Action Potentials In Axons Research Articles

Improved Hodgkin-Huxley type model for neural action potentials.

The simple Goldman-Hodgkin-Katz model for resting-state membrane potentials has been generalized to provide a new nonlinear theoretical model for action potentials in perfused axons. Our minimalistic model appeals naturally to physically based electrodiffusion principles to describe electric-current densities inside sodium and potassium-ion channels whereas the 1952 Hodgkin-Huxley model describes such current densities in an ad hoc way. Although the two models share similar schemes for the kinetics of ion-channel gating, our relaxation times for channel gating are simpler, being independent of membrane potential. Like the theoretical model of Hodgkin and Huxley, based primarily on experimental data at [Formula: see text], our dynamical system behaves as a 4-dimensional resonator exhibiting subthreshold oscillations. Although our present analysis refers to experiments at [Formula: see text], re-parameterizations of this model should permit consideration of action potentials at alternative temperatures. The predicted speed of propagating action potentials in giant axons of squid at [Formula: see text] is in excellent agreement with the Hodgkin-Huxley experimental value at [Formula: see text]. In cases where our model predictions differ from those of the Hodgkin-Huxley model, new experiments will be required to determine which model is more accurate.

Electrical match between initial segment and somatodendritic compartment for action potential backpropagation in retinal ganglion cells.

The action potential of most vertebrate neurons initiates in the axon initial segment (AIS) and is then transmitted to the soma where it is regenerated by somatodendritic sodium channels. For successful transmission, the AIS must produce a strong axial current, so as to depolarize the soma to the threshold for somatic regeneration. Theoretically, this axial current depends on AIS geometry and Na+ conductance density. We measured the axial current of mouse retinal ganglion cells using whole cell recordings with post hoc AIS labeling. We found that this current is large, implying high Na+ conductance density, and carries a charge that covaries with capacitance so as to depolarize the soma by ∼30 mV. Additionally, we observed that the axial current attenuates strongly with depolarization, consistent with sodium channel inactivation, but temporally broadens so as to preserve the transmitted charge. Thus, the AIS appears to be organized so as to reliably backpropagate the axonal action potential.NEW & NOTEWORTHY We measured the axial current produced at spike initiation by the axon initial segment of mouse retinal ganglion cells. We found that it is a large current, requiring high sodium channel conductance density, which covaries with cell capacitance so as to ensure a ∼30 mV depolarization. During sustained depolarization the current attenuated, but it broadened to preserve somatic depolarization. Thus, properties of the initial segment are adjusted to ensure backpropagation of the axonal action potential.

Effects of temperature and ion channel blocks on propagation of action potential in myelinated axons.

Potassium ion and sodium ion channels play important roles in the propagation of action potentials along a myelinated axon. The random opening and closing of ion channels can cause the fluctuation of action potentials. In this paper, an improved Hodgkin-Huxley chain network model is proposed to study the effects of ion channel blocks, temperature, and ion channel noise on the propagation of action potentials along the myelinated axon. It is found that the chain network has minimum coupling intensity threshold and maximum tolerance temperature threshold that allow the action potentials to pass along the whole axon, and the blockage of ion channels can change these two thresholds. A striking result is that the simulated value of the optimum membrane size (inversely proportional to noise intensity) coincides with the area range of feline thalamocortical relay cells in biological experiments.

Could Fampridine Attenuate the Severity of COVID-19 in Patients with Multiple Sclerosis?

The article's abstract is not available.

