Reconstruction and Simulation of Neocortical Microcircuitry.

We present a first-draft digital reconstruction of the microcircuitry of somatosensory cortex of juvenile rat. The reconstruction uses cellular and synaptic organizing principles to algorithmically reconstruct detailed anatomy and physiology from sparse experimental data. An objective anatomical method defines a neocortical volume of 0.29 ± 0.01 mm(3) containing ~31,000 neurons, and patch-clamp studies identify 55 layer-specific morphological and 207 morpho-electrical neuron subtypes. When digitally reconstructed neurons are positioned in the volume and synapse formation is restricted to biological bouton densities and numbers of synapses per connection, their overlapping arbors form ~8 million connections with ~37 million synapses. Simulations reproduce an array of in vitro and in vivo experiments without parameter tuning. Additionally, we find a spectrum of network states with a sharp transition from synchronous to asynchronous activity, modulated by physiological mechanisms. The spectrum of network states, dynamically reconfigured around this transition, supports diverse information processing strategies. PAPERCLIP: VIDEO ABSTRACT.

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.

Recent Advances at the Interface of Neuroscience and Artificial Neural Networks.

Biological neural networks adapt and learn in diverse behavioral contexts. Artificial neural networks (ANNs) have exploited biological properties to solve complex problems. However, despite their effectiveness for specific tasks, ANNs are yet to realize the flexibility and adaptability of biological cognition. This review highlights recent advances in computational and experimental research to advance our understanding of biological and artificial intelligence. In particular, we discuss critical mechanisms from the cellular, systems, and cognitive neuroscience fields that have contributed to refining the architecture and training algorithms of ANNs. Additionally, we discuss how recent work used ANNs to understand complex neuronal correlates of cognition and to process high throughput behavioral data.

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.

Computational Concepts for Reconstructing and Simulating Brain Tissue.

It has previously been shown that it is possible to derive a new class of biophysically detailed brain tissue models when one computationally analyzes and exploits the interdependencies or the multi-modal and multi-scale organization of the brain. These reconstructions, sometimes referred to as digital twins, enable a spectrum of scientific investigations. Building such models has become possible because of increase in quantitative data but also advances in computational capabilities, algorithmic and methodological innovations. This chapter presents the computational science concepts that provide the foundation to the data-driven approach to reconstructing and simulating brain tissue as developed by the EPFL Blue Brain Project, which was originally applied to neocortical microcircuitry and extended to other brain regions. Accordingly, the chapter covers aspects such as a knowledge graph-based data organization and the importance of the concept of a dataset release. We illustrate algorithmic advances in finding suitable parameters for electrical models of neurons or how spatial constraints can be exploited for predicting synaptic connections. Furthermore, we explain how in silico experimentation with such models necessitates specific addressing schemes or requires strategies for an efficient simulation. The entire data-driven approach relies on the systematic validation of the model. We conclude by discussing complementary strategies that not only enable judging the fidelity of the model but also form the basis for its systematic refinements.

Data-driven integration of hippocampal CA1 synaptic physiology in silico.

The anatomy and physiology of monosynaptic connections in rodent hippocampal CA1 have been extensively studied in recent decades. Yet, the resulting knowledge remains disparate and difficult to reconcile. Here, we present a data-driven approach to integrate the current state-of-the-art knowledge on the synaptic anatomy and physiology of rodent hippocampal CA1, including axo-dendritic innervation patterns, number of synapses per connection, quantal conductances, neurotransmitter release probability, and short-term plasticity into a single coherent resource. First, we undertook an extensive literature review of paired recordings of hippocampal neurons and compiled experimental data on their synaptic anatomy and physiology. The data collected in this manner is sparse and inhomogeneous due to the diversity of experimental techniques used by different groups, which necessitates the need for an integrative framework to unify these data. To this end, we extended a previously developed workflow for the neocortex to constrain a unifying in silico reconstruction of the synaptic physiology of CA1 connections. Our work identifies gaps in the existing knowledge and provides a complementary resource toward a more complete quantification of synaptic anatomy and physiology in the rodent hippocampal CA1 region.

Objective Morphological Classification of Neocortical Pyramidal Cells.

