The function of the neocortex is fundamentally determined by its repeating microcircuit motif, but also by its rich, interregional connectivity. We present a data-driven computational model of the anatomy of non-barrel primary somatosensory cortex of juvenile rat, integrating whole-brain scale data while providing cellular and subcellular specificity. The model consists of 4.2 million morphologically detailed neurons, placed in a digital brain atlas. They are connected by 14.2 billion synapses, comprising local, mid-range and extrinsic connectivity. We delineated the limits of determining connectivity from neuron morphology and placement, finding that it reproduces targeting by Sst+ neurons, but requires additional specificity to reproduce targeting by PV+ and VIP+ interneurons. Globally, connectivity was characterized by local clusters tied together through hub neurons in layer 5, demonstrating how local and interegional connectivity are complicit, inseparable networks. The model is suitable for simulation-based studies, and the model is made openly available to the community.

Cortical dynamics underlie many cognitive processes and emerge from complex multiscale interactions, which are challenging to study in vivo. Large-scale, biophysically detailed models offer a tool that can complement laboratory approaches. We present a model comprising eight somatosensory cortex subregions, 4.2 million morphological and electrically detailed neurons, and 13.2 billion local and mid-range synapses. In silico tools enabled reproduction and extension of complex laboratory experiments under a single parameterization, providing strong validation. The model reproduced millisecond-precise stimulus-responses, stimulus-encoding under targeted optogenetic activation, and selective propagation of stimulus-evoked activity to downstream areas. The model’s direct correspondence with biology generated predictions about how multiscale organization shapes activity; for example, how cortical activity is shaped by high-dimensional connectivity motifs in local and mid-range connectivity, and spatial targeting rules by inhibitory subpopulations. The latter was facilitated using a rewired connectome that included specific targeting rules observed for different inhibitory neuron types in electron microscopy. The model also predicted the role of inhibitory interneuron types and different layers in stimulus encoding. Simulation tools and a large subvolume of the model are made available to enable further community-driven improvement, validation, and investigation.

Synaptic plasticity underlies the brain’s ability to learn and adapt. While experiments in brain slices have revealed mechanisms and protocols for the induction of plasticity between pairs of neurons, how these synaptic changes are coordinated in biological neuronal networks to ensure the emergence of learning remains poorly understood. Simulation and modeling have emerged as important tools to study learning in plastic networks, but have yet to achieve a scale that incorporates realistic network structure, active dendrites, and multi-synapse interactions, key determinants of synaptic plasticity. To rise to this challenge, we endowed an existing large-scale cortical network model, incorporating data-constrained dendritic processing and multi-synaptic connections, with a calcium-based model of functional plasticity that captures the diversity of excitatory connections extrapolated to in vivo-like conditions. This allowed us to study how dendrites and network structure interact with plasticity to shape stimulus representations at the microcircuit level. In our exploratory simulations, plasticity acted sparsely and specifically, firing rates and weight distributions remained stable without additional homeostatic mechanisms. At the circuit level, we found plasticity was driven by co-firing stimulus-evoked functional assemblies, spatial clustering of synapses on dendrites, and the topology of the network connectivity. As a result of the plastic changes, the network became more reliable with more stimulus-specific responses. We confirmed our testable predictions in the MICrONS datasets, an openly available electron microscopic reconstruction of a large volume of cortical tissue. Our results quantify at a large scale how the dendritic architecture and higher-order structure of cortical microcircuits play a central role in functional plasticity and provide a foundation for elucidating their role in learning.

The CA1 region of the hippocampus is one of the most studied regions of the rodent brain, thought to play an important role in cognitive functions such as memory and spatial navigation. Despite a wealth of experimental data on its structure and function, it has been challenging to integrate information obtained from diverse experimental approaches. To address this challenge, we present a community-based, full-scale in silico model of the rat CA1 that integrates a broad range of experimental data, from synapse to network, including the reconstruction of its principal afferents, the Schaffer collaterals, and a model of the effects that acetylcholine has on the system. We tested and validated each model component and the final network model, and made input data, assumptions, and strategies explicit and transparent. The unique flexibility of the model allows scientists to potentially address a range of scientific questions. In this article, we describe the methods used to set up simulations to reproduce in vitro and in vivo experiments. Among several applications in the article, we focus on theta rhythm, a prominent hippocampal oscillation associated with various behavioral correlates and use our computer model to reproduce experimental findings. Finally, we make data, code, and model available through the hippocampushub.eu portal, which also provides an extensive set of analyses of the model and a user-friendly interface to facilitate adoption and usage. This community-based model represents a valuable tool for integrating diverse experimental data and provides a foundation for further research into the complex workings of the hippocampal CA1 region.