A- and D-type potassium currents regulate axonal action potential repolarization in midbrain dopamine neurons

Midbrain dopamine neurons (DANs) regulate various brain functions such as motor control and motivation. Alteration of spiking activities of these neurons could contribute to severe brain disorders including Parkinson's disease and depression. Previous studies showed important roles of somatodendritic voltage-gated K+ channels (Kv) of DANs in governing neuronal excitability and dopamine release. However, it remains largely unclear about the biophysical properties and the function of Kv channels distributed at DAN axons. We performed whole-cell recordings from the axons of DANs in acute mouse midbrain and striatal slices. We detected both rapidly activating/inactivating Kv current (i.e. A-current) and rapidly activating but slowly inactivating current (i.e. D-current) in DAN axons. Pharmacological experiments with channel blockers revealed that these currents are predominantly mediated by Kv1.4 and Kv1.2 subunits, respectively. Blocking these currents could substantially prolong axonal action potentials (APs) via a reduction of their repolarization slope. Together, our results show that Kv channels mediating A- and D-currents shape AP waveforms in midbrain DAN axons, through this regulation they may control dopamine release at the axonal terminals. Therefore, these axonal Kv channels could be drug targets for brain disorders with abnormal dopamine release.

Fields, Geometry and Their Impact on Axon Interaction

In this paper, we present a simulation program that allows for the concurrent propagation of action potentials in axons coupled via currents, as well as, for the first time, the computation of the resultant nodal electric field generated as the action potentials traverse the tract of axons. With these fields in hand, we inject currents into nodes of axons that depend on these fields and study the coupling between axons in the presence of the fields and currents present jointly in varying strengths. We find close-to-synchronized propagation in three dimensions. Further, we derive for the first time a mathematical equation for tortuous tracts (as opposed to linear) with such field-mediated coupling. The geometrical formulation enables us to consider spacetime perturbative effects, which have also not been considered in the literature so far. We investigate the case when gravitational radiation is present, in order to determine its impact on tract information processing. We find that action potential relative-timing in a tract is affected by the strength and frequency of gravitational waves and the waning of this influence with weakening strength. This latter study blurs the division between what lies inside and outside man. As an additional novelty, we investigate the influence of geometry on the information transmission capacity of the ephaptically-coupled tract, when viewed as a discrete memoryless channel, and find a rising trend in capacity with increasing axonal inclinations, which may occur in traumatic CNS injury.

A Method for Recording the Bioelectrical Activity of Neural Axons upon Stimulation with Short Pulses of Infrared Laser Radiation.

The aim of the study was to develop a method for long-term non-invasive recording of the bioelectrical activity induced in isolated neuronal axons irradiated with short infrared (IR) pulses and to study the effect of radiation on the occurrence of action potentials in axons of a neuron culture in vitro.Materials and Methods.Hippocampal cells of mouse embryos (E18) were cultured in microfluidic chips made of polydimethylsiloxane and containing microchannels for axonal growth at a distance of up to 800 μm. We studied the electrophysiological activity of a neuronal culture induced by pulses of focused laser radiation in the IR range (1907 and 2095 nm). The electrophysiological activity of the neuronal culture was recorded using a multichannel recording system (Multi Channel Systems, Germany).Results.The developed microfluidic chip and the optical stimulation system combined with the multichannel registration system made it possible to non-invasively record the action potentials caused by pulsed IR radiation in isolated neuronal axons in vitro. The propagation of action potentials in axons was detected using extracellular microelectrodes when the cells were irradiated with a laser at a wavelength of 1907 nm with a radiation power of 0.2–0.5 W for pulses with a duration of 6 ms and 0.5 W for pulses with a duration of 10 ms. It was shown that the radiation power positively correlated with the occurrence rate of axonal response. Moreover, the probability of a response evoked by optical stimulation increased at short optical pulses. In addition, we found that more responses could be evoked by irradiating the neuronal cell culture itself rather than the axon-containing microchannels.Conclusion.The developed method makes it possible to isolate the axons growing from cultured neurons into a microfluidic chip, stimulate the neurons with infrared radiation, and non-invasively record the axonal spiking. The proposed approach allowed us to study the characteristics of neuronal responses in cell cultures over a long (weeks) period of time. The method can be used both in fundamental research into the brain signaling system and in the development of a non-invasive neuro-interface.

