Systematic modelling of the development of laminar projection origins in the cerebral cortex: Interactions of spatio-temporal patterns of neurogenesis and cellular heterogeneity.

The architectonic type principle conceptualizes structural connections between brain areas in terms of the relative architectonic differentiation of connected areas. It has previously been shown that spatio-temporal interactions between the time and place of neurogenesis could underlie multiple features of empirical mammalian connectomes, such as projection existence and the distribution of projection strengths. However, so far no mechanistic explanation for the emergence of typically observed laminar patterns of projection origins and terminations has been tested. Here, we expand an in silico model of the developing cortical sheet to explore which factors could potentially constrain the development of laminar projection patterns. We show that manipulations which rely solely on spatio-temporal interactions, namely the relative density of laminar compartments, a delay in the neurogenesis of infragranular layers relative to layer 1, and a delay in the neurogenesis of supragranular layers relative to infragranular layers, do not result in the striking correlation between supragranular contribution to projections and the relative differentiation of areas that is typically observed in the mammalian cortex. In contrast, we find that if we introduce systematic variation in cell-intrinsic properties, coupling them with architectonic differentiation, the resulting laminar projection patterns closely mirror the empirically observed patterns. We also find that the spatio-temporal interactions posited to occur during neurogenesis are necessary for the formation of the characteristic laminar patterns. Hence, our results indicate that the specification of the laminar patterns of projection origins may result from systematic variation in a number of cell-intrinsic properties, superimposed on the previously identified spatio-temporal interactions which are sufficient for the emergence of the architectonic type principle on the level of inter-areal connectivity in silico.

Neuron density fundamentally relates to architecture and connectivity of the primate cerebral cortex.

Studies of structural brain connectivity have revealed many intriguing features of complex cortical networks. To advance integrative theories of cortical organization, an understanding is required of how connectivity interrelates with other aspects of brain structure. Recent studies have suggested that interareal connectivity may be related to a variety of macroscopic as well as microscopic architectonic features of cortical areas. However, it is unclear how these features are inter-dependent and which of them most strongly and fundamentally relate to structural corticocortical connectivity. Here, we systematically investigated the relation of a range of microscopic and macroscopic architectonic features of cortical organization, namely layer III pyramidal cell soma cross section, dendritic synapse count, dendritic synapse density and dendritic tree size as well as area neuron density, to multiple properties of cortical connectivity, using a comprehensive, up-to-date structural connectome of the primate brain. Importantly, relationships were investigated by multi-variate analyses to account for the interrelations of features. Of all considered factors, the classical architectonic parameter of neuron density most strongly and consistently related to essential features of cortical connectivity (existence and laminar patterns of projections, area degree), and in conjoint analyses largely abolished effects of cellular morphological features. These results confirm neuron density as a central architectonic indicator of the primate cerebral cortex that is closely related to essential aspects of brain connectivity and is also highly indicative of further features of the architectonic organization of cortical areas, such as the considered cellular morphological measures. Our findings integrate several aspects of cortical micro- and macroscopic organization, with implications for cortical development and function.

Comprehensive computational modelling of the development of mammalian cortical connectivity underlying an architectonic type principle.

