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Phase amplitude coupling (PAC) between slow and fast oscillations is found throughout the brain and plays important functional roles. Its neural origin remains unclear. Experimental findings are often puzzling and sometimes contradictory. Most computational models rely on pairs of pacemaker neurons or neural populations tuned at different frequencies to produce PAC. Here, using a data-driven model of a hippocampal microcircuit, we demonstrate that PAC can naturally emerge from a single feedback mechanism involving an inhibitory and excitatory neuron population, which interplay to generate theta frequency periodic bursts of higher frequency gamma. The model suggests the conditions under which a CA1 microcircuit can operate to elicit theta-gamma PAC, and highlights the modulatory role of OLM and PVBC cells, recurrent connectivity, and short term synaptic plasticity. Surprisingly, the results suggest the experimentally testable prediction that the generation of the slow population oscillation requires the fast one and cannot occur without it.

Fueled by breakthrough technology developments, the biological, biomedical, and behavioral sciences are now collecting more data than ever before. There is a critical need for time- and cost-efficient strategies to analyze and interpret these data to advance human health. The recent rise of machine learning as a powerful technique to integrate multimodality, multifidelity data, and reveal correlations between intertwined phenomena presents a special opportunity in this regard. However, machine learning alone ignores the fundamental laws of physics and can result in ill-posed problems or non-physical solutions. Multiscale modeling is a successful strategy to integrate multiscale, multiphysics data and uncover mechanisms that explain the emergence of function. However, multiscale modeling alone often fails to efficiently combine large datasets from different sources and different levels of resolution. Here we demonstrate that machine learning and multiscale modeling can naturally complement each other to create robust predictive models that integrate the underlying physics to manage ill-posed problems and explore massive design spaces. We review the current literature, highlight applications and opportunities, address open questions, and discuss potential challenges and limitations in four overarching topical areas: ordinary differential equations, partial differential equations, data-driven approaches, and theory-driven approaches. Towards these goals, we leverage expertise in applied mathematics, computer science, computational biology, biophysics, biomechanics, engineering mechanics, experimentation, and medicine. Our multidisciplinary perspective suggests that integrating machine learning and multiscale modeling can provide new insights into disease mechanisms, help identify new targets and treatment strategies, and inform decision making for the benefit of human health.

Biophysical modeling of neuronal networks helps to integrate and interpret rapidly growing and disparate experimental datasets at multiple scales. The NetPyNE tool (www.netpyne.org) provides both programmatic and graphical interfaces to develop data-driven multiscale network models in NEURON. NetPyNE clearly separates model parameters from implementation code. Users provide specifications at a high level via a standardized declarative language, for example connectivity rules, to create millions of cell-to-cell connections. NetPyNE then enables users to generate the NEURON network, run efficiently parallelized simulations, optimize and explore network parameters through automated batch runs, and use built-in functions for visualization and analysis – connectivity matrices, voltage traces, spike raster plots, local field potentials, and information theoretic measures. NetPyNE also facilitates model sharing by exporting and importing standardized formats (NeuroML and SONATA). NetPyNE is already being used to teach computational neuroscience students and by modelers to investigate brain regions and phenomena. The approximately 100 billion neurons in our brain are responsible for everything we do and experience. Experiments aimed at discovering how these cells encode and process information generate vast amounts of data. These data span multiple scales, from interactions between individual molecules to coordinated waves of electrical activity that spread across the entire brain surface. To understand how the brain works, we must combine and make sense of these diverse types of information. Computational modeling provides one way of doing this. Using equations, we can calculate the chemical and electrical changes that take place in neurons. We can then build models of neurons and neural circuits that reproduce the patterns of activity seen in experiments. Exploring these models can provide insights into how the brain itself works. Several software tools are available to simulate neural circuits, but none provide an easy way of incorporating data that span different scales, from molecules to cells to networks. Moreover, most of the models require familiarity with computer programming. Dura-Bernal et al. have now developed a new software tool called NetPyNE, which allows users without programming expertise to build sophisticated models of brain circuits. It features a user-friendly interface for defining the properties of the model at molecular, cellular and circuit scales. It also provides an easy and automated method to identify the properties of the model that enable it to reproduce experimental data. Finally, NetPyNE makes it possible to run the model on supercomputers and offers a variety of ways to visualize and analyze the resulting output. Users can save the model and output in standardized formats, making them accessible to as many people as possible. Researchers in labs across the world have used NetPyNE to study different brain regions, phenomena and diseases. The software also features in courses that introduce students to neurobiology and computational modeling. NetPyNE can help to interpret isolated experimental findings, and also makes it easier to explore interactions between brain activity at different scales. This will enable researchers to decipher how the brain encodes and processes information, and ultimately could make it easier to understand and treat brain disorders.