Axonal blockage with microscopic magnetic stimulation

Numerous neurological dysfunctions are characterized by undesirable nerve activity. By providing reversible nerve blockage, electric stimulation with an implanted electrode holds promise in the treatment of these conditions. However, there are several limitations to its application, including poor bio-compatibility and decreased efficacy during chronic implantation. A magnetic coil of miniature size can mitigate some of these problems, by coating it with biocompatible material for chronic implantation. However, it is unknown if miniature coils could be effective in axonal blockage and, if so, what the underlying mechanisms are. Here we demonstrate that a submillimeter magnetic coil can reversibly block action potentials in the unmyelinated axons from the marine mollusk Aplysia californica. Using a multi-compartment model of the Aplysia axon, we demonstrate that the miniature coil causes a significant local depolarization in the axon, alters activation dynamics of the sodium channels, and prevents the traveling of the invading action potentials. With improved biocompatibility and capability of emitting high-frequency stimuli, micro coils provide an interesting alternative for electric blockage of axonal conductance in clinical settings.

Cholesterol modulates presynaptic and postsynaptic properties of excitatory synaptic transmission

Cholesterol is a structural component of cellular membranes particularly enriched in synapses but its role in synaptic transmission remains poorly understood. We used rat hippocampal cultures and their acute cholesterol depletion by methyl-β-cyclodextrin as a tool to describe the physiological role of cholesterol in glutamatergic synaptic transmission. Cholesterol proved to be a key molecule for the function of synapses as its depletion resulted in a significant reduction of both NMDA receptor (NMDAR) and AMPA/kainate receptor-mediated evoked excitatory postsynaptic currents (eEPSCs), by 94% and 72%, respectively. We identified two presynaptic and two postsynaptic steps of synaptic transmission which are modulated by cholesterol and explain together the above-mentioned reduction of eEPSCs. In the postsynapse, we show that physiological levels of cholesterol are important for maintaining the normal probability of opening of NMDARs and for keeping NMDARs localized in synapses. In the presynapse, our results favour the hypothesis of a role of cholesterol in the propagation of axonal action potentials. Finally, cholesterol is a negative modulator of spontaneous presynaptic glutamate release. Our study identifies cholesterol as an important endogenous regulator of synaptic transmission and provides insight into molecular mechanisms underlying the neurological manifestation of diseases associated with impaired cholesterol synthesis or decomposition.

An axon-specific expression of HCN channels catalyzes fast action potential signaling in GABAergic interneurons

During high-frequency network activities, fast-spiking, parvalbumin-expressing basket cells (PV+-BCs) generate barrages of fast synaptic inhibition to control the probability and precise timing of action potential (AP) initiation in principal neurons. Here we describe a subcellular specialization that contributes to the high speed of synaptic inhibition mediated by PV+-BCs. Mapping of hyperpolarization-activated cyclic nucleotide-gated (HCN) channel distribution in rat hippocampal PV+-BCs with subcellular patch-clamp methods revealed that functional HCN channels are exclusively expressed in axons and completely absent from somata and dendrites. HCN channels not only enhance AP initiation during sustained high-frequency firing but also speed up the propagation of AP trains in PV+-BC axons by dynamically opposing the hyperpolarization produced by Na+-K+ ATPases. Since axonal AP signaling determines the timing of synaptic communication, the axon-specific expression of HCN channels represents a specialization for PV+-BCs to operate at high speed.

Electrical Stimulation of Muscle: Electrophysiology and Rehabilitation.

The generation of action potentials in intramuscular motor and sensory axons in response to an imposed external current source can evoke muscle contractions and elicit widespread responses throughout the nervous system that impact sensorimotor function. The benefits experienced by individuals exposed to several weeks of treatment with electrical stimulation of muscle suggest that the underlying adaptations involve several physiological systems, but little is known about the specific changes elicited by such interventions.

Emergence of an optimal temperature in action-potential propagation through myelinated axons.

