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

Detailed single-neuron modeling is widely used to study neuronal functions. While cellular and functional diversity across the mammalian cortex is vast, most of the available computational tools focus on a limited set of specific features characteristic of a single neuron. Here, we present a generalized automated workflow for the creation of robust electrical models and illustrate its performance by building cell models for the rat somatosensory cortex. Each model is based on a 3D morphological reconstruction and a set of ionic mechanisms. We use an evolutionary algorithm to optimize neuronal parameters to match the electrophysiological features extracted from experimental data. Then we validate the optimized models against additional stimuli and assess their generalizability on a population of similar morphologies. Compared to the state-of-the-art canonical models, our models show 5-fold improved generalizability. This versatile approach can be used to build robust models of any neuronal type.

Controlling morpho-electrophysiological variability of neurons with detailed biophysical models.

Variability, which is known to be a universal feature among biological units such as neuronal cells, holds significant importance, as, for example, it enables a robust encoding of a high volume of information in neuronal circuits and prevents hypersynchronizations. While most computational studies on electrophysiological variability in neuronal circuits were done with single-compartment neuron models, we instead focus on the variability of detailed biophysical models of neuron multi-compartmental morphologies. We leverage a Markov chain Monte Carlo method to generate populations of electrical models reproducing the variability of experimental recordings while being compatible with a set of morphologies to faithfully represent specifi morpho-electrical type. We demonstrate our approach on layer 5 pyramidal cells and study the morpho-electrical variability and in particular, find that morphological variability alone is insufficient to reproduce electrical variability. Overall, this approach provides a strong statistical basis to create detailed models of neurons with controlled variability.

Cell-type-specific densities in mouse somatosensory cortex derived from scRNA-seq and in situ RNA hybridization.

Cells in the mammalian cerebral cortex exhibit layer-dependent patterns in their distribution. Classical methods of determining cell type distributions typically employ a painstaking process of large-scale sampling and characterization of cellular composition. We found that by combining in situ hybridization (ISH) images with cell-type-specific transcriptomes, position-dependent cortical composition in P56 mouse could be estimated in the somatosensory cortex. The method uses ISH images from the Allen Institute for Brain Science. There are two novel aspects of the methodology. First, it is not necessary to select a subset of genes that are particular for a cell type of interest, nor is it necessary to only use ISH images with low variability among samples. Second, the method also compensated for differences in soma size and incompleteness of the transcriptomes. The soma size compensation is particularly important in order to obtain quantitative estimates since relying on bulk expression alone would overestimate the contribution of larger cells. Predicted distributions of broader classes of cell types agreed with literature distributions. The primary result is that there is a high degree of substructure in the distribution of transcriptomic types beyond the resolution of layers. Furthermore, transcriptomic cell types each exhibited characteristic soma size distributions. Results suggest that the method could also be employed to assign transcriptomic cell types to well-aligned image sets in the entire brain.

Thalamic control of sensory processing and spindles in a biophysical somatosensory thalamoreticular circuit model of wakefulness and sleep.

Thalamoreticular circuitry plays a key role in arousal, attention, cognition, and sleep spindles, and is linked to several brain disorders. A detailed computational model of mouse somatosensory thalamus and thalamic reticular nucleus has been developed to capture the properties of over 14,000 neurons connected by 6 million synapses. The model recreates the biological connectivity of these neurons, and simulations of the model reproduce multiple experimental findings in different brain states. The model shows that inhibitory rebound produces frequency-selective enhancement of thalamic responses during wakefulness. We find that thalamic interactions are responsible for the characteristic waxing and waning of spindle oscillations. In addition, we find that changes in thalamic excitability control spindle frequency and their incidence. The model is made openly available to provide a new tool for studying the function and dysfunction of the thalamoreticular circuitry in various brain states.

Mapping of morpho-electric features to molecular identity of cortical inhibitory neurons.

