Modeling and Simulation of Neocortical Micro- and Mesocircuitry. Part I: Anatomy

Abstract

The function of the neocortex is fundamentally determined by its repeating microcircuit motif, but also by its rich, hierarchical, interregional structure with a highly specific laminar architecture. The last decade has seen the emergence of extensive new data sets on anatomy and connectivity at the whole brain scale, providing promising new directions for studies of cortical function that take into account the inseparability of whole-brain and microcircuit architectures. Here, we present a data-driven computational model of the anatomy of non-barrel primary somatosensory cortex of juvenile rat, which integrates whole-brain scale data while providing cellular and subcellular specificity. This multiscale integration was achieved by building the morphologically detailed model of cortical circuitry embedded within a volumetric, digital brain atlas. The model consists of 4.2 million morphologically detailed neurons belonging to 60 different morphological types, placed in the nonbarrel subregions of the Paxinos and Watson atlas. They are connected by 13.2 billion synapses determined by axo-dendritic overlap, comprising local connectivity and long-range connectivity defined by topographic mappings between subregions and laminar axonal projection profiles, both parameterized by whole brain data sets. Additionally, we incorporated core- and matrix-type thalamocortical projection systems, associated with sensory and higher-order extrinsic inputs, respectively. An analysis of the modeled synaptic connectivity revealed a highly nonrandom topology with substantial structural differences but also synergy between local and long-range connectivity. Long-range connections featured a more divergent structure with a comparatively small group of neurons serving as hubs to distribute excitation to far away locations. Taken together with analyses at different spatial granularities, these results support the notion that local and interregional connectivity exist on a spectrum of scales, rather than as separate and distinct networks, as is commonly assumed. Finally, we predicted how the emergence of primary sensory cortical maps is constrained by the anatomy of thalamo-cortical projections. A subvolume of the model comprising 211,712 neurons in the front limb, jaw, and dysgranular zone has been made freely and openly available to the community.

Cortical cell assemblies and their underlying connectivity: anin silicostudy

“…In terms of spatial distribution of assembly neurons, the early assemblies appear more “patchy” (small distinguishable clusters), and by visual inspection can be mapped back to the locations of VPM fibers corresponding to the stimuli that activated them (Figures 2B and 3C top). Moreover, their layer profile mimics that of VPM fiber innervation (Meyer et al, 2010; Reimann et al, 2022b) (Supplementary Figure S4A), indicating that these assemblies may be determined by direct thalamic innervation. On the other hand, the late assembly neurons are more evenly distributed, and cover the entire surface of the simulated circuit, even beyond the range of VPM fiber centers, and are found mostly in deeper layers of the cortex.…”

“…The most recent version of the detailed, large-scale cortical microcircuit model of Markram et al (2015) was used for the in silico experiments in this study. Updates on its anatomy, e.g., atlas-based cell densities are described in Reimann et al (2022b). Updates on the physiology of single cell models and multi-vesicular release of synapses are described in Reva et al (2022) and Barros-Zulaica et al (2019).…”

A universal workflow for creation, validation and generalization of detailed neuronal models

“…A total of 1, 015 reconstructed rat morphologies ([Reimann et al, 2022, Ramaswamy et al, 2015], expanded dataset from Markram et al [2015]) have been curated and repaired for cut plane missing data, following the procedure outlined in Markram et al [2015]. In that study a cloning strategy was applied by successive application of rescaling operations and jitter of section lengths and bifurcations angles.…”

“…For this purpose we used a total of 1, 015 reconstructed and manually corrected morphologies of SSCx young rat cortex for the generalization routine (see Methods). The population of morphologies was artificially increased to 141, 733 by a cloning procedure on the reconstructions [Reimann et al, 2022]. Given their m-type, morphologies were then attributed to one of the possible morpho-electro combinations [Markram et al, 2015[Markram et al, , 2004] (see Methods), yielding 366,926 models, of which 233,941 passed generalization.…”

Neuromodulatory organization in the developing rat somatosensory cortex

“…Our in silico neuromodulation model was implemented in a digital microcircuit extracted from a large-scale model covering the entirety of the non-barrel primary somatosensory cortex of the juvenile rat (Reimann et al, 2022). The microcircuit is 26 times smaller than the whole S1 region and comprises 163528 cells arranged in 7 cortical columns stacked horizontally.…”