In biological organisms, an optimal temperature exists at which the system functioning is maximized or is most effective. To obtain a general and quantitative understanding of the emergence of the optimal temperature is a challenging task. We aim to gain insights into this significant problem in biological physics by addressing the problem of propagation of action potential in myelinated axons. In particular, we construct a Hodgkin-Huxley type of cortical, compartmental model to describe the nodes of Ranvier with coupling between a pair of neighboring compartments characterized by internodal conductance and investigate the effect of temperature on the propagation of the action potential. We conduct direct numerical simulations and develop a physical analysis by taking advantage of the spatially continuous approximation. We find that increasing the temperature requires a larger value of the critical internodal conductance for successful propagation. The striking finding is the spontaneous emergence of an optimal temperature in the sense that, for the propagation of a single action potential at a fixed value of the internodal conductance, the minimum average passage time for one node of Ranvier occurs at this temperature value. A remarkable phenomenon is that the value of the optimal temperature is similar to those of living biological systems observed in experiments.

A causal study of the phenomenon of ultrasound neurostimulation applied to an in vivo invertebrate nervous model

Focused ultrasound are considered to be a promising tool for the treatment of neurological conditions, overcoming the limitations of current neurostimulation techniques in terms of spatial resolution and invasiveness. Much evidence to support the feasibility of ultrasound activation of neurons at the systemic level has already been provided, but to this day, the biophysical mechanisms underlying ultrasound neurostimulation are still widely unknown. In order to be able to establish a clear and robust causality between acoustic parameters of the excitation and neurobiological characteristics of the response, it is necessary to work at the cellular level, or alternatively on very simple animal models. The study reported here responds to three objectives. Firstly, to propose a simple nervous model for the study of the ultrasound neurostimulation phenomenon, associated with a clear and simple experimental protocol. Secondly, to compare the characteristics of this model’s nervous response to ultrasound neurostimulation with its nervous response to mechanical and electrical stimulation. Thirdly, to study the role played by certain acoustic parameters in the success rate of the phenomenon of ultrasound stimulation. The feasibility of generating action potentials (APs) in the giant axons of an earthworm’s ventral nerve cord, using pulsed ultrasound stimuli (f = 1.1 MHz, Ncycles = 175–1150, PRF = 25–125 Hz, Npulses = 20, PA = 2.5–7.3 MPa), was demonstrated. The time of generation (TOG) of APs associated with ultrasound stimulation was found to be significantly shorter and more stable than the TOG associated with mechanical stimulation (p < 0.001). By applying a causal approach to interpret the results of this study, it was concluded that, in this model, the nervous response to focused ultrasound is initiated along the afferent neurons, in between the mechanosensors and the synaptic connections with the giant axons. Additionally, early results are provided, highlighting a trend for the success rate of ultrasound neurostimulation and number of APs triggered per response to increase with increasing pulse repetition frequency (p < 0.05 and p < 0.001, respectively), increasing pulse duration and increasing pulse amplitude.

Excitability Tuning of Axons by Afterdepolarization.

The axon provides a sole output of the neuron which propagates action potentials reliably to the axon terminal and transmits neuronal information to the postsynaptic neuron across the synapse. A classical view of neuronal signaling is based on these two processes, namely binary (all or none) signaling along the axon and graded (tunable) signaling at the synapse. Recent studies, however, have revealed that the excitability of the axon is subject to dynamic tuning for a short period after axonal action potentials. This was first described as post-spike hyperexcitability, as measured by the changes in stimulus threshold for a short period after an action potential. Later on, direct recordings from central nervous system (CNS) axons or axon terminals using subcellular patch-clamp recording showed that axonal spikes are often followed by afterdepolarization (ADP) lasting for several tens of milliseconds and has been suggested to mediate post-spike hyperexcitability. In this review article, I focused on the mechanisms as well as the functional significance of ADP in fine-scale modulation of axonal spike signaling in the CNS, with special reference to hippocampal mossy fibers, one of the best-studied CNS axons. As a common basic mechanism underlying axonal ADP, passive propagation by the capacitive discharge of the axonal membrane as well as voltage-dependent K+ conductance underlies the generation of ADP. Small but prolonged axonal ADP lasting for several tens of milliseconds may influence the subsequent action potential and transmitter release from the axon terminals. Both duration and amplitude of axonal spike are subject to such modulation by preceding action potential-ADP sequence, deviating from the conventional assumption of digital nature of axonal spike signaling. Impact on the transmitter release is also discussed in the context of axonal spike plasticity. Axonal spike is subject to dynamic control on a fine-scale and thereby contributes to the short-term plasticity at the synapse.

