VIDEO ABSTRACT.

At many scales in neuroscience, appropriate mathematical models take the form of complex dynamical systems. Parameterizing such models to conform to the multitude of available experimental constraints is a global non-linear optimisation problem with a complex fitness landscape, requiring numerical techniques to find suitable approximate solutions. Stochastic optimisation approaches, such as evolutionary algorithms, have been shown to be effective, but often the setting up of such optimisations and the choice of a specific search algorithm and its parameters is non-trivial, requiring domain-specific expertise. Here we describe BluePyOpt, a Python package targeted at the broad neuroscience community to simplify this task. BluePyOpt is an extensible framework for data-driven model parameter optimisation that wraps and standardizes several existing open-source tools. It simplifies the task of creating and sharing these optimisations, and the associated techniques and knowledge. This is achieved by abstracting the optimisation and evaluation tasks into various reusable and flexible discrete elements according to established best-practices. Further, BluePyOpt provides methods for setting up both small- and large-scale optimisations on a variety of platforms, ranging from laptops to Linux clusters and cloud-based compute infrastructures. The versatility of the BluePyOpt framework is demonstrated by working through three representative neuroscience specific use cases.

Every neuron is part of a network, exerting its function by transforming multiple spatiotemporal synaptic input patterns into a single spiking output. This function is specified by the particular shape and passive electrical properties of the neuronal membrane, and the composition and spatial distribution of ion channels across its processes. For a variety of physiological or pathological reasons, the intrinsic input/output function may change during a neuron’s lifetime. This process results in high variability in the peak specific conductance of ion channels in individual neurons. The mechanisms responsible for this variability are not well understood, although there are clear indications from experiments and modeling that degeneracy and correlation among multiple channels may be involved. Here, we studied this issue in biophysical models of hippocampal CA1 pyramidal neurons and interneurons. Using a unified data-driven simulation workflow and starting from a set of experimental recordings and morphological reconstructions obtained from rats, we built and analyzed several ensembles of morphologically and biophysically accurate single cell models with intrinsic electrophysiological properties consistent with experimental findings. The results suggest that the set of conductances expressed in any given hippocampal neuron may be considered as belonging to two groups: one subset is responsible for the major characteristics of the firing behavior in each population and the other is responsible for a robust degeneracy. Analysis of the model neurons suggests several experimentally testable predictions related to the combination and relative proportion of the different conductances that should be expressed on the membrane of different types of neurons for them to fulfill their role in the hippocampus circuitry.

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The increase in complexity of computational neuron models makes the hand tuning of model parameters more difficult than ever. Fortunately, the parallel increase in computer power allows scientists to automate this tuning. Optimization algorithms need two essential components. The first one is a function that measures the difference between the output of the model with a given set of parameter and the data. This error function or fitness function makes the ranking of different parameter sets possible. The second component is a search algorithm that explores the parameter space to find the best parameter set in a minimal amount of time. In this review we distinguish three types of error functions: feature-based ones, point-by-point comparison of voltage traces and multi-objective functions. We then detail several popular search algorithms, including brute-force methods, simulated annealing, genetic algorithms, evolution strategies, differential evolution and particle-swarm optimization. Last, we shortly describe Neurofitter, a free software package that combines a phase-plane trajectory density fitness function with several search algorithms.

In realistic neuronal modeling, once the ionic channel complement has been defined, the maximum ionic conductance (Gi-max) values need to be tuned in order to match the firing pattern revealed by electrophysiological recordings. Recently, selection/mutation genetic algorithms have been proposed to efficiently and automatically tune these parameters. Nonetheless, since similar firing patterns can be achieved through different combinations of Gi-max values, it is not clear how well these algorithms approximate the corresponding properties of real cells. Here we have evaluated the issue by exploiting a unique opportunity offered by the cerebellar granule cell (GrC), which is electrotonically compact and has therefore allowed the direct experimental measurement of ionic currents. Previous models were constructed using empirical tuning of Gi-max values to match the original data set. Here, by using repetitive discharge patterns as a template, the optimization procedure yielded models that closely approximated the experimental Gi-max values. These models, in addition to repetitive firing, captured additional features, including inward rectification, near-threshold oscillations, and resonance, which were not used as features. Thus, parameter optimization using genetic algorithms provided an efficient modeling strategy for reconstructing the biophysical properties of neurons and for the subsequent reconstruction of large-scale neuronal network models.

Highlights d Open Source Brain: an online resource of standardized models of neurons and circuits d Automated 3D visualization, analysis, and simulation of models through the browser d Open source infrastructure and tools for collaborative model development and testing d Accessible, transparent, up-to-date models from different brain regions

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.