A consensus on the number of morphologically different types of pyramidal cells (PCs) in the neocortex has not yet been reached, despite over a century of anatomical studies, due to the lack of agreement on the subjective classifications of neuron types, which is based on expert analyses of neuronal morphologies. Even for neurons that are visually distinguishable, there is no common ground to consistently define morphological types. The objective classification of PCs can be achieved with methods from algebraic topology, and the dendritic arborization is sufficient for the reliable identification of distinct types of cortical PCs. Therefore, we objectively identify 17 types of PCs in the rat somatosensory cortex. In addition, we provide a solution to the challenging problem of whether 2 similar neurons belong to different types or to a continuum of the same type. Our topological classification does not require expert input, is stable, and helps settle the long-standing debate on whether cell-types are discrete or continuous morphological variations of each other.

Morphological Diversity Strongly Constrains Synaptic Connectivity and Plasticity.

Synaptic connectivity between neurons is naturally constrained by the anatomical overlap of neuronal arbors, the space on the axon available for synapses, and by physiological mechanisms that form synapses at a subset of potential synapse locations. What is not known is how these constraints impact emergent connectivity in a circuit with diverse morphologies. We investigated the role of morphological diversity within and across neuronal types on emergent connectivity in a model of neocortical microcircuitry. We found that the average overlap between the dendritic and axonal arbors of different types of neurons determines neuron-type specific patterns of distance-dependent connectivity, severely constraining the space of possible connectomes. However, higher order connectivity motifs depend on the diverse branching patterns of individual arbors of neurons belonging to the same type. Morphological diversity across neuronal types, therefore, imposes a specific structure on first order connectivity, and morphological diversity within neuronal types imposes a higher order structure of connectivity. We estimate that the morphological constraints resulting from diversity within and across neuron types together lead to a 10-fold reduction of the entropy of possible connectivity configurations, revealing an upper bound on the space explored by structural plasticity.

Data-driven multiscale computational models of cortical and subcortical regions.

Data-driven computational models of neurons, synapses, microcircuits, and mesocircuits have become essential tools in modern brain research. The goal of these multiscale models is to integrate and synthesize information from different levels of brain organization, from cellular properties, dendritic excitability, and synaptic dynamics to microcircuits, mesocircuits, and ultimately behavior. This article surveys recent advances in the genesis of data-driven computational models of mammalian neural networks in cortical and subcortical areas. I discuss the challenges and opportunities in developing data-driven multiscale models, including the need for interdisciplinary collaborations, the importance of model validation and comparison, and the potential impact on basic and translational neuroscience research. Finally, I highlight future directions and emerging technologies that will enable more comprehensive and predictive data-driven models of brain function and dysfunction.

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.

Intrinsic morphological diversity of thick-tufted layer 5 pyramidal neurons ensures robust and invariant properties of in silico synaptic connections.

The morphology of neocortical pyramidal neurons is not only highly characteristic but also displays an intrinsic diversity that renders each neuron morphologically unique. We investigated the significance of this intrinsic morphological diversity in in silico networks composed of thick-tufted layer 5 (TTL5) pyramidal neurons, by comparing the in silico and in vitro properties of TTL5 synaptic connections. The synaptic locations of in silico connections were determined by placing 3D reconstructed TTL5 neurons randomly in a volume equivalent to that of layer 5 in the juvenile rat somatosensory cortex and using a 'collision-detection' algorithm to identify the incidental loci of axo-dendritic overlap. The activation time of the modelled synapses and their biophysical properties were characterized based on experimental measurements. We found that the anatomical loci of synapses and the physiological properties of the somatically recorded EPSPs closely matched those recorded experimentally without the need for any fine-tuning. Furthermore, perturbations to both the physiological or anatomical parameters of the model did not alter the average physiological properties of the population of modelled synaptic connections. This microcircuit-level robust behaviour was due to the intrinsic diversity of the morphology of pyramidal neurons in the microcircuit. We conclude that synaptic transmission in a network of TTL5 neurons is highly invariant across microcircuits suggesting that intrinsic diversity is a mechanism to ensure the same average synaptic properties in different animals of the same species. Finally, we show that the average physiological properties of the TTL5 microcircuit are surprisingly robust to anatomical and physiological perturbations also partly due to the intrinsic diversity of pyramidal neuron morphology.

Informing deep neural networks by multiscale principles of neuromodulatory systems.

Our brains have evolved the ability to configure and adapt their processing states to match the unique challenges of acting and learning in diverse environments and behavioral contexts. In biological nervous systems, such state specification and adaptation arise in part from neuromodulators, including acetylcholine, noradrenaline, serotonin, and dopamine, whose diffuse release fine-tunes neuronal and synaptic dynamics and plasticity to complement the behavioral context in real-time. Despite the demonstrated effectiveness of deep neural networks for specific tasks, they remain relatively inflexible at generalizing across tasks or adapting to ever-changing behavioral demands. In this article, we provide an overview of neuromodulatory systems and their relationship to emerging pertinent principles in deep neural networks. We further outline opportunities for the integration of neuromodulatory principles into deep neural networks, towards endowing artificial intelligence with a key ingredient underlying the flexibility and learning capability of biological systems.