Knowledge of the cell-type-specific composition of the brain is useful in order to understand the role of each cell type as part of the network. Here, we estimated the composition of the whole cortex in terms of well characterized morphological and electrophysiological inhibitory neuron types (me-types). We derived probabilistic me-type densities from an existing atlas of molecularly defined cell-type densities in the mouse cortex. We used a well-established me-type classification from rat somatosensory cortex to populate the cortex. These me-types were well characterized morphologically and electrophysiologically but they lacked molecular marker identity labels. To extrapolate this missing information, we employed an additional dataset from the Allen Institute for Brain Science containing molecular identity as well as morphological and electrophysiological data for mouse cortical neurons. We first built a latent space based on a number of comparable morphological and electrical features common to both data sources. We then identified 19 morpho-electrical clusters that merged neurons from both datasets while being molecularly homogeneous. The resulting clusters best mirror the molecular identity classification solely using available morpho-electrical features. Finally, we stochastically assigned a molecular identity to a me-type neuron based on the latent space cluster it was assigned to. The resulting mapping was used to derive inhibitory me-types densities in the cortex.

Overexpression of UCP4 in astrocytic mitochondria prevents multilevel dysfunctions in a mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is becoming increasingly prevalent worldwide. It represents one of the greatest medical challenges as no pharmacologic treatments are available to prevent disease progression. Astrocytes play crucial functions within neuronal circuits by providing metabolic and functional support, regulating interstitial solute composition, and modulating synaptic transmission. In addition to these physiological functions, growing evidence points to an essential role of astrocytes in neurodegenerative diseases like AD. Early-stage AD is associated with hypometabolism and oxidative stress. Contrary to neurons that are vulnerable to oxidative stress, astrocytes are particularly resistant to mitochondrial dysfunction and are therefore more resilient cells. In our study, we leveraged astrocytic mitochondrial uncoupling and examined neuronal function in the 3xTg AD mouse model. We overexpressed the mitochondrial uncoupling protein 4 (UCP4), which has been shown to improve neuronal survival in vitro. We found that this treatment efficiently prevented alterations of hippocampal metabolite levels observed in AD mice, along with hippocampal atrophy and reduction of basal dendrite arborization of subicular neurons. This approach also averted aberrant neuronal excitability observed in AD subicular neurons and preserved episodic-like memory in AD mice assessed in a spatial recognition task. These findings show that targeting astrocytes and their mitochondria is an effective strategy to prevent the decline of neurons facing AD-related stress at the early stages of the disease.

Ultraliser: a framework for creating multiscale, high-fidelity and geometrically realistic 3D models for in silico neuroscience.

Ultraliser is a neuroscience-specific software framework capable of creating accurate and biologically realistic 3D models of complex neuroscientific structures at intracellular (e.g. mitochondria and endoplasmic reticula), cellular (e.g. neurons and glia) and even multicellular scales of resolution (e.g. cerebral vasculature and minicolumns). Resulting models are exported as triangulated surface meshes and annotated volumes for multiple applications in in silico neuroscience, allowing scalable supercomputer simulations that can unravel intricate cellular structure-function relationships. Ultraliser implements a high-performance and unconditionally robust voxelization engine adapted to create optimized watertight surface meshes and annotated voxel grids from arbitrary non-watertight triangular soups, digitized morphological skeletons or binary volumetric masks. The framework represents a major leap forward in simulation-based neuroscience, making it possible to employ high-resolution 3D structural models for quantification of surface areas and volumes, which are of the utmost importance for cellular and system simulations. The power of Ultraliser is demonstrated with several use cases in which hundreds of models are created for potential application in diverse types of simulations. Ultraliser is publicly released under the GNU GPL3 license on GitHub (BlueBrain/Ultraliser). SIGNIFICANCE: There is crystal clear evidence on the impact of cell shape on its signaling mechanisms. Structural models can therefore be insightful to realize the function; the more realistic the structure can be, the further we get insights into the function. Creating realistic structural models from existing ones is challenging, particularly when needed for detailed subcellular simulations. We present Ultraliser, a neuroscience-dedicated framework capable of building these structural models with realistic and detailed cellular geometries that can be used for simulations.

Strong and reliable synaptic communication between pyramidal neurons in adult human cerebral cortex.

