MOTIVATION: Agent-based modeling is an indispensable tool for studying complex biological systems. However, existing simulation platforms do not always take full advantage of modern hardware and often have a field-specific software design. RESULTS: We present a novel simulation platform called BioDynaMo that alleviates both of these problems. BioDynaMo features a modular and high-performance simulation engine. We demonstrate that BioDynaMo can be used to simulate use cases in: neuroscience, oncology and epidemiology. For each use case, we validate our findings with experimental data or an analytical solution. Our performance results show that BioDynaMo performs up to three orders of magnitude faster than the state-of-the-art baselines. This improvement makes it feasible to simulate each use case with one billion agents on a single server, showcasing the potential BioDynaMo has for computational biology research. AVAILABILITY AND IMPLEMENTATION: BioDynaMo is an open-source project under the Apache 2.0 license and is available at www.biodynamo.org. Instructions to reproduce the results are available in the supplementary information. SUPPLEMENTARY INFORMATION: Available at https://doi.org/10.5281/zenodo.5121618.

Axonal morphology displays large variability and complexity, yet the canonical regularities of the cortex suggest that such wiring is based on the repeated initiation of a small set of genetically encoded rules. Extracting underlying developmental principles can hence shed light on what genetically encoded instructions must be available during cortical development. Within a generative model, we investigate growth rules for axonal branching patterns in cat area 17, originating from the lateral geniculate nucleus of the thalamus. This target area of synaptic connections is characterized by extensive ramifications and a high bouton density, characteristics thought to preserve the spatial resolution of receptive fields and to enable connections for the ocular dominance columns. We compare individual and global statistics, such as a newly introduced length-weighted asymmetry index and the global segment-length distribution, of generated and biological branching patterns as the benchmark for growth rules. We show that the proposed model surpasses the statistical accuracy of the Galton-Watson model, which is the most commonly employed model for biological growth processes. In contrast to the Galton-Watson model, our model can recreate the log-normal segment-length distribution of the experimental dataset and is considerably more accurate in recreating individual axonal morphologies. To provide a biophysical interpretation for statistical quantifications of the axonal branching patterns, the generative model is ported into the physically accurate simulation framework of Cx3D. In this 3D simulation environment we demonstrate how the proposed growth process can be formulated as an interactive process between genetic growth rules and chemical cues in the local environment.

The prenatal development of neural circuits must provide sufficient configuration to support at least a set of core postnatal behaviors. Although knowledge of various genetic and cellular aspects of development is accumulating rapidly, there is less systematic understanding of how these various processes play together in order to construct such functional networks. Here we make some steps toward such understanding by demonstrating through detailed simulations how a competitive co-operative ('winner-take-all', WTA) network architecture can arise by development from a single precursor cell. This precursor is granted a simplified gene regulatory network that directs cell mitosis, differentiation, migration, neurite outgrowth and synaptogenesis. Once initial axonal connection patterns are established, their synaptic weights undergo homeostatic unsupervised learning that is shaped by wave-like input patterns. We demonstrate how this autonomous genetically directed developmental sequence can give rise to self-calibrated WTA networks, and compare our simulation results with biological data.

Current models of embryological development focus on intracellular processes such as gene expression and protein networks, rather than on the complex relationship between subcellular processes and the collective cellular organization these processes support. We have explored this collective behavior in the context of neocortical development, by modeling the expansion of a small number of progenitor cells into a laminated cortex with layer and cell type specific projections. The developmental process is steered by a formal language analogous to genomic instructions, and takes place in a physically realistic three-dimensional environment. A common genome inserted into individual cells control their individual behaviors, and thereby gives rise to collective developmental sequences in a biologically plausible manner. The simulation begins with a single progenitor cell containing the artificial genome. This progenitor then gives rise through a lineage of offspring to distinct populations of neuronal precursors that migrate to form the cortical laminae. The precursors differentiate by extending dendrites and axons, which reproduce the experimentally determined branching patterns of a number of different neuronal cell types observed in the cat visual cortex. This result is the first comprehensive demonstration of the principles of self-construction whereby the cortical architecture develops. In addition, our model makes several testable predictions concerning cell migration and branching mechanisms.