The architectonic type principle relates patterns of cortico-cortical connectivity to the relative architectonic differentiation of cortical regions. One mechanism through which the observed close relation between cortical architecture and connectivity may be established is the joint development of cortical areas and their connections in developmental time windows. Here, we describe a theoretical exploration of the possible mechanistic underpinnings of the architectonic type principle, by performing systematic computational simulations of cortical development. The main component of our in silico model was a developing two-dimensional cortical sheet, which was gradually populated by neurons that formed cortico-cortical connections. To assess different explanatory mechanisms, we varied the spatiotemporal trajectory of the simulated neurogenesis. By keeping the rules governing axon outgrowth and connection formation constant across all variants of simulated development, we were able to create model variants which differed exclusively by the specifics of when and where neurons were generated. Thus, all differences in the resulting connectivity were due to the variations in spatiotemporal growth trajectories. Our results demonstrated that a prescribed targeting of interareal connection sites was not necessary for obtaining a realistic replication of the experimentally observed relation between connection patterns and architectonic differentiation. Instead, we found that spatiotemporal interactions within the forming cortical sheet were sufficient if a small number of empirically well-grounded assumptions were met, namely planar, expansive growth of the cortical sheet around two points of origin as neurogenesis progressed, stronger architectonic differentiation of cortical areas for later neurogenetic time windows, and stochastic connection formation. Thus, our study highlights a potential mechanism of how relative architectonic differentiation and cortical connectivity become linked during development. We successfully predicted connectivity in two species, cat and macaque, from simulated cortico-cortical connection networks, which further underscored the general applicability of mechanisms through which the architectonic type principle can explain cortical connectivity in terms of the relative architectonic differentiation of cortical regions.

The primate connectome in context: Principles of connections of the cortical visual system.

Which principles determine the organization of the intricate network formed by nerve fibers that link the primate cerebral cortex? We addressed this issue for the connections of primate visual cortices by systematically analyzing how the existence or absence of connections, their density as well as laminar patterns of projection origins and terminations are correlated with distance, similarity in cortical type as well as neuronal density or the thickness of cortical areas. Analyses were based on four extensive compilations of qualitative as well as quantitative data for connections of the primate visual cortical system in macaque monkeys (Felleman and Van Essen 1991; Barbas 1986; Barbas and Rempel-Clower 1997; Barone et al. 2000; Markov et al. 2014). Distance and thickness similarity were not consistently correlated with connection features, but similarity of cortical type, determined by qualitative features of laminar differentiation, or measured quantitatively as the areas' overall neuronal density, was a reliable predictor for the existence of connections between areas. Cortical type similarity was also consistently and closely correlated with characteristic laminar connection profiles: structurally dissimilar areas had origin and termination patterns that were biased to the upper or deep cortical layers, while similar areas showed more bilaminar origins and terminations. These results suggest that patterns of corticocortical connections of primate visual cortices are closely linked to the stratified architecture of the cerebral cortex. In particular, the regularity of laminar projection origins and terminations arises from the structural differences between cortical areas. The observed integration of projections with the intrinsic cortical architecture provides a structural basis for advanced theories of cortical organization and function.

An architectonic type principle in the development of laminar patterns of cortico-cortical connections.

Structural connections between cortical areas form an intricate network with a high degree of specificity. Many aspects of this complex network organization in the adult mammalian cortex are captured by an architectonic type principle, which relates structural connections to the architectonic differentiation of brain regions. In particular, the laminar patterns of projection origins are a prominent feature of structural connections that varies in a graded manner with the relative architectonic differentiation of connected areas in the adult brain. Here we show that the architectonic type principle is already apparent for the laminar origins of cortico-cortical projections in the immature cortex of the macaque monkey. We find that prenatal and neonatal laminar patterns correlate with cortical architectonic differentiation, and that the relation of laminar patterns to architectonic differences between connected areas is not substantially altered by the complete loss of visual input. Moreover, we find that the degree of change in laminar patterns that projections undergo during development varies in proportion to the relative architectonic differentiation of the connected areas. Hence, it appears that initial biases in laminar projection patterns become progressively strengthened by later developmental processes. These findings suggest that early neurogenetic processes during the formation of the brain are sufficient to establish the characteristic laminar projection patterns. This conclusion is in line with previously suggested mechanistic explanations underlying the emergence of the architectonic type principle and provides further constraints for exploring the fundamental factors that shape structural connectivity in the mammalian brain.

An architectonic type principle integrates macroscopic cortico-cortical connections with intrinsic cortical circuits of the primate brain.