The rapid evolution of software libraries presents a significant challenge for code generation models, which must adapt to frequent version updates while maintaining compatibility with previous versions. Existing code completion benchmarks often overlook this dynamic aspect, and the one that does consider it relies on static code prediction tasks without execution-based evaluation, offering a limited perspective on a model's practical usability. To address this gap, we introduce , a novel, manually curated dataset comprising 116 Python code completion problems, each conditioned on specific library versions and accompanied by executable unit tests. is designed to rigorously assess the ability of modern large language models (LLMs) to generate version-specific code that is not only syntactically correct but also functionally accurate upon execution. Our comprehensive evaluations reveal that state-of-the-art LLMs struggle with this task; for instance, GPT-4o achieves a pass@10 of only 39.9% (43.7% when provided with error feedback), highlighting the complexity of the problem and the limitations of current models. By providing an execution-based benchmark that emphasizes the dynamic nature of code libraries, serves as a critical tool to advance the development of more adaptable and reliable code generation models. For facilitation for further exploration of version-conditioned code generation, we make our code repository publicly accessible at .

The NEURON simulator, established in 1984 and continuously developed since, stands as the preeminent tool for neuron simulation within computational neuroscience.Its widespread adoption and compatibility with computational clusters and supercomputers underscore its pivotal role in large-scale neuronal research.However, its integration with the Python programming language has introduced complexities, particularly concerning memory management and object lifecycle.To conceal these challenges from the user and seamlessly interface with community standards for neural network representation data formats such as SONATA, we introduce BlueCelluLab.The high-level Python API simplifies the execution of neural simulations, ranging from single neurons to intricate networks, by managing complexities related to memory management and object lifecycle, thus providing a streamlined experience for users.Today, BlueCelluLab is powering various Python packages, command line interfaces, web applications, and data analysis workflows.

Artificial neural networks (ANNs) can generate useful hypotheses about neural computation, but many features of the brain are not captured by standard ANNs. Top-down feedback is a particularly notable missing feature. Its role in the brain is often debated, and it's unclear whether top-down feedback would improve an ANN's ability to model the brain. Here we develop a deep neural network model that captures the core functional properties of top down feedback in the neocortex. This feedback allows identically connected recurrent models to have different processing hierarchies based on the direction of feedforward and feedback connectivity. We then explored the functional impact of different hierarchies on audiovisual categorization tasks. We find that certain hierarchies, such as the one seen in the human brain, impart ANN models with a light visual bias similar to that seen in humans while maintaining excellent performance on all audio-visual tasks. The results further suggest that different configurations of top-down feedback make otherwise identically connected models functionally distinct from each other and from traditional feedforward only recurrent models. Altogether our findings demonstrate that top-down feedback is a relevant feature of biological brains that improves the explanatory power of ANN models in computational neuroscience. ### Competing Interest Statement The authors have declared no competing interest.

Neurons are thought to act as parts of assemblies with strong internal excitatory connectivity. Conversely, inhibition is often reduced to blanket inhibition with no targeting specificity. We analyzed the structure of excitation and inhibition in the MICrONS mm(3) dataset, an electron microscopic reconstruction of a piece of cortical tissue. We found that excitation was structured around a feed-forward flow in large non-random neuron motifs with a structure of information flow from a small number of sources to a larger number of potential targets. Inhibitory neurons connected with neurons in specific sequential positions of these motifs, implementing targeted and symmetrical competition between them. None of these trends are detectable in only pairwise connectivity, demonstrating that inhibition is structured by these large motifs. While descriptions of inhibition in cortical circuits range from non-specific blanket-inhibition to targeted, our results describe a form of targeting specificity existing in the higher-order structure of the connectome. These findings have important implications for the role of inhibition in learning and synaptic plasticity.

One of the most striking features of neocortical anatomy is the presence of extensive top-down projections into primary sensory areas. Notably, many of these top-down projections impinge on the distal apical dendrites of pyramidal neurons, where they exert a modulatory effect, altering the gain of responses. It is thought that these top-down projections carry contextual information that can help animals to resolve ambiguities in sensory data. However, it has yet to be demonstrated how such modulatory connections to the distal apical dendrites can serve this computational function. Here, we develop a computational model of pyramidal cells that integrates contextual information from top-down projections to apical compartments with sensory representations driven by bottom-up projections to basal compartments. When input stimuli are ambiguous and relevant contextual information is available, the apical feedback modulates the basal signals to recover unambiguous sensory representations. Importantly, when stimuli are unambiguous, contextual information which is irrelevant or opposes sensory evidence is appropriately ignored by the model. By generalizing the task to temporal sequences, we further show that our model can learn to integrate contextual information across time. Using layer-wise relevance propagation, we extract the importance of individual neurons to the prediction of each category, revealing that neurons that are most relevant for the overlap of categories receive the largest magnitude of top-down signals, and are necessary for solving the task. This work thus provides a proof-of-concept demonstrating how the top-down modulatory inputs to apical dendrites in sensory regions could be used by the cortex to handle the ambiguities that animals encounter in the real world.