Synaptic transmission constitutes the primary mode of communication between neurons. It is extensively studied in rodent but not human neocortex. We characterized synaptic transmission between pyramidal neurons in layers 2 and 3 using neurosurgically resected human middle temporal gyrus (MTG, Brodmann area 21), which is part of the distributed language circuitry. We find that local connectivity is comparable with mouse layer 2/3 connections in the anatomical homologue (temporal association area), but synaptic connections in human are 3-fold stronger and more reliable (0% vs 25% failure rates, respectively). We developed a theoretical approach to quantify properties of spinous synapses showing that synaptic conductance and voltage change in human dendritic spines are 3-4-folds larger compared with mouse, leading to significant NMDA receptor activation in human unitary connections. This model prediction was validated experimentally by showing that NMDA receptor activation increases the amplitude and prolongs decay of unitary excitatory postsynaptic potentials in human but not in mouse connections. Since NMDA-dependent recurrent excitation facilitates persistent activity (supporting working memory), our data uncovers cortical microcircuit properties in human that may contribute to language processing in MTG.

A method to estimate the cellular composition of the mouse brain from heterogeneous datasets.

The mouse brain contains a rich diversity of inhibitory neuron types that have been characterized by their patterns of gene expression. However, it is still unclear how these cell types are distributed across the mouse brain. We developed a computational method to estimate the densities of different inhibitory neuron types across the mouse brain. Our method allows the unbiased integration of diverse and disparate datasets into one framework to predict inhibitory neuron densities for uncharted brain regions. We constrained our estimates based on previously computed brain-wide neuron densities, gene expression data from in situ hybridization image stacks together with a wide range of values reported in the literature. Using constrained optimization, we derived coherent estimates of cell densities for the different inhibitory neuron types. We estimate that 20.3% of all neurons in the mouse brain are inhibitory. Among all inhibitory neurons, 18% predominantly express parvalbumin (PV), 16% express somatostatin (SST), 3% express vasoactive intestinal peptide (VIP), and the remainder 63% belong to the residual GABAergic population. We find that our density estimations improve as more literature values are integrated. Our pipeline is extensible, allowing new cell types or data to be integrated as they become available. The data, algorithms, software, and results of our pipeline are publicly available and update the Blue Brain Cell Atlas. This work therefore leverages the research community to collectively converge on the numbers of each cell type in each brain region.

Optimum trajectory learning in musculoskeletal systems with model predictive control and deep reinforcement learning.

From the computational point of view, musculoskeletal control is the problem of controlling high degrees of freedom and dynamic multi-body system that is driven by redundant muscle units. A critical challenge in the control perspective of skeletal joints with antagonistic muscle pairs is finding methods robust to address this ill-posed nonlinear problem. To address this computational problem, we implemented a twofold optimization and learning framework to be specialized in addressing the redundancies in the muscle control . In the first part, we used model predictive control to obtain energy efficient skeletal trajectories to mimick human movements. The second part is to use deep reinforcement learning to obtain a sequence of stimulus to be given to muscles in order to obtain the skeletal trajectories with muscle control. We observed that the desired stimulus to muscles is only efficiently constructed by integrating the state and control input in a closed-loop setting as it resembles the proprioceptive integration in the spinal cord circuits. In this work, we showed how a variety of different reference trajectories can be obtained with optimal control and how these reference trajectories are mapped to the musculoskeletal control with deep reinforcement learning. Starting from the characteristics of human arm movement to obstacle avoidance experiment, our simulation results confirm the capabilities of our optimization and learning framework for a variety of dynamic movement trajectories. In summary, the proposed framework is offering a pipeline to complement the lack of experiments to record human motion-capture data as well as study the activation range of muscles to replicate the specific trajectory of interest. Using the trajectories from optimal control as a reference signal for reinforcement learning implementation has allowed us to acquire optimum and human-like behaviour of the musculoskeletal system which provides a framework to study human movement in-silico experiments. The present framework can also allow studying upper-arm rehabilitation with assistive robots given that one can use healthy subject movement recordings as reference to work on the control architecture of assistive robotics in order to compensate behavioural deficiencies. Hence, the framework opens to possibility of replicating or complementing labour-intensive, time-consuming and costly experiments with human subjects in the field of movement studies and digital twin of rehabilitation.

A calcium-based plasticity model for predicting long-term potentiation and depression in the neocortex.

