Cytoarchitectonic gradients of laminar degeneration in behavioural variant frontotemporal dementia.

Behavioral variant frontotemporal dementia (bvFTD) is a clinical syndrome primarily caused by either tau (bvFTD-tau) or TDP-43 (bvFTD-TDP) proteinopathies. We previously found lower cortical layers and dorsolateral regions accumulate greater tau than TDP-43 pathology; however, patterns of laminar neurodegeneration across diverse cytoarchitecture in bvFTD is understudied. We hypothesized that bvFTD-tau and bvFTD-TDP have distinct laminar distributions of pyramidal neurodegeneration along cortical gradients, a topologic order of cytoarchitectonic subregions based on increasing pyramidal density and laminar differentiation. Here, we tested this hypothesis in a frontal cortical gradient consisting of five cytoarchitectonic types (i.e., periallocortex, agranular mesocortex, dysgranular mesocortex, eulaminate-I isocortex, eulaminate-II isocortex) spanning anterior cingulate, paracingulate, orbitofrontal, and mid-frontal gyri in bvFTD-tau (n=27), bvFTD-TDP (n=47), and healthy controls (HC; n=32). We immunostained all tissue for total neurons (NeuN; neuronal-nuclear protein) and pyramidal neurons (SMI32; non-phosphorylated neurofilament) and digitally quantified NeuN-immunoreactivity (ir) and SMI32-ir in supragranular II-III, infragranular V-VI, and all I-VI layers in each cytoarchitectonic type. We used linear mixed-effects models adjusted for demographic and biologic variables to compare SMI32-ir between groups and examine relationships with the cortical gradient, long-range pathways, and clinical symptoms. We found regional and laminar distributions of SMI32-ir expected for HC, validating our measures within the cortical gradient framework. While SMI32-ir loss was relatively uniform along the cortical gradient in bvFTD-TDP, SMI32-ir progressively decreased along the cortical gradient of bvFTD-tau and included greater SMI32-ir loss in supragranular eulaminate-II isocortex in bvFTD-tau versus bvFTD-TDP (p=0.039). Using a ratio of SMI32-ir to model known long-range connectivity between infragranular mesocortex and supragranular isocortex, we found a larger laminar ratio in bvFTD-tau versus bvFTD-TDP (p=0.019), suggesting select long-projecting pathways may contribute to isocortical-predominant degeneration in bvFTD-tau. In cytoarchitectonic types with the highest NeuN-ir, we found lower SMI32-ir in bvFTD-tau versus bvFTD-TDP (p=0.047), suggesting pyramidal neurodegeneration may occur earlier in bvFTD-tau. Lastly, we found that reduced SMI32-ir related to behavioral severity and frontal-mediated letter fluency, not temporal-mediated confrontation naming, demonstrating the clinical relevance and specificity of frontal pyramidal neurodegeneration to bvFTD-related symptoms. Our data suggest loss of neurofilament-rich pyramidal neurons is a clinically relevant feature of bvFTD that selectively worsens along a frontal cortical gradient in bvFTD-tau, not bvFTD-TDP. Therefore, tau-mediated degeneration may preferentially involve pyramidal-rich layers that connect more distant cytoarchitectonic types. Moreover, the hierarchical arrangement of cytoarchitecture along cortical gradients may be an important neuroanatomical framework for identifying which types of cells and pathways are differentially involved between proteinopathies.

Signature laminar distributions of pathology in frontotemporal lobar degeneration.

