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Introduction: In addition to gap junction conduction, recent reports implicate possible ephaptic coupling contributions to action potential (AP) propagation between successive adjacent cardiomyocytes. Here, AP generation in an active cell, withdraws Na + from, creating a negative potential within, ephaptic spaces between the participating membranes, activating the initially quiescent neighbouring cardiomyocyte. However, sustainable ephaptic transmission requires subsequent complete recovery of the ephaptic charge difference. We explore physical contributions of passive electrodiffusive ion exchange with the remaining extracellular space to this recovery for the first time. Materials and Methods: Computational, finite element, analysis examined limiting, temporal and spatial, ephaptic [Na + ], [Cl - ], and the consequent Gaussian charge differences and membrane potential recovery patterns following a Δ V ∼130 mV AP upstroke at physiological (37°C) temperatures. This incorporated Nernst-Planck formalisms into equations for the time-dependent spatial concentration gradient profiles. Results: Mammalian atrial, ventricular and purkinje cardiomyocyte ephaptic junctions were modelled by closely apposed circularly symmetric membranes, specific capacitance 1 μF cm -2 , experimentally reported radii a = 8,000, 12,000 and 40,000 nm respectively and ephaptic axial distance w = 20 nm. This enclosed an ephaptic space containing principal ions initially at normal extracellular [Na + ] = 153.1 mM and [Cl - ] = 145.8 mM, respective diffusion coefficients D Na = 1.3 × 10 9 and D Cl = 2 × 10 9 nm 2 s -1 . Stable, concordant computational solutions were confirmed exploring ≤1,600 nm mesh sizes and Δ t ≤0.08 ms stepsize intervals. The corresponding membrane voltage profile changes across the initially quiescent membrane were obtainable from computed, graphically represented a and w -dependent ionic concentration differences adapting Gauss's flux theorem. Further simulations explored biological variations in ephaptic dimensions, membrane anatomy, and diffusion restrictions within the ephaptic space. Atrial, ventricular and Purkinje cardiomyocytes gave 40, 180 and 2000 ms 99.9% recovery times, with 720 or 360 ms high limits from doubling ventricular radius or halving diffusion coefficient. Varying a , and D Na and D Cl markedly affected recovery time-courses with logarithmic and double-logarithmic relationships, Varying w exerted minimal effects. Conclusion: We thereby characterise the properties of, and through comparing atrial, ventricular and purkinje recovery times with interspecies in vivo background cardiac cycle duration data, (blue whale ∼2000, human∼90, Etruscan shrew, ∼40 ms) can determine physical limits to, electrodiffusive contributions to ephaptic recovery., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Morris, Bardsley, Salvage, Jackson, Matthews and Huang.)

Myelination enhances the conduction velocity of action potentials (AP) and increases energy efficiency. Thick myelin sheaths are typically found on large-distance axonal connections or in fast-spiking interneurons, which are critical for synchronizing neuronal networks during gamma-band oscillations. Loss of myelin sheath is associated with multiple alterations in axonal architecture leading to impaired AP propagation. While numerous studies are devoted to the effects of demyelination on conduction velocity, the metabolic effects and the consequences for network synchronization have not been investigated. Here we present a unifying computational model for electrophysiology and metabolism of the myelinated axon. The computational model suggested that demyelination not only decreases the AP speed but AP propagation in demyelinated axons requires compensatory processes like mitochondrial mass increase and a switch from saltatory to continuous propagation to rescue axon functionality at the cost of reduced AP propagation speed and increased energy expenditure. Indeed, these predictions were proven to be true in a culture model of demyelination where the pharmacologically-induced loss of myelin was associated with increased oxygen consumption rates, and a significant broadening of bandwidth as well as a decrease in the power of gamma oscillations.