Predictive processing theories conceptualize neocortical feedback as conveying expectations and contextual attention signals derived from internal cortical models, playing an essential role in the perception and interpretation of sensory information. However, few predictive processing frameworks outline concrete mechanistic roles for the corticothalamic (CT) feedback from layer 6 (L6), despite the fact that the number of CT axons is an order of magnitude greater than that of feedforward thalamocortical (TC) axons. Here we review the functional architecture of CT circuits and propose a mechanism through which L6 could regulate thalamic firing modes (burst, tonic) to detect unexpected inputs. Using simulations in a model of a TC cell, we show how the CT feedback could support prediction-based input discrimination in TC cells by promoting burst firing. This type of CT control can enable the thalamic circuit to implement spatial and context selective attention mechanisms. The proposed mechanism generates specific experimentally testable hypotheses. We suggest that the L6 CT feedback allows the thalamus to detect deviance from predictions of internal cortical models, thereby supporting contextual attention and routing operations, a far more powerful role than traditionally assumed.

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 need for reproducible, credible, multiscale biological modeling has led to the development of standardized simulation platforms, such as the widely-used NEURON environment for computational neuroscience. Developing and maintaining NEURON over several decades has required attention to the competing needs of backwards compatibility, evolving computer architectures, the addition of new scales and physical processes, accessibility to new users, and efficiency and flexibility for specialists. In order to meet these challenges, we have now substantially modernized NEURON, providing continuous integration, an improved build system and release workflow, and better documentation. With the help of a new source-to-source compiler of the NMODL domain-specific language we have enhanced NEURON's ability to run efficiently, via the CoreNEURON simulation engine, on a variety of hardware platforms, including GPUs. Through the implementation of an optimized in-memory transfer mechanism this performance optimized backend is made easily accessible to users, providing training and model-development paths from laptop to workstation to supercomputer and cloud platform. Similarly, we have been able to accelerate NEURON's reaction-diffusion simulation performance through the use of just-in-time compilation. We show that these efforts have led to a growing developer base, a simpler and more robust software distribution, a wider range of supported computer architectures, a better integration of NEURON with other scientific workflows, and substantially improved performance for the simulation of biophysical and biochemical models.

The primary somatosensory cortex (S1) of mammals is critically important in the perception of touch and related sensorimotor behaviors. In 2015, the Blue Brain Project developed a groundbreaking rat S1 microcircuit simulation with over 31,000 neurons with 207 morpho-electrical neuron types, and 37 million synapses, incorporating anatomical and physiological information from a wide range of experimental studies. We have implemented this highly-detailed and complex S1 model in NetPyNE, using the data available in the Neocortical Microcircuit Collaboration Portal. NetPyNE provides a Python high-level interface to NEURON and allows defining complicated multiscale models using an intuitive declarative standardized language. It also facilitates running parallel simulations, automates the optimization and exploration of parameters using supercomputers, and provides a wide range of built-in analysis functions. This will make the S1 model more accessible and simpler to scale, modify and extend in order to explore research questions or interconnect to other existing models. Despite some implementation differences, the NetPyNE model preserved the original cell morphologies, electrophysiological responses and spatial distribution for all 207 cell types; and the connectivity properties of all 1941 pathways, including synaptic dynamics and short-term plasticity (STP). The NetPyNE S1 simulations produced reasonable physiological firing rates and activity patterns across all populations. The network generated a 1 Hz oscillation comparable to the original model in vitro-like state. By then reducing the extracellular calcium concentration, the model reproduced the original S1 in vivo-like states with asynchronous activity. These results validate the original study using a new modeling tool. Simulated local field potentials (LFPs) exhibited realistic oscillatory patterns and features, including distance- and frequency-dependent attenuation. The model was extended by adding thalamic circuits, including 6 distinct thalamic populations with intrathalamic, thalamocortical and corticothalamic connectivity derived from experimental data. The thalamic model reproduced single known cell and circuit-level dynamics, including burst and tonic firing modes and oscillatory patterns, providing a more realistic input to cortex and enabling study of thalamocortical interactions. Overall, our work provides a widely accessible, data-driven and biophysically-detailed model of the somatosensory thalamocortical circuits that can be employed as a community tool for researchers to study neural dynamics, function and disease.