Pyramidal cells (PCs) form the backbone of the layered structure of the neocortex, and plasticity of their synapses is thought to underlie learning in the brain. However, such long-term synaptic changes have been experimentally characterized between only a few types of PCs, posing a significant barrier for studying neocortical learning mechanisms. Here we introduce a model of synaptic plasticity based on data-constrained postsynaptic calcium dynamics, and show in a neocortical microcircuit model that a single parameter set is sufficient to unify the available experimental findings on long-term potentiation (LTP) and long-term depression (LTD) of PC connections. In particular, we find that the diverse plasticity outcomes across the different PC types can be explained by cell-type-specific synaptic physiology, cell morphology and innervation patterns, without requiring type-specific plasticity. Generalizing the model to in vivo extracellular calcium concentrations, we predict qualitatively different plasticity dynamics from those observed in vitro. This work provides a first comprehensive null model for LTP/LTD between neocortical PC types in vivo, and an open framework for further developing models of cortical synaptic plasticity.

Reconstruction of the Hippocampus.

The hippocampus is a widely studied brain region thought to play an important role in higher cognitive functions such as learning, memory, and navigation. The amount of data on this region increases every day and delineates a complex and fragmented picture, but an integrated understanding of hippocampal function remains elusive. Computational methods can help to move the research forward, and reconstructing a full-scale model of the hippocampus is a challenging yet feasible task that the research community should undertake.In this chapter, we present strategies for reconstructing a large-scale model of the hippocampus. Based on a previously published approach to reconstruct and simulate brain tissue, which is also explained in Chap. 10 , we discuss the characteristics of the hippocampus in the light of its special anatomical and physiological features, data availability, and existing large-scale hippocampus models. A large-scale model of the hippocampus is a compound model of several building blocks: ion channels, morphologies, single cell models, connections, synapses. We discuss each of those building blocks separately and discuss how to merge them back and simulate the resulting network model.

Computational synthesis of cortical dendritic morphologies.

Neuronal morphologies provide the foundation for the electrical behavior of neurons, the connectomes they form, and the dynamical properties of the brain. Comprehensive neuron models are essential for defining cell types, discerning their functional roles, and investigating brain-disease-related dendritic alterations. However, a lack of understanding of the principles underlying neuron morphologies has hindered attempts to computationally synthesize morphologies for decades. We introduce a synthesis algorithm based on a topological descriptor of neurons, which enables the rapid digital reconstruction of entire brain regions from few reference cells. This topology-guided synthesis generates dendrites that are statistically similar to biological reconstructions in terms of morpho-electrical and connectivity properties and offers a significant opportunity to investigate the links between neuronal morphology and brain function across different spatiotemporal scales. Synthesized cortical networks based on structurally altered dendrites associated with diverse brain pathologies revealed principles linking branching properties to the structure of large-scale networks.

Representing stimulus information in an energy metabolism pathway.

We explored a computational model of astrocytic energy metabolism and demonstrated the theoretical plausibility that this type of pathway might be capable of coding information about stimuli in addition to its known functions in cellular energy and carbon budgets. Simulation results indicate that glycogenolytic glycolysis triggered by activation of adrenergic receptors can capture the intensity and duration features of a neuromodulator waveform and can respond in a dose-dependent manner, including non-linear state changes that are analogous to action potentials. We show how this metabolic pathway can translate information about external stimuli to production profiles of energy-carrying molecules such as lactate with a precision beyond simple signal transduction or non-linear amplification. The results suggest the operation of a metabolic state-machine from the spatially discontiguous yet interdependent metabolite elements. Such metabolic pathways might be well-positioned to code an additional level of salient information about a cell's environmental demands to impact its function. Our hypothesis has implications for the computational power and energy efficiency of the brain.

A Standardized Brain Molecular Atlas: A Resource for Systems Modeling and Simulation.

Accurate molecular concentrations are essential for reliable analyses of biochemical networks and the creation of predictive models for molecular and systems biology, yet protein and metabolite concentrations used in such models are often poorly constrained or irreproducible. Challenges of using data from different sources include conflicts in nomenclature and units, as well as discrepancies in experimental procedures, data processing and implementation of the model. To obtain a consistent estimate of protein and metabolite levels, we integrated and normalized data from a large variety of sources to calculate Adjusted Molecular Concentrations. We found a high degree of reproducibility and consistency of many molecular species across brain regions and cell types, consistent with tight homeostatic regulation. We demonstrated the value of this normalization with differential protein expression analyses related to neurodegenerative diseases, brain regions and cell types. We also used the results in proof-of-concept simulations of brain energy metabolism. The standardized Brain Molecular Atlas overcomes the obstacles of missing or inconsistent data to support systems biology research and is provided as a resource for biomolecular modeling.