Computational modeling has contributed significantly to present understanding of cardiac electrophysiology including cardiac conduction, excitation-contraction coupling, and the effects and side-effects of drugs. However, the accuracy of in silico analysis of electrochemical wave dynamics in cardiac tissue is limited by the homogenization procedure (spatial averaging) intrinsic to standard continuum models of conduction. Averaged models cannot resolve the intricate dynamics in the vicinity of individual cardiomyocytes simply because the myocytes are not present in these models. Here we demonstrate how recently developed mathematical models based on representing every myocyte can significantly increase the accuracy, and thus the utility of modeling electrophysiological function and dysfunction in collections of coupled cardiomyocytes. The present gold standard of numerical simulation for cardiac electrophysiology is based on the bidomain model. In the bidomain model, the extracellular (E) space, the cell membrane (M) and the intracellular (I) space are all assumed to be present everywhere in the tissue. Consequently, it is impossible to study biophysical processes taking place close to individual myocytes. The bidomain model represents the tissue by averaging over several hundred myocytes and this inherently limits the accuracy of the model. In our alternative approach both E, M, and I are represented in the model which is therefore referred to as the EMI model. The EMI model approach allows for detailed analysis of the biophysical processes going on in functionally important spaces very close to individual myocytes, although at the cost of significantly increased CPU-requirements., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Jæger, Edwards, Giles and Tveito.)

Significance: Systematic studies of the physiological outputs induced by infrared (IR)-mediated inhibition of motor nerves can provide guidance for therapeutic applications and offer critical insights into IR light modulation of complex neural networks. Aim: We explore the IR-mediated inhibition of action potentials (APs) that either propagate along single axons or are initiated locally and their downstream synaptic transmission responses. Approach: APs were evoked locally by two-electrode current clamp or at a distance for propagating APs. The neuromuscular transmission was recorded with intracellular electrodes in muscle cells or macro-patch pipettes on terminal bouton clusters. Results: IR light pulses completely and reversibly terminate the locally initiated APs firing at low frequencies, which leads to blocking of the synaptic transmission. However, IR light pulses only suppress but do not block the amplitude and duration of propagating APs nor locally initiated APs firing at high frequencies. Such suppressed APs do not influence the postsynaptic responses at a distance. While the suppression of AP amplitude and duration is similar for propagating and locally evoked APs, only the former exhibits a 7% to 21% increase in the maximum time derivative of the AP rising phase. Conclusions: The suppressed APs of motor axons can resume their waveforms after passing the localized IR light illumination site, leaving the muscular and synaptic responses unchanged. IR-mediated modulation on propagating and locally evoked APs should be considered as two separate models for axonal and somatic modulations., (© The Authors. Published by SPIE under a Creative Commons Attribution 4.0 Unported License. Distribution or reproduction of this work in whole or in part requires full attribution of the original publication, including its DOI.)

Understanding the role of axons in neuronal information processing is a fundamental task in neuroscience. Over the last years, sophisticated patch-clamp investigations have provided unexpected and exciting data on axonal phenomena and functioning, but there is still a need for methods to investigate full axonal arbors at sufficient throughput. Here, we present a new method for the simultaneous mapping of the axonal arbors of a large number of individual neurons, which relies on their extracellular signals that have been recorded with high-density microelectrode arrays (HD-MEAs). The segmentation of axons was performed based on the local correlation of extracellular signals. Comparison of the results with both, ground truth and receiver operator characteristics, shows that the new segmentation method outperforms previously used methods. Using a standard HD-MEA, we mapped the axonal arbors of 68 neurons in <6 h. The fully automated method can be extended to new generations of HD-MEAs with larger data output and is estimated to provide data of axonal arbors of thousands of neurons within recording sessions of a few hours.

During early postnatal life, speed up of signal propagation through many central and peripheral neurons has been associated with an increase in axon diameter or/and myelination. Especially in unmyelinated axons postnatal adjustments of axonal membrane conductances is potentially a third mechanism but solid evidence is lacking. Here, we show that axonal action potential (AP) conduction velocity in the Drosophila giant fiber (GF) interneuron, which is required for fast long-distance signal conduction through the escape circuit, is increased by 80% during the first day of adult life. Genetic manipulations indicate that this postnatal increase in AP conduction velocity in the unmyelinated GF axon is likely owed to adjustments of ion channel expression or properties rather than axon diameter increases. Specifically, targeted RNAi knock-down of either Para fast voltage-gated sodium, Shaker potassium ( Kv1 homologue), or surprisingly, L-type like calcium channels counteracts postnatal increases in GF axonal conduction velocity. By contrast, the calcium-dependent potassium channel Slowpoke (BK) is not essential for postnatal speeding, although it also significantly increases conduction velocity. Therefore, we identified multiple ion channels that function to support fast axonal AP conduction velocity, but only a subset of these are regulated during early postnatal life to maximize conduction velocity. Despite its large diameter (∼7 µm) and postnatal regulation of multiple ionic conductances, mature GF axonal conduction velocity is still 20-60 times slower than that of vertebrate Aβ sensory axons and α motoneurons, thus unraveling the limits of long-range information transfer speed through invertebrate circuits., (Copyright © 2019 Kadas et al.)