This is the Proceedings of the ICML Expressive Vocalization (ExVo) Competition. The ExVo competition focuses on understanding and generating vocal bursts: laughs, gasps, cries, and other non-verbal vocalizations that are central to emotional expression and communication. ExVo 2022, included three competition tracks using a large-scale dataset of 59,201 vocalizations from 1,702 speakers. The first, ExVo-MultiTask, requires participants to train a multi-task model to recognize expressed emotions and demographic traits from vocal bursts. The second, ExVo-Generate, requires participants to train a generative model that produces vocal bursts conveying ten different emotions. The third, ExVo-FewShot, requires participants to leverage few-shot learning incorporating speaker identity to train a model for the recognition of 10 emotions conveyed by vocal bursts.

We present a data-driven computational model of the anatomy of non-barrel primary somatosensory cortex of juvenile rat. The modeling process is based on a previously established workflow for a single cortical column, but is extended here to build a much larger circuit in an atlas-based geometry. Neurons in the model belong to 60 different morphological types and are connected by synapses placed by two established algorithms, one modeling local connectivity determined by axo-dendritic overlap, and one for long-range connectivity between sub-regions. Long-range connectivity is defined with topographic mapping and laminar connectivity profiles, providing intrinsic feed-forward and feedback pathways. Additionally, we incorporate core- and matrix-type thalamocortical projection systems, associated with VPM and POm thalamic nuclei respectively, that enable extrinsic input. The model comprises 211712 neurons in the front limb and jaw subregions and the dysgranular zone of the Paxinos & Watson rat brain atlas, scaled down to juvenile size. It is available in the open SONATA standard and contains neuron locations and their properties (such as morphological types, cortical layer, etc.), their detailed morphologies, and synaptic connectivity associated with all systems described above. Modeled synapses are associated with their exact location in the dendritic tree, and additional anatomical parameters, such as spine length (where biologically plausible). Extrinsic synaptic connections from neurons in the remainder of non-barrel somatosensory cortex and thalamic inputs are also contained. Note that this is an anatomical model: Parameters and files related to neuronal and synaptic physiology can be found in our release of the physiological model. Please refer to the documentation of the SONATA format for information how to load and analyze the model. A jupyter notebook has been included with basic examples of how to load the data using our open-source packages NeuroM and Blue Brain SNAP. This study was supported by funding to the Blue Brain Project, a research center of the Ecole polytechnique federale de Lausanne (EPFL), from the Swiss government’s ETH Board of the Swiss Federal Institutes of Technology. RL, JPS and JL were supported by EPSRC under grant number EP/P025072/1. RL was supported by a collaboration grant from EPFL.

Anatomically and biophysically detailed data-driven neuronal models have become widely used tools for understanding and predicting the behavior and function of neurons. Due to the increasing availability of experimental data from anatomical and electrophysiological measurements as well as the growing number of computational and software tools that enable accurate neuronal modeling, there are now a large number of different models of many cell types available in the literature. These models were usually built to capture a few important or interesting properties of the given neuron type, and it is often unknown how they would behave outside their original context. In addition, there is currently no simple way of quantitatively comparing different models regarding how closely they match specific experimental observations. This limits the evaluation, re-use and further development of the existing models. Further, the development of new models could also be significantly facilitated by the ability to rapidly test the behavior of model candidates against the relevant collection of experimental data. We address these problems for the representative case of the CA1 pyramidal cell of the rat hippocampus by developing an open-source Python test suite, which makes it possible to automatically and systematically test multiple properties of models by making quantitative comparisons between the models and electrophysiological data. The tests cover various aspects of somatic behavior, and signal propagation and integration in apical dendrites. To demonstrate the utility of our approach, we applied our tests to compare the behavior of several different rat hippocampal CA1 pyramidal cell models from the ModelDB database against electrophysiological data available in the literature, and evaluated how well these models match experimental observations in different domains. We also show how we employed the test suite to aid the development of models within the European Human Brain Project (HBP), and describe the integration of the tests into the validation framework developed in the HBP, with the aim of facilitating more reproducible and transparent model building in the neuroscience community.

Voltage-sensitive dye imaging (VSDI) is a powerful technique for interrogating membrane potential dynamics in assemblies of cortical neurons, but with effective resolution limits that confound interpretation. To address this limitation, we developed an in silico model of VSDI in a biologically faithful digital reconstruction of rodent neocortical microcircuitry. Using this model, we extend previous experimental observations regarding the cellular origins of VSDI, finding that the signal is driven primarily by neurons in layers 2/3 and 5, and that VSDI measurements do not capture individual spikes. Furthermore, we test the capacity of VSD image sequences to discriminate between afferent thalamic inputs at various spatial locations to estimate a lower bound on the functional resolution of VSDI. Our approach underscores the power of a bottom-up computational approach for relating scales of cortical processing.