A Computational Model of Loss of Dopaminergic Cells in Parkinson's Disease Due to Glutamate-Induced Excitotoxicity.

Parkinson's disease (PD) is a neurodegenerative disease associated with progressive and inexorable loss of dopaminergic cells in Substantia Nigra pars compacta (SNc). Although many mechanisms have been suggested, a decisive root cause of this cell loss is unknown. A couple of the proposed mechanisms, however, show potential for the development of a novel line of PD therapeutics. One of these mechanisms is the peculiar metabolic vulnerability of SNc cells compared to other dopaminergic clusters; the other is the SubThalamic Nucleus (STN)-induced excitotoxicity in SNc. To investigate the latter hypothesis computationally, we developed a spiking neuron network-model of SNc-STN-GPe system. In the model, prolonged stimulation of SNc cells by an overactive STN leads to an increase in 'stress' variable; when the stress in a SNc neuron exceeds a stress threshold, the neuron dies. The model shows that the interaction between SNc and STN involves a positive-feedback due to which, an initial loss of SNc cells that crosses a threshold causes a runaway-effect, leading to an inexorable loss of SNc cells, strongly resembling the process of neurodegeneration. The model further suggests a link between the two aforementioned mechanisms of SNc cell loss. Our simulation results show that the excitotoxic cause of SNc cell loss might initiate by weak-excitotoxicity mediated by energy deficit, followed by strong-excitotoxicity, mediated by a disinhibited STN. A variety of conventional therapies were simulated to test their efficacy in slowing down SNc cell loss. Among them, glutamate inhibition, dopamine restoration, subthalamotomy and deep brain stimulation showed superior neuroprotective-effects in the proposed model.

Cellular, Synaptic and Network Effects of Acetylcholine in the Neocortex.

The neocortex is densely innervated by basal forebrain (BF) cholinergic neurons. Long-range axons of cholinergic neurons regulate higher-order cognitive function and dysfunction in the neocortex by releasing acetylcholine (ACh). ACh release dynamically reconfigures neocortical microcircuitry through differential spatiotemporal actions on cell-types and their synaptic connections. At the cellular level, ACh release controls neuronal excitability and firing rate, by hyperpolarizing or depolarizing target neurons. At the synaptic level, ACh impacts transmission dynamics not only by altering the presynaptic probability of release, but also the magnitude of the postsynaptic response. Despite the crucial role of ACh release in physiology and pathophysiology, a comprehensive understanding of the way it regulates the activity of diverse neocortical cell-types and synaptic connections has remained elusive. This review aims to summarize the state-of-the-art anatomical and physiological data to develop a functional map of the cellular, synaptic and microcircuit effects of ACh in the neocortex of rodents and non-human primates, and to serve as a quantitative reference for those intending to build data-driven computational models on the role of ACh in governing brain states.

Estimating the Readily-Releasable Vesicle Pool Size at Synaptic Connections in the Neocortex.

Previous studies based on the 'Quantal Model' for synaptic transmission suggest that neurotransmitter release is mediated by a single release site at individual synaptic contacts in the neocortex. However, recent studies seem to contradict this hypothesis and indicate that multi-vesicular release (MVR) could better explain the synaptic response variability observed in vitro. In this study we present a novel method to estimate the number of release sites per synapse, also known as the size of the readily releasable pool (NRRP), from paired whole-cell recordings of connections between layer 5 thick tufted pyramidal cell (L5_TTPC) in the juvenile rat somatosensory cortex. Our approach extends the work of Loebel et al. (2009) by leveraging a recently published data-driven biophysical model of neocortical tissue. Using this approach, we estimated NRRP to be between two to three for synaptic connections between L5_TTPCs. To constrain NRRP values for other connections in the microcircuit, we developed and validated a generalization approach using published data on the coefficient of variation (CV) of the amplitudes of post-synaptic potentials (PSPs) from literature and comparing them against in silico experiments. Our study predicts that transmitter release at synaptic connections in the neocortex could be mediated by MVR and provides a data-driven approach to constrain the MVR model parameters in the microcircuit.

Data-Driven Modeling of Cholinergic Modulation of Neural Microcircuits: Bridging Neurons, Synapses and Network Activity.