Axons convey information in neuronal circuits via reliable conduction of action potentials (APs) from the axon initial segment (AIS) to the presynaptic terminals. Recent experimental findings increasingly evidence that the axonal function is not limited to the simple transmission of APs. Advances in subcellular-resolution recording techniques have shown that axons display activity-dependent modulation in spike shape and conduction velocity, which influence synaptic strength and latency. We briefly review here, how recent methodological developments facilitate the understanding of the axon physiology. We included the three most common methods, i.e., genetically encoded voltage imaging (GEVI), subcellular patch-clamp and high-density microelectrode arrays (HD-MEAs). We then describe the potential of using HD-MEAs in studying axonal physiology in more detail. Due to their robustness, amenability to high-throughput and high spatiotemporal resolution, HD-MEAs can provide a direct functional electrical readout of single cells and cellular ensembles at subcellular resolution. HD-MEAs can, therefore, be employed in investigating axonal pathologies, the effects of large-scale genomic interventions (e.g., with RNAi or CRISPR) or in compound screenings. A combination of extracellular microelectrode arrays (MEAs), intracellular microelectrodes and optical imaging may potentially reveal yet unexplored repertoires of axonal functions.

The action potential is a regenerative electrical phenomenon observed on excitable cell membranes that allows the propagation of signals without attenuation. It is the cornerstone of neurophysiology. This chapter is a review of the action potential and its relationship to the signals that are studied in clinical neurophysiology. The first section traces the history of key scientific discoveries over the last 250 years that have led to our present-day understanding of the electrical properties of nerve and muscle. The second section considers the molecular and biophysical mechanisms that are responsible for the electrical potentials that can be measured across all eukaryotic cell membranes, but specifically in neurons, nerves, and muscle. Mechanisms underlying propagation action potentials within the nervous system are also examined. The concluding section is a brief overview of the normal "macroscopic" signals that are commonly recorded from the central and peripheral nervous system, and how they are derived from action potentials., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Modeling is a useful tool for investigating various biophysical characteristics of neurons. Recent simulation studies of propagating action potentials (spike conduction) along axons include the investigation of neuronal activity evoked by electrical stimulation from implantable prosthetic devices. In contrast to point-neuron simulations, where a large variety of models are readily available, Hodgkin-Huxley-type conductance-based models have been almost the only option for simulating axonal spike conduction, as simpler models cannot faithfully replicate the waveforms of propagating spikes. Since the amount of available physiological data, especially in humans, is usually limited, calibration, and justification of the large number of parameters of a complex model is generally difficult. In addition, not all simulation studies of axons require detailed descriptions of nonlinear ionic dynamics. In this study, we construct a simple model of spike generation and conduction based on the exponential integrate-and-fire model, which can simulate the rapid growth of the membrane potential at spike initiation. In terms of the number of parameters and equations, this model is much more compact than conventional models, but can still reliably simulate spike conduction along myelinated and unmyelinated axons that are stimulated intracellularly or extracellularly. Our simulations of auditory nerve fibers with this new model suggest that, because of the difference in intrinsic membrane properties, the axonal spike conduction of high-frequency nerve fibers is faster than that of low-frequency fibers. The simple model developed in this study can serve as a computationally efficient alternative to more complex models for future studies, including simulations of neuroprosthetic devices.