Frontotemporal lobar degeneration (FTLD) with either tau (FTLD-tau) or TDP-43 (FTLD-TDP) inclusions are distinct proteinopathies that frequently cause similar frontotemporal dementia (FTD) clinical syndromes. FTD syndromes often display macroscopic signatures of neurodegeneration at the level of regions and networks, but it is unclear if subregional laminar pathology display patterns unique to proteinopathy or clinical syndrome. We hypothesized that FTLD-tau and FTLD-TDP accumulate pathology in relatively distinct cortical layers independent of clinical syndrome, with greater involvement of lower layers in FTLD-tau. The current study examined 170 patients with either FTLD-tau (n = 73) or FTLD-TDP (n = 97) spanning dementia and motor phenotypes in the FTD spectrum. We digitally measured the percent area occupied by tau and TDP-43 pathology in upper layers (I-III), lower layers (IV-VI), and juxtacortical white matter (WM) from isocortical regions in both hemispheres where available. Linear mixed-effects models compared ratios of upper to lower layer pathology between FTLD groups and investigated relationships with regions, WM pathology, and global cognitive impairment while adjusting for demographics. We found lower ratios of layer pathology in FTLD-tau and higher ratios of layer pathology in FTLD-TDP, reflecting lower layer-predominant tau pathology and upper layer-predominant TDP-43 pathology, respectively (p < 0.001). FTLD-tau displayed lower ratios of layer pathology related to greater WM tau pathology (p = 0.002) and to earlier involved/severe pathology regions (p = 0.007). In contrast, FTLD-TDP displayed higher ratios of layer pathology not related to either WM pathology or regional severity. Greater cognitive impairment was associated with higher ratios of layer pathology in FTLD-tau (p = 0.018), but was not related to ratios of layer pathology in FTLD-TDP. Lower layer-predominant tau pathology and upper layer-predominant TDP-43 pathology are proteinopathy-specific, regardless of clinical syndromes or regional networks that define these syndromes. Thus, patterns of laminar change may provide a useful anatomical framework for investigating how degeneration of select cells and corresponding laminar circuits influence large-scale networks and clinical symptomology in FTLD.

Cutting across structural and transcriptomic scales translates time across the lifespan in humans and chimpanzees.

How the unique capacities of human cognition arose in evolution is a question of enduring interest. It is still unclear which developmental programmes are responsible for the emergence of the human brain. The inability to determine corresponding ages between humans and apes has hampered progress in detecting developmental programmes leading to the emergence of the human brain. I harness temporal variation in anatomical, behavioural and transcriptional variation to determine corresponding ages from fetal to postnatal development and ageing, between humans and chimpanzees. This multi-dimensional approach results in 137 corresponding time points across the lifespan, from embryonic day 44 to approximately 55 years of age, in humans and their equivalent ages in chimpanzees. I used these data to test whether developmental programmes, such as the timeline of prefrontal cortex (PFC) maturation, previously claimed to differ between humans and chimpanzees, do so once variation in developmental schedules is controlled for. I compared the maturation of frontal cortex projections from structural magnetic resonance (MR) scans and from temporal variation in the expression of genes used to track long-range projecting neurons (i.e. supragranular-enriched genes) in chimpanzees and humans. Contrary to what has been suggested, the timetable of PFC maturation is not unusually extended in humans. This dataset, which is the largest with which to determine corresponding ages across humans and chimpanzees, provides a rigorous approach to control for variation in developmental schedules and to identify developmental programmes responsible for unique features of the human brain.

Brain Wiring and Supragranular-Enriched Genes Linked to Protracted Human Frontal Cortex Development.

The human frontal cortex is unusually large compared with many other species. The expansion of the human frontal cortex is accompanied by both connectivity and transcriptional changes. Yet, the developmental origins generating variation in frontal cortex circuitry across species remain unresolved. Nineteen genes that encode filaments, synapse, and voltage-gated channels are especially enriched in the supragranular layers of the human cerebral cortex, which suggests enhanced corticocortical projections emerging from layer III. We identify species differences in connections with the use of diffusion MR tractography as well as gene expression in adulthood and in development to identify developmental mechanisms generating variation in frontal cortical circuitry. We demonstrate that increased expression of supragranular-enriched genes in frontal cortex layer III is concomitant with an expansion in corticocortical pathways projecting within the frontal cortex in humans relative to mice. We also demonstrate that the growth of the frontal cortex white matter and transcriptional profiles of supragranular-enriched genes are protracted in humans relative to mice. The expansion of projections emerging from the human frontal cortex arises by extending frontal cortical circuitry development. Integrating gene expression with neuroimaging level phenotypes is an effective strategy to assess deviations in developmental programs leading to species differences in connections.

MRI-Based Markers of Changes in the Supragranular Cortical Layer in Individuals at Clinically High Risk of Endogenous Psychosis.

We analyzed morphometric MRI parameters indirectly attesting to structural changes in the supragranular layer in 33 non-converted individuals at clinical high risk for endogenous psychosis (follow-up period of 6.7±0.6 years) and in 34 sex- and age-matched healthy controls. In the group of clinical high-risk individuals, changes indicative of potential predominance of supragranular thinning in comparison with a decrease of infragranular cortical layer thickness were revealed. The results are discussed in the context of the concepts of resilience and risk markers of developing endogenous psychosis.