NanoTouch: intracellular recording using transmembrane conductive nanoparticles.

Observations of the electrophysiological properties of cells are important for understanding cellular functions and their underlying mechanisms. Short action potentials in axons are essential to rapidly deliver signals from the neuronal cell body to the terminals, whereas longer action potentials are required for sufficient calcium influx for transmitter release at the synaptic terminals and for cardiomyocyte and smooth muscle contractions. To accurately observe the shape and timing of depolarizations, it is essential to measure changes in the intracellular membrane potential. The ability to record action potentials and intracellular membrane potentials from mammalian cells and neurons was made possible by Ling and Gerard’s discovery in 1949, when they introduced sharp glass electrode with a submicron sized tip. Because of the small tip size, the sharp glass electrode could penetrate the cell membrane with little damage, which was one of the major breakthroughs in cellular electrophysiology and is the basic principle of the intracellular recording technique to date, providing the basis for further innovation of patch-clamp electrophysiology. I report a proof-of-principle demonstration of a novel method for recording intracellular potentials without penetrating the cell membrane using glass electrodes. We discovered that magnetically held transmembrane conductive nanoparticles can function as an intracellular electrode to detect transmembrane membrane potentials similar to those obtained by the conventional patch-clamp recording method.NEW & NOTEWORTHY To accurately observe the shape of action potentials, it is essential to perform intracellular recordings. I present a method to record intracellular potentials using magnetically held magnetic conductive nanoparticles in the membrane as an electrode. These nanoparticles function similarly to a conventional intracellular microelectrode. This is the first report to apply conductive nanoparticles to detect action potentials in the form of electrical signals.

Spikelets in pyramidal neurons: generating mechanisms, distinguishing properties, and functional implications.

Spikelets are small spike-like depolarizations that are found in somatic recordings of many neuron types. Spikelets have been assigned important functions, ranging from neuronal synchronization to the regulation of synaptic plasticity, which are specific to the particular mechanism of spikelet generation. As spikelets reflect spiking activity in neuronal compartments that are electrotonically distinct from the soma, four modes of spikelet generation can be envisaged: (1) dendritic spikes or (2) axonal action potentials occurring in a single cell as well as action potentials transmitted via (3) gap junctions or (4) ephaptic coupling in pairs of neurons. In one of the best studied neuron type, cortical pyramidal neurons, the origins and functions of spikelets are still unresolved; all four potential mechanisms have been proposed, but the experimental evidence remains ambiguous. Here we attempt to reconcile the scattered experimental findings in a coherent theoretical framework. We review in detail the various mechanisms that can give rise to spikelets. For each mechanism, we present the biophysical underpinnings as well as the resulting properties of spikelets and compare these predictions to experimental data from pyramidal neurons. We also discuss the functional implications of each mechanism. On the example of pyramidal neurons, we illustrate that several independent spikelet-generating mechanisms fulfilling vastly different functions might be operating in a single cell.

A Low Noise Amplifier Suitable for Biomedical Recording Analog Front-End in 65nm CMOS Technology

This paper presents a fully integrated front-end, low noise amplifier (LNA), dedicated to the processing of various types of bio-medical signals, such as Electrocardiogram (ECG), Electroencephalography (EEG), Axon Action Potential (AAP). A novel noise reduction technique, for an operational transconductance amplifier (OTA), has been proposed. This adds a current steering branch parallel to the differential pair, with a view to reducing the noise contribution by the cascode current sources. Hence, this reduces the overall input-referred noise of the LNA, without adding any additional power. The proposed technique implemented in 65[Formula: see text]nm CMOS technology achieves 30 dB closed-loop voltage gain, 0.05[Formula: see text]Hz lower cut-off frequency and 100 MHz 3-dB bandwidth. It operates at 1.2[Formula: see text]V power supply and draws 1[Formula: see text][Formula: see text]A static current. The prototype described in this paper occupies 3300[Formula: see text][Formula: see text]m2 silicon area.