Characterization of the least number of muscle fibers analyzed for a quick and reliable, evaluation of intramuscular fiber conduction velocity (MFCV) is of importance for sport scientists. The aim of this study was to evaluate the reliability of vastus lateralis' intramuscular MFCV measuring either 25 or 50 different muscle fibers per participant, as well as to compare intramuscular MFCV measured in 25 (C 25 ), 50 (C 50 ), or 140 (C 140 ) muscle fibers. Resting vastus lateralis' MFCV was measured in 21 young healthy males (age 22.1±2.4 years) using intramuscular microelectrodes in different days. Test-retest reliability of MFCV's parameters was calculated for C 25 and C 50 , while MFCV was compared among C 25 , C 50 , and C 140 . Significant differences of MFCV parameters were observed between C 25 condition and those of C 50 and C 140 . The differences in MFCV values between conditions C 50 and C 140 were non-significant. A close correlation was found for MFCV between C 50 and C 140 (r=0.884-0.988, P=.000). All reliability measures of MFCV measured with 50 fibers were high (eg, ICC=0.813-0.980, P=.000), in contrast to C 25 (eg, ICC=0.023-0.580 P>.05). In conclusion, an average of 50 different fibers per subject is sufficient to provide a quick and reliable intramuscular evaluation of vastus lateralis MFCV., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Fibrotic myocardial remodeling is typically accompanied by the appearance of myofibroblasts (MFBs). In vitro , MFBs were shown to slow conduction and precipitate ectopic activity following gap junctional coupling to cardiomyocytes (CMCs). To gain further mechanistic insights into this arrhythmogenic MFB-CMC crosstalk, we performed numerical simulations in cell-based high-resolution two-dimensional tissue models that replicated experimental conditions. Cell dimensions were determined using confocal microscopy of single and co-cultured neonatal rat ventricular CMCs and MFBs. Conduction was investigated as a function of MFB density in three distinct cellular tissue architectures: CMC strands with endogenous MFBs, CMC strands with coating MFBs of two different sizes, and CMC strands with MFB inserts. Simulations were performed to identify individual contributions of heterocellular gap junctional coupling and of the specific electrical phenotype of MFBs. With increasing MFB density, both endogenous and coating MFBs slowed conduction. At MFB densities of 5-30%, conduction slowing was most pronounced in strands with endogenous MFBs due to the MFB-dependent increase in axial resistance. At MFB densities >40%, very slow conduction and spontaneous activity was primarily due to MFB-induced CMC depolarization. Coating MFBs caused non-uniformities of resting membrane potential, which were more prominent with large than with small MFBs. In simulations of MFB inserts connecting two CMC strands, conduction delays increased with increasing insert lengths and block appeared for inserts >1.2 mm. Thus, electrophysiological properties of engineered CMC-MFB co-cultures depend on MFB density, MFB size and their specific positioning in respect to CMCs. These factors may influence conduction characteristics in the heterocellular myocardium.

The efficient propagation of action potentials along nervous fibers is necessary for animals to interact with the environment with timeliness and precision. Myelination of axons is an essential step to ensure fast action potential propagation by saltatory conduction, a process that requires highly concentrated voltage-gated sodium channels at the nodes of Ranvier. Recent studies suggest that the clustering of sodium channels can influence axonal impulse conduction in both myelinated and unmyelinated fibers, which could have major implications in disease, particularly demyelinating pathology. This comprehensive review summarizes the mechanisms governing the clustering of sodium channels at the peripheral and central nervous system nodes and the specific roles of their clustering in influencing action potential conduction. We further highlight the classical biophysical parameters implicated in conduction timing, followed by a detailed discussion on how sodium channel clustering along unmyelinated axons can impact axonal impulse conduction in both physiological and pathological contexts.

Genetic factors may be learnt from families with gene mutations that render nerve-injury susceptibility even to ordinary physical activities. A typical example is hereditary neuropathy with liability to pressure palsies (HNPP). HNPP is caused by a heterozygous deletion of PMP22 gene. PMP22 deficiency disrupts myelin junctions (such as tight junction and adherens junctions), leading to abnormally increased myelin permeability that explains the nerve susceptibility to injury. This finding should motivate investigators to identify additional genetic factors contributing to nerve vulnerability of injury.