In this article we first point at the expansion of associative cortical areas in primates, as well as at the intrinsic changes in the structure of the cortical column. There is a huge increase in proportion of glutamatergic cortical projecting neurons located in the upper cortical layers (II/III). Inside this group, a novel class of associative neurons becomes recognized for its growing necessity in both inter-areal and intra-areal columnar integration. Equally important to the changes in glutamatergic population, we found that literature data suggest a 50% increase in the proportion of neocortical GABAergic neurons between primates and rodents. This seems to be a result of increase in proportion of calretinin interneurons in layers II/III, population which in associative areas represents 15% of all neurons forming those layers. Evaluating data about functional properties of their connectivity we hypothesize that such an increase in proportion of calretinin interneurons might lead to supra-linear growth in memory capacity of the associative neocortical network. An open question is whether there are some new calretinin interneuron subtypes, which might substantially change micro-circuitry structure of the primate cerebral cortex.

The vast majority of cortical GABAergic neurons can be defined by parvalbumin, somatostatin or calretinin expression. In most mammalians, parvalbumin and somatostatin interneurons have constant proportions, each representing 5–7% of the total neuron number. In contrast, there is a threefold increase in the proportion of calretinin interneurons, which do not exceed 4% in rodents and reach 12% in higher order areas of primate cerebral cortex. In rodents, almost all parvalbumin and somatostatin interneurons originate from the medial part of the subpallial proliferative structure, the ganglionic eminence (GE), while almost all calretinin interneurons originate from its caudal part. The spatial pattern of cortical GABAergic neurons origin from the GE is preserved in the monkey and human brain. However, it could be expected that the evolution is changing developmental rules to enable considerable expansion of calretinin interneuron population. During the early fetal period in primates, cortical GABAergic neurons are almost entirely generated in the subpallium, as in rodents. Already at that time, the primate caudal ganglionic eminence (CGE) shows a relative increase in size and production of calretinin interneurons. During the second trimester of gestation, that is the main neurogenetic stage in primates without clear correlates found in rodents, the pallial production of cortical GABAergic neurons together with the extended persistence of the GE is observed. We propose that the CGE could be the main source of calretinin interneurons for the posterior and lateral cortical regions, but not for the frontal cortex. The associative granular frontal cortex represents around one third of the cortical surface and contains almost half of cortical calretinin interneurons. The majority of calretinin interneurons destined for the frontal cortex could be generated in the pallium, especially in the newly evolved outer subventricular zone that becomes the main pool of cortical progenitors.

Von Economo neurons (VENs) are modified pyramidal neurons characterized by an extremely elongated rodshaped soma. They are abundant in layer V of the anterior cingulate cortex (ACC) and fronto-insular cortex (FI) of the human brain, and have long been described as a human-specific neuron type. Recently, VENs have been reported in the ACC of apes and the FI of macaque monkeys. The first description of the somato-dendritic morphology of VENs in the FI by Cajal in 1899 (Textura del Sistema Nervioso del Hombre y de los Vertebrados, Tomo II. Madrid: Nicolas Moya) strongly suggested that they were a unique neuron subtype with specific morphological features. It is surprising that a clarification of this extremely important observation has not yet been attempted, especially as possible misidentification of other oval or fusiform cells as VENs has become relevant in many recently published studies. Here, we analyzed sections of Brodmann area 24 (ACC) stained with rapid Golgi and Golgi-Cox in five adult human specimens, and confirmed Cajal's observations. In addition, we established a comprehensive morphological description of VENs. VENs have a distinct somato-dendritic morphology that allows their clear distinction from other modified pyramidal neurons. We established that VENs have a perpendicularly oriented, stick-shaped core part consisting of the cell body and two thick extensionsan apical and basal stem. The perpendicular length of the core part was 150-250 lm and the thickness was 10-21 lm. The core part was characterized by a lack of clear demarcation between the cell body and the two extensions. Numerous thin, spiny and horizontally oriented side dendrites arose from the cell body. The basal extension of the core part typically ended by giving numerous smaller dendrites with a brushlike branching pattern. The apical extension had a topology typical for apical dendrites of pyramidal neurons. The dendrites arising from the core part had a high dendritic spine density. The most distinct feature of VENs was the distant origin site of the axon, which arose from the ending of the basal extension, often having a common origin with a dendrite. Quantitative analysis found that VENs could be divided into two groups based on total dendritic lengthsmall VENs with a peak total dendritic length of 1500-2500 lm and large VENs with a peak total dendritic length of 5000-6000 lm. Comparative morphological analysis of VENs and other oval and fusiform modified pyramidal neurons showed that on Nissl sections small VENs might be difficult to identify, and that oval and fusiform neurons could be misidentified as VENs. Our analysis of Golgi slides of Brodmann area 9 from a total of 32 adult human subjects revealed only one cell resembling VEN morphology. Thus, our Journal of Anatomy data show that the numerous recent reports on the presence of VENs in non-primates in other layers and regions of the cortex need further confirmation by showing the dendritic and axonal morphology of these cells. In conclusion, our study provides a foundati...

