The Subcortical-Allocortical- Neocortical continuum for the Emergence and Morphological Heterogeneity of Pyramidal Neurons in the Human Brain

Abstract

Human cortical and subcortical areas integrate emotion, memory, and cognition when interpreting various environmental stimuli for the elaboration of complex, evolved social behaviors. Pyramidal neurons occur in developed phylogenetic areas advancing along with the allocortex to represent 70–85% of the neocortical gray matter. Here, we illustrate and discuss morphological features of heterogeneous spiny pyramidal neurons emerging from specific amygdaloid nuclei, in CA3 and CA1 hippocampal regions, and in neocortical layers II/III and V of the anterolateral temporal lobe in humans. Three-dimensional images of Golgi-impregnated neurons were obtained using an algorithm for the visualization of the cell body, dendritic length, branching pattern, and pleomorphic dendritic spines, which are specialized plastic postsynaptic units for most excitatory inputs. We demonstrate the emergence and development of human pyramidal neurons in the cortical and basomedial (but not the medial, MeA) nuclei of the amygdala with cells showing a triangular cell body shape, basal branched dendrites, and a short apical shaft with proximal ramifications as “pyramidal-like” neurons. Basomedial neurons also have a long and distally ramified apical dendrite not oriented to the pial surface. These neurons are at the beginning of the allocortex and the limbic lobe. “Pyramidal-like” to “classic” pyramidal neurons with laminar organization advance from the CA3 to the CA1 hippocampal regions. These cells have basal and apical dendrites with specific receptive synaptic domains and several spines. Neocortical pyramidal neurons in layers II/III and V display heterogeneous dendritic branching patterns adapted to the space available and the afferent inputs of each brain area. Dendritic spines vary in their distribution, density, shapes, and sizes (classified as stubby/wide, thin, mushroom-like, ramified, transitional forms, “atypical” or complex forms, such as thorny excrescences in the MeA and CA3 hippocampal region). Spines were found isolated or intermingled, with evident particularities (e.g., an extraordinary density in long, deep CA1 pyramidal neurons), and some showing a spinule. We describe spiny pyramidal neurons considerably improving the connectional and processing complexity of the brain circuits. On the other hand, these cells have some vulnerabilities, as found in neurodegenerative Alzheimer’s disease and in temporal lobe epilepsy.

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

“…Notably, thick-tufted layer V pyramidal neurons are a heterogeneous class of cells, but are morphologically different from their neighboring VENs ( Watson et al, 2006 ; compare with Ramaswamy and Markram, 2015 ; Cembrowski and Spruston, 2019 ; Rasia-Filho et al, 2021 ); see also comments on the likely coexistence of discrete and continuous variations that underlie cell-type diversity in BRAIN Initiative Cell Census Network (BICCN), 2021 . VENs emerge mainly after birth, increase in number until age 4 years ( Allman et al, 2005 ), and can be susceptible to alterations in some neuropsychiatric disorders (as described below).…”

“…The axon could not be readily distinguished from these finer dendrites” (shown in Figure 5C in Hodge et al, 2020 ). Considering the likelihood of morphological heterogeneity within the same class of neurons (e.g., as occurs in pyramidal ones, Cembrowski and Spruston, 2019 ; Benavides-Piccione et al, 2020 ; Rasia-Filho et al, 2021 ), it would be plausible to consider that the description of some morphological variability for the dendrites of VENs would not be conflicting; rather, they would be complementary to the original descriptions of these cells. The integration of multiple approaches and criteria are need to reach a consensus in this field ( Banovac et al, 2021 ).…”

“…There are few data on the axonal morphology of human VENs (but see relevant figures in Banovac et al, 2019 , 2021 ). The adapted Golgi method used here for human postmortem brain ( Dall’Oglio et al, 2010 , 2015 ; Vásquez et al, 2018 ; Rasia-Filho et al, 2021 ) does not always provide the identification of the axon to trace its origin and ramification, which was also mentioned in Correa-Júnior et al (2020) . We described the diffuse axonal pattern (which would imply that the observed fibers would be not myelinated) in the neuropil of the human medial amygdaloid nucleus, and identified the axon hillock emerging from the cell body or in close primary dendrite in some local cells using this same Golgi technique ( Dall’Oglio et al, 2013 ).…”

“…The identification and classification of each type of 3D-reconstructed dendritic spine was based on previous descriptions ( Fiala and Harris, 1999 ; Arellano et al, 2007a , b ; Brusco et al, 2014 ; González-Ramírez et al, 2014 ; Dall’Oglio et al, 2015 ; Vásquez et al, 2018 ; Correa-Júnior et al, 2020 ; Rasia-Filho et al, 2021 ). By rotating the reconstructed images, spines were observed at different angles to determine occurrence from proximal to distal dendrites, number, shape, and size ( Reberger et al, 2018 ).…”

“…The Golgi Method and the Two-Dimensional and Three-Dimensional Image Reconstruction Procedures We used the "single-section" Golgi method adapted for longterm fixed postmortem human brain (Dall'Oglio et al, 2010 on the original Gabbott and Somogyi, 1984; developed for 3D image processing by Reberger et al, 2018) as previously done for the characterization of neurons and dendritic spines in both subcortical (amygdaloid nuclei) and cortical human brain areas (Dall'Oglio et al, 2013, 2015Vásquez et al, 2018;Correa-Júnior et al, 2020;Rasia-Filho et al, 2021). Brain sections were sectioned and kept immersed in the same post-fixation solution as mentioned above for three more days.…”