a common root with a dendrite were included in the group with somatic axons. Yet, in recent studies cells with the shared root configuration have been considered AcD neurons, also using immunofluorescence (Hamada et al., 2016; Thome et al., 2014). As expected, when plotting the sum of AcD plus shared root for the various staining methods, values for all species were increasing. However, the non-primate-to-macaque difference can be easily seen. For instance, our summed values from adult rat visual cortex sampled across all layers come closer to proportions reported for layer V neurons by Hamada et al., 2016; about 28% in adult Wistar rat somatosensory cortex. Of note, however, Hamada et al., 2016 reported on neurons which by our criteria would not be AcD cells; their criterion for inclusion has been the distance of the spectrin/ankyrin G-labeled AIS to the soma irrespective of whether the axon emerges from a shared root or unequivocally from a dendrite. Together, considering a fraction of shared root will be tolerable, at least in non-primate mammals with their substantial numbers of unequivocal AcD neurons.

The human Golgi material yielded the lowest values of AcD and of AcD plus shared root cells (Figure 5B) and the lowest proportion in supragranular layers (Figure 3B). We did not run statistical comparisons with our human data for the following reason. After analyzing more and more individuals and/or brain areas it became evident that the Golgi methods yielded a lower proportion of AcD neurons and the higher proportion of shared root cells. In line with this, also the biocytin material yielded higher proportions of shared root cells. A parsimonious explanation may be as follows. The Golgi reaction product is a chromate precipitate deposited at the plasma membrane. The pitch-black reaction product, the thickness of the tissue sections, on top of the complexity of basal dendrites in primate (Hendry and Jones, 1983) and even more so in human (Mohan et al., 2015; review by Goriounova and Mansvelder, 2019) can make it difficult to determine if an axon emerges from a soma, or from a shared root, or already from a very proximal dendritic trunk. The same accounts for the black biocytin reaction product (see Figure 2 and Figure 2—figure supplements 1 and 2) although the section thickness here was thinner. An additional argument comes from the axon itself. Axons originating from dendrites are thinner and have less prominent hillocks (Peters et al., 1968; Mendizabal-Zubiaga et al., 2007; Benavides-Piccione et al., 2020). With dark reaction products it was difficult to precisely determine where exactly a thin process lacking a clear hillock arises from a large dendritic root. This way we counted somewhat higher percentages of shared root and somewhat lower percentages of AcD in the Golgi Cox and Golgi-Kopsch material. By contrast, the intracellular staining of much thinner sections such as the 20–50 µm thick sections of the biocytin and immunofluorescence material allowed to visualize structures at better optical resolution. In particular, the confocal analysis allowed to walk micrometer-by-micrometer through the optical stack to decide ‘pro AcD’ or ‘pro shared root’ for each case in question arguing that the optical resolution was the crucial parameter. Nevertheless, biocytin staining was equal to the immunofluorescence in detecting clear-cut AcD, but was inferior to immunofluorescence and confocal analysis when it comes to deciding on shared root. It should be noted that the frequently used SMI-32 staining method may also have a certain bias in that it stains preferentially type 1 pyramidal neurons (Molnár and Cheung, 2006). Future studies are needed before a final conclusion on the areal and laminar proportion of human pyramidal AcD neurons can be made, and for a species comparison intracellular staining methods should be applied as recently done for CA1 pyramidal cells (Benavides-Piccione et al., 2020).

Pyramidal cell AcDs in isocortex and allocortex are basal dendrites. We found less than 10 axons in rat, ferret, and macaque emerging from an apical dendrite of a classical upright pyramidal cell of layers II–V. Pyramidal cells of layer VI can be L-shaped or fusiform-bipolar with two major dendrites, or inverted, in rodent as well as in primate (Hendry and Jones, 1983). In human, the large-sized Von Economo neurons in cingulate and other cortices have been reported to regularly have an axon from a thick descending basal dendrite which in addition often shares a common root with a secondary dendrite (Banovac et al., 2021). A study comparing human and mouse hippocampal CA1 pyramidal cells with intracellular injections reported that axons may arise from basal dendrites. The proportions are 40% AcD cells in human and 20% AcD cells in mouse (Benavides-Piccione et al., 2020). The latter proportion differs markably from the 52% AcD neurons visualized by DsRed expression in mouse CA1 neurons, and the 47% AcD neurons visualized via intracellular injection in Wistar rat CA1 neurons reported by Thome et al., 2014. Electron microscopy has revealed that in rat cortex the AIS of axons originating from one of these major dendrites of inverted pyramidal cells are thinner (Peters et al., 1968; Mendizabal-Zubiaga et al., 2007; Benavides-Piccione et al., 2020), and the initial segment is shorter and less innervated by symmetric synapses than AIS of axons arising from the soma (Mendizabal-Zubiaga et al., 2007). In cat visual cortex, inverted-fusiform pyramidal neurons of layer VI serve corticocortical, but not corticothalamic projections; for instance, the feedback projection to area 17 from the suprasylvian sulcus (Einstein, 1996), an area involved in motion detection, processing of optical flow, and pupillary constriction. With regard to the functional concept of AcD cells, the kinetics of intra- and interareal information processing may have so far unrecognized facets.