Evidence that distinct human primary motor cortex circuits control discrete and rhythmic movements.

KEY POINTS: Discrete and rhythmic dynamics are inherent components of (human) movements. We provide evidence that distinct human motor cortex circuits contribute to discrete and rhythmic movements. Excitability of supragranular layer circuits of the human motor cortex was higher during discrete movements than during rhythmic movements. Conversely, more complex corticospinal circuits showed higher excitability during rhythmic movements than during discrete movements. No task-specific differences existed for corticospinal output neurons at infragranular layers. The excitability differences were found to be time(phase)-specific and could not be explained by the kinematic properties of the movements. The same task-specific differences were found between the last cycle of a rhythmic movement period and ongoing rhythmic movements. ABSTRACT: Human actions entail discrete and rhythmic movements (DM and RM, respectively). Recent insights from human and animal studies indicate different neural control mechanisms for DM and RM, emphasizing the intrinsic nature of the task. However, how distinct human motor cortex circuits contribute to these movements remains largely unknown. In the present study, we tested distinct primary motor cortex and corticospinal circuits and proposed that they show differential excitability between DM and RM. Human subjects performed either 1) DM or 2) RM using their right wrist. We applied an advanced electrophysiological approach involving transcranial magnetic stimulation and peripheral nerve stimulation to test the excitability of the neural circuits. Probing was performed at different movement phases: movement initiation (MI, 20 ms after EMG onset) and movement execution (ME, 200 ms after EMG onset) of the wrist flexion. At MI, excitability at supragranular layers was significantly higher in DM than in RM. Conversely, excitability of more complex corticospinal circuits was significantly lower in DM than RM at ME. No task-specific differences were found for direct corticospinal output neurons at infragranular layers. The neural differences could not be explained by the kinematic properties of the movements and also existed between ongoing RM and the last cycle of RM. Our results therefore strengthen the hypothesis that different neural control mechanisms engage in DM and RM.

Transcriptional profiles of supragranular-enriched genes associate with corticocortical network architecture in the human brain.

The human brain is patterned with disproportionately large, distributed cerebral networks that connect multiple association zones in the frontal, temporal, and parietal lobes. The expansion of the cortical surface, along with the emergence of long-range connectivity networks, may be reflected in changes to the underlying molecular architecture. Using the Allen Institute's human brain transcriptional atlas, we demonstrate that genes particularly enriched in supragranular layers of the human cerebral cortex relative to mouse distinguish major cortical classes. The topography of transcriptional expression reflects large-scale brain network organization consistent with estimates from functional connectivity MRI and anatomical tracing in nonhuman primates. Microarray expression data for genes preferentially expressed in human upper layers (II/III), but enriched only in lower layers (V/VI) of mouse, were cross-correlated to identify molecular profiles across the cerebral cortex of postmortem human brains (n = 6). Unimodal sensory and motor zones have similar molecular profiles, despite being distributed across the cortical mantle. Sensory/motor profiles were anticorrelated with paralimbic and certain distributed association network profiles. Tests of alternative gene sets did not consistently distinguish sensory and motor regions from paralimbic and association regions: (i) genes enriched in supragranular layers in both humans and mice, (ii) genes cortically enriched in humans relative to nonhuman primates, (iii) genes related to connectivity in rodents, (iv) genes associated with human and mouse connectivity, and (v) 1,454 gene sets curated from known gene ontologies. Molecular innovations of upper cortical layers may be an important component in the evolution of long-range corticocortical projections.

Sublaminar Subdivision of Mouse Auditory Cortex Layer 2/3 Based on Functional Translaminar Connections.