We propose an interactive art project to make those rendered invisible by the COVID-19 crisis and its concomitant solitude reappear through the welcome melody of laughter, and connections created and explored through advanced laughter synthesis approaches. However, the unconditional generation of the diversity of human emotional responses in high-quality auditory synthesis remains an open problem, with important implications for the application of these approaches in artistic settings. We developed LaughGANter, an approach to reproduce the diversity of human laughter using generative adversarial networks (GANs). When trained on a dataset of diverse laughter samples, LaughGANter generates diverse, high quality laughter samples, and learns a latent space suitable for emotional analysis and novel artistic applications such as latent mixing/interpolation and emotional transfer.

The anatomy and physiology of synaptic connections in rodent hippocampal CA1 have been exhaustively characterized 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 labs, 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 towards a more complete quantification of synaptic anatomy and physiology in the rodent hippocampal CA1 region.

The nervous system is notorious for its strong response evoked by a surprising sensory input, but the biophysical and anatomical underpinnings of this phenomenon are only partially understood. Here we utilized in-silico experiments of a biologically-detailed model of a neocortical microcircuit to study stimulus specific adaptation (SSA) in the auditory cortex, whereby the neuronal response adapts significantly for a repeated (“expected”) tone but not for a rare (“surprise”) tone. SSA experiments were mimicked by stimulating tonotopically-mapped thalamo-cortical afferents projecting to the microcircuit; the activity of these afferents was modeled based on our in-vivo recordings from individual thalamic neurons. The modeled microcircuit expressed naturally many experimentally-observed properties of SSA, suggesting that SSA is a general property of neocortical microcircuits. By systematically modulating circuit parameters, we found that key features of SSA depended on synergistic effects of synaptic depression, spike frequency adaptation and recurrent network connectivity. The relative contribution of each of these mechanisms in shaping SSA was explored, additional SSA-related experimental results were explained and new experiments for further studying SSA were suggested.### Competing Interest StatementThe authors have declared no competing interest.

The rapid global spread of COVID-19 has led to an unprecedented demand for effective methods to mitigate the spread of the disease, and various digital contact tracing (DCT) methods have emerged as a component of the solution. In order to make informed public health choices, there is a need for tools which allow evaluation and comparison of DCT methods. We introduce an agent-based compartmental simulator we call COVI-AgentSim, integrating detailed consideration of virology, disease progression, social contact networks, and mobility patterns, based on parameters derived from empirical research. We verify by comparing to real data that COVI-AgentSim is able to reproduce realistic COVID-19 spread dynamics, and perform a sensitivity analysis to verify that the relative performance of contact tracing methods are consistent across a range of settings. We use COVI-AgentSim to perform cost-benefit analyses comparing no DCT to: 1) standard binary contact tracing (BCT) that assigns binary recommendations based on binary test results; and 2) a rule-based method for feature-based contact tracing (FCT) that assigns a graded level of recommendation based on diverse individual features. We find all DCT methods consistently reduce the spread of the disease, and that the advantage of FCT over BCT is maintained over a wide range of adoption rates. Feature-based methods of contact tracing avert more disability-adjusted life years (DALYs) per socioeconomic cost (measured by productive hours lost). Our results suggest any DCT method can help save lives, support re-opening of economies, and prevent second-wave outbreaks, and that FCT methods are a promising direction for enriching BCT using self-reported symptoms, yielding earlier warning signals and a significantly reduced spread of the virus per socioeconomic cost.

Increasing availability of comprehensive experimental datasets and of high-performance computing resources are driving rapid growth in scale, complexity, and biological realism of computational models in neuroscience. To support construction and simulation, as well as sharing of such large-scale models, a broadly applicable, flexible, and high-performance data format is necessary. To address this need, we have developed the Scalable Open Network Architecture TemplAte (SONATA) data format. It is designed for memory and computational efficiency and works across multiple platforms. The format represents neuronal circuits and simulation inputs and outputs via standardized files and provides much flexibility for adding new conventions or extensions. SONATA is used in multiple modeling and visualization tools, and we also provide reference Application Programming Interfaces and model examples to catalyze further adoption. SONATA format is free and open for the community to use and build upon with the goal of enabling efficient model building, sharing, and reproducibility.

The cover image is based on the Research Article Optogenetic “low-theta” pacing of the septohippocampal circuit is sufficient for spatial goal finding and is influenced by behavioral state and cognitive demand by Philippe R. Mouchati et al., https://doi.org/10.1002/hipo.23248.