Data-driven models of neurons and circuits are important for understanding how the properties of membrane conductances, synapses, dendrites, and the anatomical connectivity between neurons generate the complex dynamical behaviors of brain circuits in health and disease. However, the inherent complexity of these biological processes makes the construction and reuse of biologically detailed models challenging. A wide range of tools have been developed to aid their construction and simulation, but differences in design and internal representation act as technical barriers to those who wish to use data-driven models in their research workflows. NeuroML, a model description language for computational neuroscience, was developed to address this fragmentation in modeling tools. Since its inception, NeuroML has evolved into a mature community standard that encompasses a wide range of model types and approaches in computational neuroscience. It has enabled the development of a large ecosystem of interoperable open-source software tools for the creation, visualization, validation, and simulation of data-driven models. Here, we describe how the NeuroML ecosystem can be incorporated into research workflows to simplify the construction, testing, and analysis of standardized models of neural systems, and supports the FAIR (Findability, Accessibility, Interoperability, and Reusability) principles, thus promoting open, transparent and reproducible science.

Recent models of spiking neuronal networks have been trained to perform behaviors in static environments using a variety of learning rules, with varying degrees of biological realism. Most of these models have not been tested in dynamic visual environments where models must make predictions on future states and adjust their behavior accordingly. The models using these learning rules are often treated as black boxes, with little analysis on circuit architectures and learning mechanisms supporting optimal performance. Here we developed visual/motor spiking neuronal network models and trained them to play a virtual racket-ball game using several reinforcement learning algorithms inspired by the dopaminergic reward system. We systematically investigated how different architectures and circuit-motifs (feed-forward, recurrent, feedback) contributed to learning and performance. We also developed a new biologically-inspired learning rule that significantly enhanced performance, while reducing training time. Our models included visual areas encoding game inputs and relaying the information to motor areas, which used this information to learn to move the racket to hit the ball. Neurons in the early visual area relayed information encoding object location and motion direction across the network. Neuronal association areas encoded spatial relationships between objects in the visual scene. Motor populations received inputs from visual and association areas representing the dorsal pathway. Two populations of motor neurons generated commands to move the racket up or down. Model-generated actions updated the environment and triggered reward or punishment signals that adjusted synaptic weights so that the models could learn which actions led to reward. Here we demonstrate that our biologically-plausible learning rules were effective in training spiking neuronal network models to solve problems in dynamic environments. We used our models to dissect the circuit architectures and learning rules most effective for learning. Our model shows that learning mechanisms involving different neural circuits produce similar performance in sensory-motor tasks. In biological networks, all learning mechanisms may complement one another, accelerating the learning capabilities of animals. Furthermore, this also highlights the resilience and redundancy in biological systems.

When standard optimization methods fail to find a satisfactory solution for a parameter fitting problem, a tempting recourse is to adjust parameters manually. While tedious, this approach can be surprisingly powerful in terms of achieving optimal or near-optimal solutions. This paper outlines an optimization algorithm, Adaptive Stochastic Descent (ASD), that has been designed to replicate the essential aspects of manual parameter fitting in an automated way. Specifically, ASD uses simple principles to form probabilistic assumptions about (a) which parameters have the greatest effect on the objective function, and (b) optimal step sizes for each parameter. We show that for a certain class of optimization problems (namely, those with a moderate to large number of scalar parameter dimensions, especially if some dimensions are more important than others), ASD is capable of minimizing the objective function with far fewer function evaluations than classic optimization methods, such as the Nelder-Mead nonlinear simplex, Levenberg-Marquardt gradient descent, simulated annealing, and genetic algorithms. As a case study, we show that ASD outperforms standard algorithms when used to determine how resources should be allocated in order to minimize new HIV infections in Swaziland.