The cerebral cortex is subdivided into six layers based on morphological features. The supragranular layers 2/3 (L2/3) contain morphologically and genetically diverse populations of neurons, suggesting the existence of discrete classes of cells. In primates and carnivores L2/3 can be subdivided morphologically, but cytoarchitectonic divisions are less clear in rodents. Nevertheless, discrete classes of cells could exist based on their computational requirement, which might be linked to their associated functional microcircuits. Through in vitro slice recordings coupled with laser-scanning photostimulation we investigated whether L2/3 of male mouse auditory cortex contains discrete subpopulations of cells with specific functional microcircuits. We use hierarchical clustering on the laminar connection patterns to reveal the existence of multiple distinct classes of L2/3 neurons. The classes of L2/3 neurons are distinguished by the pattern of their laminar and columnar inputs from within A1 and their location within L2/3. Cells in superficial L2 show more extensive columnar integration than deeper L3 cells. Moreover, L3 cells receive more translaminar input from L4. In vivo imaging in awake mice revealed that L2 cells had higher bandwidth than L3 cells, consistent with the laminar differences in columnar integration. These results suggest that similar to higher mammals, rodent L2/3 is not a homogenous layer but contains several parallel microcircuits.SIGNIFICANCE STATEMENT Layer 2/3 of auditory cortex is functionally diverse. We investigated whether L2/3 cells form classes based on their functional connectivity. We used in vitro whole-cell patch-clamp recordings with laser-scanning photostimulation and performed unsupervised clustering on the resulting excitatory and inhibitory connection patterns. Cells within each class were located in different sublaminae. Superficial cells showed wider integration along the tonotopic axis and the amount of L4 input varied with sublaminar location. To identify whether sensory responses varied with sublaminar location, we performed in vivo Ca2+ imaging and found that L2 cells were less frequency-selective than L3 cells. Our results show that the diversity of receptive fields in L2/3 is likely due to diversity in the underlying functional circuits.

Comparative effects of adaptation on layers II-III and V-VI neurons in cat V1.

V1 is fundamentally grouped into columns that descend from layers II-III to V-VI. Neurons inherent to visual cortex are capable of adapting to changes in the incoming stimuli that drive the cortical plasticity. A principle feature called orientation selectivity can be altered by the presentation of non-optimal stimulus called 'adapter'. When triggered, LGN cells impinge upon layer IV and further relay the information to deeper layers via layers II-III. Using different adaptation protocols, neuronal plasticity can be investigated. Superficial neurons in area V1 are well acknowledged to exhibit attraction and repulsion by shifting their tuning peaks when challenged by a non-optimal stimulus called 'adapter'. Layers V-VI neurons in spite of partnering layers II-III neurons in cortical computation have not been explored simultaneously toward adaptation. We believe that adaptation not only affects cells specific to a layer but modifies the entire column. In this study, through simultaneous multiunit recordings in anesthetized cats using a multichannel depth electrode, we show for the first time how layers V-VI neurons (1000-1200 µm) along with layers II-III neurons (300-500 µm) exhibit plasticity in response to adaptation. Our results demonstrate that superficial and deeper layer neurons react synonymously toward adapter by exhibiting similar behavioral properties. The neurons displayed similar amplitude of shift and maintained equivalent sharpness of Gaussian tuning peaks before and the following adaptation. It appears that a similar mechanism, belonging to all layers, is responsible for the analog outcome of the neurons' experience with adapter.

Radial Migration Dynamics Is Modulated in a Laminar and Area-Specific Manner During Primate Corticogenesis.

The orderly radial migration of cortical neurons from their birthplace in the germinal zones to their final destination in the cortical plate is a prerequisite for the functional assembly of microcircuits in the neocortex. Rodent and primate corticogenesis differ both quantitatively and qualitatively, particularly with respect to the generation of neurons of the supragranular layers. Marked area differences in the outer subventricular zone progenitor cell density impact the radial glia scaffold compactness which is likely to induce area differences in radial migration strategy. Here, we describe specific features of radial migration in the non-human primate, including the absence of the premigratory multipolar stage found in rodents. Ex vivo approaches in the embryonic macaque monkey visual cortex, show that migrating neurons destined for supragranular and infragranular layers exhibit significant differences in morphology and velocity. Migrating neurons destined for the supragranular layers show a more complex bipolar morphology and higher motility rates than do infragranular neurons. There are area differences in the gross morphology and membrane growth behavior of the tip of the leading process. In the subplate compartment migrating neurons destined for the supragranular layers of presumptive area 17 exhibit radial constrained trajectories and leading processes with filopodia, which contrast with the meandering trajectories and leading processes capped by lamellipodia observed in the migrating neurons destined for presumptive area 18. Together these results present evidence that migrating neurons may exhibit autonomy and in addition show marked area-specific differences. We hypothesize that the low motility and high radial trajectory of area 17 migrating neurons contribute to the unique structural features of this area.

