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Pyramidal neurons in neocortex have complex input-output relationships that depend on their morphologies, ion channel distributions, and the nature of their inputs, but which cannot be replicated by simple integrate-and-fire models. The impedance properties of their dendritic arbors, such as resonance and phase shift, shape neuronal responses to synaptic inputs and provide intraneuronal functional maps reflecting their intrinsic dynamics and excitability. Experimental studies of dendritic impedance have shown that neocortical pyramidal tract neurons exhibit distance-dependent changes in resonance and impedance phase with respect to the soma. We, therefore, investigated how well several biophysically detailed multicompartment models of neocortical layer 5 pyramidal tract neurons reproduce the location-dependent impedance profiles observed experimentally. Each model tested here exhibited location-dependent impedance profiles, but most captured either the observed impedance amplitude or phase, not both. The only model that captured features from both incorporates hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and a shunting current, such as that produced by Twik-related acid-sensitive K + (TASK) channels. TASK-like channel density in this model was proportional to local HCN channel density. We found that although this shunting current alone is insufficient to produce resonance or realistic phase response, it modulates all features of dendritic impedance, including resonance frequencies, resonance strength, synchronous frequencies, and total inductive phase. We also explored how the interaction of HCN channel current ( I h ) and a TASK-like shunting current shape synaptic potentials and produce degeneracy in dendritic impedance profiles, wherein different combinations of I h and shunting current can produce the same impedance profile. NEW & NOTEWORTHY We simulated chirp current stimulation in the apical dendrites of 5 biophysically detailed multicompartment models of neocortical pyramidal tract neurons and found that a combination of HCN channels and TASK-like channels produced the best fit to experimental measurements of dendritic impedance. We then explored how HCN and TASK-like channels can shape the dendritic impedance as well as the voltage response to synaptic currents. 

Dendritic spikes in thin dendritic branches (basal and oblique dendrites) are traditionally inferred from spikelets measured in the cell body. Here, we used laser-spot voltage-sensitive dye imaging in cortical pyramidal neurons (rat brain slices) to investigate the voltage waveforms of dendritic potentials occurring in response to spatially restricted glutamatergic inputs. Local dendritic potentials lasted 200–500 ms and propagated to the cell body, where they caused sustained 10- to 20-mV depolarizations. Plateau potentials propagating from dendrite to soma and action potentials propagating from soma to dendrite created complex voltage waveforms in the middle of the thin basal dendrite, comprised of local sodium spikelets, local plateau potentials, and backpropagating action potentials, superimposed on each other. Our model replicated these voltage waveforms across a gradient of glutamatergic stimulation intensities. The model then predicted that somatic input resistance ( R in ) and membrane time constant (tau) may be reduced during dendritic plateau potential. We then tested these model predictions in real neurons and found that the model correctly predicted the direction of R in and tau change but not the magnitude. In summary, dendritic plateau potentials occurring in basal and oblique branches put pyramidal neurons into an activated neuronal state (“prepared state”), characterized by depolarized membrane potential and smaller but faster membrane responses. The prepared state provides a time window of 200–500 ms, during which cortical neurons are particularly excitable and capable of following afferent inputs. At the network level, this predicts that sets of cells with simultaneous plateaus would provide cellular substrate for the formation of functional neuronal ensembles. NEW & NOTEWORTHY In cortical pyramidal neurons, we recorded glutamate-mediated dendritic plateau potentials with voltage imaging and created a computer model that recreated experimental measures from dendrite and cell body. Our model made new predictions, which were then tested in experiments. Plateau potentials profoundly change neuronal state: a plateau potential triggered in one basal dendrite depolarizes the soma and shortens membrane time constant, making the cell more susceptible to firing triggered by other afferent inputs. 

What is the topic of this review?

The vagus nerve is a crucial regulator of cardiovascular homeostasis, and its activity is linked to heart health. Vagal activity originates from two brainstem nuclei: the nucleus ambiguus (fast lane) and the dorsal motor nucleus of the vagus (slow lane), nicknamed for the time scales that they require to transmit signals.

What advances does it highlight?

Computational models are powerful tools for organizing multi‐scale, multimodal data on the fast and slow lanes in a physiologically meaningful way. A strategy is laid out for how these models can guide experiments aimed at harnessing the cardiovascular health benefits of differential activation of the fast and slow lanes.

The vagus nerve is a key mediator of brain–heart signaling, and its activity is necessary for cardiovascular health. Vagal outflow stems from the nucleus ambiguus, responsible primarily for fast, beat‐to‐beat regulation of heart rate and rhythm, and the dorsal motor nucleus of the vagus, responsible primarily for slow regulation of ventricular contractility. Due to the high‐dimensional and multimodal nature of the anatomical, molecular and physiological data on neural regulation of cardiac function, data‐derived mechanistic insights have proven elusive. Elucidating insights has been complicated further by the broad distribution of the data across heart, brain and peripheral nervous system circuits. Here we lay out an integrative framework based on computational modelling for combining these disparate and multi‐scale data on the two vagal control lanes of the cardiovascular system. Newly available molecular‐scale data, particularly single‐cell transcriptomic analyses, have augmented our understanding of the heterogeneous neuronal states underlying vagally mediated fast and slow regulation of cardiac physiology. Cellular‐scale computational models built from these data sets represent building blocks that can be combined using anatomical and neural circuit connectivity, neuronal electrophysiology, and organ/organismal‐scale physiology data to create multi‐system, multi‐scale models that enablein silicoexploration of the fast versus slow lane vagal stimulation. The insights from the computational modelling and analyses will guide new experimental questions on the mechanisms regulating the fast and slow lanes of the cardiac vagus toward exploiting targeted vagal neuromodulatory activity to promote cardiovascular health.

 

Machine learning is increasingly recognized as a promising technology in the biological, biomedical, and behavioral sciences. There can be no argument that this technique is incredibly successful in image recognition with immediate applications in diagnostics including electrophysiology, radiology, or pathology, where we have access to massive amounts of annotated data. However, machine learning often performs poorly in prognosis, especially when dealing with sparse data. This is a field where classical physics-based simulation seems to remain irreplaceable. In this review, we identify areas in the biomedical sciences where machine learning and multiscale modeling can mutually benefit from one another: Machine learning can integrate physics-based knowledge in the form of governing equations, boundary conditions, or constraints to manage ill-posted problems and robustly handle sparse and noisy data; multiscale modeling can integrate machine learning to create surrogate models, identify system dynamics and parameters, analyze sensitivities, and quantify uncertainty to bridge the scales and understand the emergence of function. With a view towards applications in the life sciences, we discuss the state of the art of combining machine learning and multiscale modeling, identify applications and opportunities, raise open questions, and address potential challenges and limitations. This review serves as introduction to a special issue on Uncertainty Quantification, Machine Learning, and Data-Driven Modeling of Biological Systems that will help identify current roadblocks and areas where computational mechanics, as a discipline, can play a significant role. We anticipate that it will stimulate discussion within the community of computational mechanics and reach out to other disciplines including mathematics, statistics, computer science, artificial intelligence, biomedicine, systems biology, and precision medicine to join forces towards creating robust and efficient models for biological systems. 

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.