The Role of Hub Neurons in Modulating Cortical Dynamics.

Many neurodegenerative diseases are associated with the death of specific neuron types in particular brain regions. What makes the death of specific neuron types particularly harmful for the integrity and dynamics of the respective network is not well understood. To start addressing this question we used the most up-to-date biologically realistic dense neocortical microcircuit (NMC) of the rodent, which has reconstructed a volume of 0.3 mm3 and containing 31,000 neurons, ∼37 million synapses, and 55 morphological cell types arranged in six cortical layers. Using modern network science tools, we identified hub neurons in the NMC, that are connected synaptically to a large number of their neighbors and systematically examined the impact of abolishing these cells. In general, the structural integrity of the network is robust to cells' attack; yet, attacking hub neurons strongly impacted the small-world topology of the network, whereas similar attacks on random neurons have a negligible effect. Such hub-specific attacks are also impactful on the network dynamics, both when the network is at its spontaneous synchronous state and when it was presented with synchronized thalamo-cortical visual-like input. We found that attacking layer 5 hub neurons is most harmful to the structural and functional integrity of the NMC. The significance of our results for understanding the role of specific neuron types and cortical layers for disease manifestation is discussed.

Morphology, physiology and synaptic connectivity of local interneurons in the mouse somatosensory thalamus.

The thalamic reticular nucleus (TRN) neurons, projecting across the external medullary lamina, have long been considered to be the only significant source of inhibition of the somatosensory ventral posterior (VP) nuclei of the thalamus. Here we report for the first time effective local inhibition and disinhibition in the VP. Inhibitory interneurons were found in GAD67-GFP-expressing mice and studied using in vitro multiple patch clamp. Inhibitory interneurons have expansive bipolar or tripolar morphologies, reach across most of the VP nucleus and display low threshold bursting behaviour. They form triadic and non-triadic synaptic connections onto thalamocortical relay neurons and other interneurons, mediating feedforward inhibition and disinhibition. Synaptic inputs arrive before those expected from the TRN neurons, suggesting that local inhibition plays an early and significant role in the functioning of the somatosensory thalamus. KEY POINTS: The physiology and structure of local interneurons in the mouse somatosensory thalamus is described for the first time. Inhibitory interneurons have extensive dendritic arborization providing significant local dendro-dendritic inhibition in the somatosensory thalamus. Triadic and non-triadic synaptic connectivity onto thalamic relay neurons and other interneurons provides both local feedforward inhibition and disinhibition. Interneurons of the somatosensory thalamus provide inhibition before the thalamic reticular nucleus, suggesting they play an important role in sensory perception.

Digital Reconstruction of the Neuro-Glia-Vascular Architecture.

Astrocytes connect the vasculature to neurons mediating the supply of nutrients and biochemicals. They are involved in a growing number of physiological and pathophysiological processes that result from biophysical, physiological, and molecular interactions in this neuro-glia-vascular ensemble (NGV). The lack of a detailed cytoarchitecture severely restricts the understanding of how they support brain function. To address this problem, we used data from multiple sources to create a data-driven digital reconstruction of the NGV at micrometer anatomical resolution. We reconstructed 0.2 mm3 of the rat somatosensory cortex with 16 000 morphologically detailed neurons, 2500 protoplasmic astrocytes, and its microvasculature. The consistency of the reconstruction with a wide array of experimental measurements allows novel predictions of the NGV organization, allowing the anatomical reconstruction of overlapping astrocytic microdomains and the quantification of endfeet connecting each astrocyte to the vasculature, as well as the extent to which they cover the latter. Structural analysis showed that astrocytes optimize their positions to provide uniform vascular coverage for trophic support and signaling. However, this optimal organization rapidly declines as their density increases. The NGV digital reconstruction is a resource that will enable a better understanding of the anatomical principles and geometric constraints, which govern how astrocytes support brain function.