The connections linking neurons within and between cerebral cortical areas form a multiscale network for communication. We review recent work relating essential features of cortico-cortical connections, such as their existence and laminar origins and terminations, to fundamental structural parameters of cortical areas, such as their distance, similarity in cytoarchitecture, defined by lamination or neuronal density, and other macroscopic and microscopic structural features. These analyses demonstrate the presence of an architectonic type principle. Across species and cortices, the essential features of cortico-cortical connections vary consistently and strongly with the cytoarchitectonic similarity of cortical areas. By contrast, in multivariate analyses such relations were not found consistently for distance, similarity of cortical thickness, or cellular morphology. Gradients of laminar cortical differentiation, as reflected in overall neuronal density, also correspond to regional variations of cellular features, forming a spatially ordered natural axis of concerted architectonic and connectional changes across the cortical sheet. The robustness of findings across mammalian brains allows cross-species predictions of the existence and laminar patterns of projections, including estimates for the human brain that are not yet available experimentally. The architectonic type principle integrates cortical connectivity and architecture across scales, with implications for computational explorations of cortical physiology and developmental mechanisms.

A Predictive Structural Model of the Primate Connectome.

Anatomical connectivity imposes strong constraints on brain function, but there is no general agreement about principles that govern its organization. Based on extensive quantitative data, we tested the power of three factors to predict connections of the primate cerebral cortex: architectonic similarity (structural model), spatial proximity (distance model) and thickness similarity (thickness model). Architectonic similarity showed the strongest and most consistent influence on connection features. This parameter was strongly associated with the presence or absence of inter-areal connections and when integrated with spatial distance, the factor allowed predicting the existence of projections with very high accuracy. Moreover, architectonic similarity was strongly related to the laminar pattern of projection origins, and the absolute number of cortical connections of an area. By contrast, cortical thickness similarity and distance were not systematically related to connection features. These findings suggest that cortical architecture provides a general organizing principle for connections in the primate brain, providing further support for the well-corroborated structural model.

A predictive model of the cat cortical connectome based on cytoarchitecture and distance.

Information processing in the brain is strongly constrained by anatomical connectivity. However, the principles governing the organization of corticocortical connections remain elusive. Here, we tested three models of relationships between the organization of cortical structure and features of connections linking 49 areas of the cat cerebral cortex. Factors taken into account were relative cytoarchitectonic differentiation ('structural model'), relative spatial position ('distance model'), or relative hierarchical position ('hierarchical model') of the areas. Cytoarchitectonic differentiation and spatial distance (themselves uncorrelated) correlated strongly with the existence of inter-areal connections, whereas no correlation was found with relative hierarchical position. Moreover, a strong correlation was observed between patterns of laminar projection origin or termination and cytoarchitectonic differentiation. Additionally, cytoarchitectonic differentiation correlated with the absolute number of corticocortical connections formed by areas, and varied characteristically between different cortical subnetworks, including a 'rich-club' module of hub areas. Thus, connections between areas of the cat cerebral cortex can, to a large part, be explained by the two independent factors of relative cytoarchitectonic differentiation and spatial distance of brain regions. As both the structural and distance model were originally formulated in the macaque monkey, their applicability in another mammalian species suggests a general principle of global cortical organization.

Brain activation during associative short-term memory maintenance is not predictive for subsequent retrieval.