Cross-Regional Gradient of Dendritic Morphology in Isochronically-Sourced Mouse Supragranular Pyramidal Neurons.

Architectonic heterogeneity in neurons is thought to be important for equipping the mammalian cerebral cortex with an adaptable network that can organize the manifold totality of information it receives. To this end, the dendritic arbors of supragranular pyramidal neurons, even those of the same class, are known to vary substantially. This diversity of dendritic morphology appears to have a rostrocaudal configuration in some brain regions of various species. For example, in humans and non-human primates, neurons in more rostral visual association areas (e.g., V4) tend to have more complex dendritic arbors than those in the caudal primary visual cortex. A rostrocaudal configuration is not so clear in any region of the mouse, which is increasingly being used as a model for neurodevelopmental disorders that arise from dysfunctional cerebral cortical circuits. Therefore, in this study we investigated the complexity of dendritic arbors of neurons distributed throughout a broad area of the mouse cerebral cortex. We reduced selection bias by labeling neurons restricted to become supragranular pyramidal neurons using in utero electroporation. While we observed that the simple rostrocaudal position, cortical depth, or even functional region of a neuron was not directly related to its dendritic morphology, a model that instead included a caudomedial-to-rostrolateral gradient accounted for a significant amount of the observed dendritic morphological variance. In other words, rostrolateral neurons from our data set were generally more complex when compared to caudomedial neurons. Furthermore, dividing the cortex into a visual area and a non-visual area maintained the power of the relationship between caudomedial-to-rostrolateral position and dendritic complexity. Our observations therefore support the idea that dendritic morphology of mouse supragranular excitatory pyramidal neurons across much of the tangential plane of the cerebral cortex is partly shaped by a developmental gradient spanning several functional regions.

Multiple Transmitter Receptors in Regions and Layers of the Human Cerebral Cortex.

We measured the densities (fmol/mg protein) of 15 different receptors of various transmitter systems in the supragranular, granular and infragranular strata of 44 areas of visual, somatosensory, auditory and multimodal association systems of the human cerebral cortex. Receptor densities were obtained after labeling of the receptors using quantitative in vitro receptor autoradiography in human postmortem brains. The mean density of each receptor type over all cortical layers and of each of the three major strata varies between cortical regions. In a single cortical area, the multi-receptor fingerprints of its strata (i.e., polar plots, each visualizing the densities of multiple different receptor types in supragranular, granular or infragranular layers of the same cortical area) differ in shape and size indicating regional and laminar specific balances between the receptors. Furthermore, the three strata are clearly segregated into well definable clusters by their receptor fingerprints. Fingerprints of different cortical areas systematically vary between functional networks, and with the hierarchical levels within sensory systems. Primary sensory areas are clearly separated from all other cortical areas particularly by their very high muscarinic M2 and nicotinic α4ß2 receptor densities, and to a lesser degree also by noradrenergic α2 and serotonergic 5-HT2 receptors. Early visual areas of the dorsal and ventral streams are segregated by their multi-receptor fingerprints. The results are discussed on the background of functional segregation, cortical hierarchies, microstructural types, and the horizontal (layers) and vertical (columns) organization in the cerebral cortex. We conclude that a cortical column is composed of segments, which can be assigned to the cortical strata. The segments differ by their patterns of multi-receptor balances, indicating different layer-specific signal processing mechanisms. Additionally, the differences between the strata-and area-specific fingerprints of the 44 areas reflect the segregation of the cerebral cortex into functionally and topographically definable groups of cortical areas (visual, auditory, somatosensory, limbic, motor), and reveals their hierarchical position (primary and unimodal (early) sensory to higher sensory and finally to multimodal association areas). Highlights Densities of transmitter receptors vary between areas of human cerebral cortex.Multi-receptor fingerprints segregate cortical layers.The densities of all examined receptor types together reach highest values in the supragranular stratum of all areas.The lowest values are found in the infragranular stratum.Multi-receptor fingerprints of entire areas and their layers segregate functional systemsCortical types (primary sensory, motor, multimodal association) differ in their receptor fingerprints.