Neuromodulators, such as acetylcholine (ACh), control information processing in neural microcircuits by regulating neuronal and synaptic physiology. Computational models and simulations enable predictions on the potential role of ACh in reconfiguring network activity. As a prelude into investigating how the cellular and synaptic effects of ACh collectively influence emergent network dynamics, we developed a data-driven framework incorporating phenomenological models of the physiology of cholinergic modulation of neocortical cells and synapses. The first-draft models were integrated into a biologically detailed tissue model of neocortical microcircuitry to investigate the effects of levels of ACh on diverse neuron types and synapses, and consequently on emergent network activity. Preliminary simulations from the framework, which was not tuned to reproduce any specific ACh-induced network effects, not only corroborate the long-standing notion that ACh desynchronizes spontaneous network activity, but also predict that a dose-dependent activation of ACh gives rise to a spectrum of neocortical network activity. We show that low levels of ACh, such as during non-rapid eye movement (nREM) sleep, drive microcircuit activity into slow oscillations and network synchrony, whereas high ACh concentrations, such as during wakefulness and REM sleep, govern fast oscillations and network asynchrony. In addition, spontaneous network activity modulated by ACh levels shape spike-time cross-correlations across distinct neuronal populations in strikingly different ways. These effects are likely due to the regulation of neurons and synapses caused by increasing levels of ACh, which enhances cellular excitability and decreases the efficacy of local synaptic transmission. We conclude by discussing future directions to refine the biological accuracy of the framework, which will extend its utility and foster the development of hypotheses to investigate the role of neuromodulators in neural information processing.

Rich cell-type-specific network topology in neocortical microcircuitry.

Uncovering structural regularities and architectural topologies of cortical circuitry is vital for understanding neural computations. Recently, an experimentally constrained algorithm generated a dense network reconstruction of a ∼0.3-mm3 volume from juvenile rat somatosensory neocortex, comprising ∼31,000 cells and ∼36 million synapses. Using this reconstruction, we found a small-world topology with an average of 2.5 synapses separating any two cells and multiple cell-type-specific wiring features. Amounts of excitatory and inhibitory innervations varied across cells, yet pyramidal neurons maintained relatively constant excitation/inhibition ratios. The circuit contained highly connected hub neurons belonging to a small subset of cell types and forming an interconnected cell-type-specific rich club. Certain three-neuron motifs were overrepresented, matching recent experimental results. Cell-type-specific network properties were even more striking when synaptic strength and sign were considered in generating a functional topology. Our systematic approach enables interpretation of microconnectomics 'big data' and provides several experimentally testable predictions.

Anatomy and physiology of the thick-tufted layer 5 pyramidal neuron.

The thick-tufted layer 5 (TTL5) pyramidal neuron is one of the most extensively studied neuron types in the mammalian neocortex and has become a benchmark for understanding information processing in excitatory neurons. By virtue of having the widest local axonal and dendritic arborization, the TTL5 neuron encompasses various local neocortical neurons and thereby defines the dimensions of neocortical microcircuitry. The TTL5 neuron integrates input across all neocortical layers and is the principal output pathway funneling information flow to subcortical structures. Several studies over the past decades have investigated the anatomy, physiology, synaptology, and pathophysiology of the TTL5 neuron. This review summarizes key discoveries and identifies potential avenues of research to facilitate an integrated and unifying understanding on the role of a central neuron in the neocortex.

An algorithm to predict the connectome of neural microcircuits.

Experimentally mapping synaptic connections, in terms of the numbers and locations of their synapses and estimating connection probabilities, is still not a tractable task, even for small volumes of tissue. In fact, the six layers of the neocortex contain thousands of unique types of synaptic connections between the many different types of neurons, of which only a handful have been characterized experimentally. Here we present a theoretical framework and a data-driven algorithmic strategy to digitally reconstruct the complete synaptic connectivity between the different types of neurons in a small well-defined volume of tissue-the micro-scale connectome of a neural microcircuit. By enforcing a set of established principles of synaptic connectivity, and leveraging interdependencies between fundamental properties of neural microcircuits to constrain the reconstructed connectivity, the algorithm yields three parameters per connection type that predict the anatomy of all types of biologically viable synaptic connections. The predictions reproduce a spectrum of experimental data on synaptic connectivity not used by the algorithm. We conclude that an algorithmic approach to the connectome can serve as a tool to accelerate experimental mapping, indicating the minimal dataset required to make useful predictions, identifying the datasets required to improve their accuracy, testing the feasibility of experimental measurements, and making it possible to test hypotheses of synaptic connectivity.