The human specific cognitive shift starts around the age of 2 years with the onset of self-awareness, and continues with extraordinary increase in cognitive capacities during early childhood. Diffuse changes in functional connectivity in children aged 2–6 years indicate an increase in the capacity of cortical network. Interestingly, structural network complexity does not increase during this time and, thus, it is likely to be induced by selective maturation of a specific neuronal subclass. Here, we provide an overview of a subclass of cortico-cortical neurons, the associative layer IIIC pyramids of the human prefrontal cortex. Their local axonal collaterals are in control of the prefrontal cortico-cortical output, while their long projections modulate inter-areal processing. In this way, layer IIIC pyramids are the major integrative element of cortical processing, and changes in their connectivity patterns will affect global cortical functioning. Layer IIIC neurons have a unique pattern of dendritic maturation. In contrast to other classes of principal neurons, they undergo an additional phase of extensive dendritic growth during early childhood, and show characteristic molecular changes. Taken together, circuits associated with layer IIIC neurons have the most protracted period of developmental plasticity. This unique feature is advanced but also provides a window of opportunity for pathological events to disrupt normal formation of cognitive circuits involving layer IIIC neurons. In this manuscript, we discuss how disrupted dendritic and axonal maturation of layer IIIC neurons may lead into global cortical disconnectivity, affecting development of complex communication and social abilities. We also propose a model that developmentally dictated incorporation of layer IIIC neurons into maturing cortico-cortical circuits between 2 to 6 years will reveal a previous (perinatal) lesion affecting other classes of principal neurons. This “disclosure” of pre-existing functionally silent lesions of other neuronal classes induced by development of layer IIIC associative neurons, or their direct alteration, could be found in different forms of autism spectrum disorders. Understanding the gene-environment interaction in shaping cognitive microcircuitries may be fundamental for developing rehabilitation and prevention strategies in autism spectrum and other cognitive disorders.

AimTo analyze postnatal development and life-span changes of apical dendrite side branches (oblique dendrites) from associative layer IIIC magnopyramidal neurons in the human dorsolateral prefrontal cortex and to compare the findings with the previously established pattern of basal dendrite development.MethodsWe analyzed dendritic morphology from 352 rapid-Golgi impregnated neurons (10-18 neurons per subject) in Brodmann area 9 from the post-mortem tissue of 25 subjects ranging in age from 1 week to 91 years. Data were collected in the period between 1994 and 1996, and the analysis was performed between September 2017 and February 2018. Quantitative dendritic parameters were statistically analyzed using one-way analysis of variance and two-tailed t tests.ResultsOblique dendrites grew rapidly during the first postnatal months, and the increase in the dendrite length was accompanied by the outgrowth of new dendritic segments. After a more than one-year-long “dormant” period of only fine dendritic rearrangements (2.5-16 months), oblique dendrites displayed a second period of marked growth, continuing through the third postnatal year. Basal and oblique dendrites displayed roughly the same growth pattern, but had considerably different topological organization in adulthood.ConclusionOur analysis confirmed that a biphasic pattern of postnatal dendritic development, together with a second growth spurt at the age of 2-3 years, represents a unique feature of the associative layer IIIC magnopyramidal neurons in the human dorsolateral prefrontal cortex. We propose that these structural changes relate to rapid cognitive development during early childhood.