Postnatal Increases in Axonal Conduction Velocity of an Identified Drosophila Interneuron Require Fast Sodium, L-Type Calcium and Shaker Potassium Channels.

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.

Modeling Analysis of Axonal After Potential at Hippocampal Mossy Fibers.

Action potentials reliably propagate along the axons, and after potential often follows the axonal action potentials. After potential lasts for several tens of millisecond and plays a crucial role in regulating excitability during repetitive firings of the axon. Several mechanisms underlying the generation of after potential have been suggested, including activation of ionotropic autoreceptors, accumulation of K+ ions in the surrounding extracellular space, the opening of slow voltage-dependent currents, and capacitive discharge of upstream action potentials passively propagated through axon cable. Among them, capacitive discharge is difficult to examine experimentally, since the quantitative evaluation of a capacitive component requires simultaneous recordings from at least two different sites on the connecting axon. In this study, a series of numerical simulation of the axonal action potential was performed using a proposed model of the hippocampal mossy fiber where morphological as well as electrophysiological data are accumulated. To evaluate the relative contribution of the capacitive discharge in axonal after potential, voltage-dependent Na+ current as well as voltage-dependent K+ current was omitted from a distal part of mossy fiber axons. Slow depolarization with a similar time course with the recorded after potential in the previous study was left after blockade of Na+ and K+ currents, suggesting that a capacitive component contributes substantially in axonal after potential following propagating action potentials. On the other hand, it has been shown that experimentally recorded after potential often showed clear voltage-dependency upon changes in the initial membrane potential, obviously deviating from voltage-independent nature of the capacitive component. The simulation revealed that activation of voltage-dependent K+ current also contributes to shape a characteristic waveform of axonal after potential and reconstitute similar voltage-dependency with that reported for the after potential recorded from mossy fiber terminals. These findings suggest that the capacitive component reflecting passive propagation of upstream action potential substantially contributes to the slow time course of axonal after potential, although voltage-dependent K+ current provided a characteristic voltage dependency of after potential waveform.

Scorpion venom increases acetylcholine release by prolonging the duration of somatic nerve action potentials

Scorpionism is frequently accompanied by a massive release of catecholamines and acetylcholine from peripheral nerves caused by neurotoxic peptides present in these venoms, which have high specificity and affinity for ion channels. Tityus bahiensis is the second most medically important scorpion species in Brazil but, despite this, its venom remains scarcely studied, especially with regard to its pharmacology on the peripheral (somatic and autonomic) nervous system. Here, we evaluated the activity of T. bahiensis venom on somatic neurotransmission using myographic (chick and mouse neuromuscular preparations), electrophysiological (MEPP, EPP, resting membrane potentials, perineural waveforms, compound action potentials) and calcium imaging (on DRG neurons and muscle fibres) techniques. Our results show that the major toxic effects of T. bahiensis venom on neuromuscular function are presynaptically driven by the increase in evoked and spontaneous neurotransmitter release. Low venom concentrations prolong the axonal action potential, leading to a longer depolarization of the nerve terminals that enhances neurotransmitter release and facilitates nerve-evoked muscle contraction. The venom also stimulates the spontaneous release of neurotransmitters, probably through partial neuronal depolarization that allows calcium influx. Higher venom concentrations block the generation of action potentials and resulting muscle twitches. These effects of the venom were reversed by low concentrations of TTX, indicating voltage-gated sodium channels as the primary target of the venom toxins. These results suggest that the major neuromuscular toxicity of T. bahiensis venom is probably mediated mainly by α- and β-toxins interacting with presynaptic TTX-sensitive ion channels on both axons and nerve terminals.