Local axon GABA-ergic cortical interneurons often have axons emerging from dendrites in rodent as well as in monkey (Jones, 1975) and human (Kisvárday et al., 1990). Our data confirm earlier observations in vivo (Wahle and Meyer, 1987; Meyer and Wahle, 1988; Wahle, 1993) and in vitro (Höfflin et al., 2017) in that the frequency of AcD is cell type specific. About half of the bitufted and Martinotti neurons in cat cortex had an AcD whereas most Parvalbumin-positive neurons, in particular, large basket cells in the human cortex had somatic axons regardless of laminar position. Intriguingly, cat subplate axonal loop cells turned out to be lowest with just about 5% AcD cells. This was in contrast to >40% AcD subplate pyramidal cells present at the very same ages in the very same compartment, with both types being co-generated from the cortical ventricular zone early during corticogenesis. Also intriguingly, about one-third of the interneurons of human cortex had an AcD. Our sample represents a mixture of types because the axons were stained only initially, and it was not possible to separate by type, as numbers were too small for this. Interestingly, however, the proportion of AcD interneurons in human was fairly close to an average proportion of AcD interneurons in cat cortex, whereas the proportion AcD pyramidal cells in human was substantially lower compared to pyramidal cells of cat and other non-primate mammals. Why interneurons do not seem to follow the primate trend toward less AcD cells remains to be unraveled.

Our data add to the view that human cortical pyramidal neurons differ in important aspects from those of non-primates (Elston et al., 2011; Elston and Fujita, 2014; Defelipe, 2011; Beaulieu-Laroche et al., 2018; Gidon et al., 2020; Rich et al., 2021). For instance, human supragranular pyramidal neurons have highly complex basal dendrites (Hendry and Jones, 1983), each being a unique computational unit (reviewed by Goriounova and Mansvelder, 2019). Furthermore, layer II/III human pyramidal cell dendrites have unique membrane properties (Eyal et al., 2016) and are more excitable than those of rat (Beaulieu-Laroche et al., 2018). Another feature is the unique design of the human cortical excitatory synapses having pools of synaptic vesicles, release sites, and active zones that are much larger compared to those in rodents (Molnár et al., 2016; Yakoubi et al., 2019). Large and efficient presynapses and more excitable dendrites may reliably depolarize the target cell’s somatodendritic compartment such that electrical dendroaxonic short circuits might become obsolete. We propose, from non-primate to primate isocortical pyramidal neurons, an evolutionary trend toward inputs that are conventionally integrated within the somatodendritic compartment and can be precisely modulated by inhibition to generate an optimally tuned cellular and, finally, behavioral output.

All data generated or analysed during this study are included in the manuscript and supporting file; source data files have been provided for Figures 3 , 4, 5, 6, and 7.

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Author details

1. Petra Wahle

   Ruhr University Bochum, Faculty of Biology and Biotechnology, Developmental Neurobiology, Bochum, Germany

   Contribution

   Conceptualization, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Visualization, Writing - original draft, Writing - review and editing

   For correspondence

   petra.wahle@rub.de

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-8710-0375

2. Eric Sobierajski

   Ruhr University Bochum, Faculty of Biology and Biotechnology, Developmental Neurobiology, Bochum, Germany

   Contribution

   Formal analysis, Investigation, Visualization

   Contributed equally with

   Ina Gasterstädt

   Competing interests

   No competing interests declared

3. Ina Gasterstädt

   Ruhr University Bochum, Faculty of Biology and Biotechnology, Developmental Neurobiology, Bochum, Germany

   Contribution

   Formal analysis, Investigation, Visualization

   Contributed equally with

   Eric Sobierajski

   Competing interests

   No competing interests declared

4. Nadja Lehmann

   Heidelberg University, Medical Faculty Mannheim, Mannheim Center for Translational Neuroscience, Institute of Neuroanatomy, Mannheim, Germany

   Contribution

   Investigation

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-4801-3057

5. Susanna Weber

   Heidelberg University, Medical Faculty Mannheim, Mannheim Center for Translational Neuroscience, Institute of Neuroanatomy, Mannheim, Germany

   Contribution

   Investigation

   Competing interests

   No competing interests declared

6. Joachim HR Lübke

   JARA-Institute Brain Structure Function Relationship, Jülich, Germany

   Contribution

   Resources

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-4086-3199

7. Maren Engelhardt

   Johannes Kepler University Linz, Faculty of Medicine, Institute of Anatomy and Cell Biology, Linz, Austria

   Contribution

   Formal analysis, Funding acquisition, Investigation, Resources, Writing - original draft, Writing - review and editing

   Competing interests

   No competing interests declared

8. Claudia Distler

   Ruhr University Bochum, Faculty of Biology and Biotechnology, Zoology and Neurobiology, Bochum, Germany

   Contribution

   Funding acquisition, Investigation, Resources, Writing - original draft, Writing - review and editing

   Competing interests

   No competing interests declared

9. Gundela Meyer

   University of La Laguna, Faculty of Medicine, Department of Basic Medical Science, Santa Cruz de Tenerife, Spain

   Contribution

   Formal analysis, Investigation, Resources, Writing - original draft, Writing - review and editing

   Competing interests

   No competing interests declared