Performance on working memory (WM) tasks may partially be supported by long-term memory (LTM) processing. Hence, brain activation recently being implicated in WM may actually have been driven by (incidental) LTM formation. We examined which brain regions actually support successful WM processing, rather than being confounded by LTM processes, during the maintenance and probe phase of a WM task. We administered a four-pair (faces and houses) associative delayed-match-to-sample (WM) task using event-related functional MRI (fMRI) and a subsequent associative recognition LTM task, using the same stimuli. This enabled us to analyze subsequent memory effects for both the WM and the LTM test by contrasting correctly recognized pairs with incorrect pairs for either task. Critically, with respect to the subsequent WM effect, we computed this analysis exclusively for trials that were forgotten in the subsequent LTM recognition task. Hence, brain activity associated with successful WM processing was less likely to be confounded by incidental LTM formation. The subsequent LTM effect, in contrast, was analyzed exclusively for pairs that previously had been correctly recognized in the WM task, disclosing brain regions involved in successful LTM formation after successful WM processing. Results for the subsequent WM effect showed no significantly activated brain areas for WM maintenance, possibly due to an insensitivity of fMRI to mechanisms underlying active WM maintenance. In contrast, a correct decision at WM probe was linked to activation in the "retrieval success network" (anterior and posterior midline brain structures). The subsequent LTM analyses revealed greater activation in left dorsolateral prefrontal cortex and posterior parietal cortex in the early phase of the maintenance stage. No supra-threshold activation was found during the WM probe. Together, we obtained clearer insights in which brain regions support successful WM and LTM without the potential confound of the respective memory system.

Towards a "canonical" agranular cortical microcircuit.

Based on regularities in the intrinsic microcircuitry of cortical areas, variants of a "canonical" cortical microcircuit have been proposed and widely adopted, particularly in computational neuroscience and neuroinformatics. However, this circuit is founded on striate cortex, which manifests perhaps the most extreme instance of cortical organization, in terms of a very high density of cells in highly differentiated cortical layers. Most other cortical regions have a less well differentiated architecture, stretching in gradients from the very dense eulaminate primary cortical areas to the other extreme of dysgranular and agranular areas of low density and poor laminar differentiation. It is unlikely for the patterns of inter- and intra-laminar connections to be uniform in spite of strong variations of their structural substrate. This assumption is corroborated by reports of divergence in intrinsic circuitry across the cortex. Consequently, it remains an important goal to define local microcircuits for a variety of cortical types, in particular, agranular cortical regions. As a counterpoint to the striate microcircuit, which may be anchored in an exceptional cytoarchitecture, we here outline a tentative microcircuit for agranular cortex. The circuit is based on a synthesis of the available literature on the local microcircuitry in agranular cortical areas of the rodent brain, investigated by anatomical and electrophysiological approaches. A central observation of these investigations is a weakening of interlaminar inhibition as cortical cytoarchitecture becomes less distinctive. Thus, our study of agranular microcircuitry revealed deviations from the well-known "canonical" microcircuit established for striate cortex, suggesting variations in the intrinsic circuitry across the cortex that may be functionally relevant.

Differential roles for medial prefrontal and medial temporal cortices in schema-dependent encoding: from congruent to incongruent.

Information that is congruent with prior knowledge is generally remembered better than incongruent information. This effect of congruency on memory has been attributed to a facilitatory influence of activated schemas on memory encoding and consolidation processes, and hypothesised to reflect a shift between processing in medial temporal lobes (MTL) towards processing in medial prefrontal cortex (mPFC). To investigate this shift, we used functional magnetic resonance imaging (fMRI) to compare brain activity during paired-associate encoding across three levels of subjective congruency of the association with prior knowledge. Participants indicated how congruent they found an object-scene pair during scanning, and were tested on item and associative recognition memory for these associations one day later. Behaviourally, we found a monotonic increase in memory performance with increasing congruency for both item and associative memory. Moreover, as hypothesised, encoding-related activity in mPFC increased linearly with increasing congruency, whereas MTL showed the opposite pattern of increasing encoding-related activity with decreasing congruency. Additionally, mPFC showed increased functional connectivity with a region in the ventral visual stream, presumably related to the binding of visual representations. These results support predictions made by a recent neuroscientific framework concerning the effects of schema on memory. Specifically, our findings show that enhanced memory for more congruent information is mediated by the mPFC, which is hypothesised to guide integration of new information into a pre-existing schema represented in cortical areas, while memory for more incongruent information relies instead on automatic encoding of arbitrary associations by the MTL.