Mechanisms Of Action Potential Generation Research Articles

Temperature elevations can induce switches to homoclinic action potentials that alter neural encoding and synchronization

Almost seventy years after the discovery of the mechanisms of action potential generation, some aspects of their computational consequences are still not fully understood. Based on mathematical modeling, we here explore a type of action potential dynamics – arising from a saddle-node homoclinic orbit bifurcation - that so far has received little attention. We show that this type of dynamics is to be expected by specific changes in common physiological parameters, like an elevation of temperature. Moreover, we demonstrate that it favours synchronization patterns in networks – a feature that becomes particularly prominent when system parameters change such that homoclinic spiking is induced. Supported by in-vitro hallmarks for homoclinic spikes in the rodent brain, we hypothesize that the prevalence of homoclinic spikes in the brain may be underestimated and provide a missing link between the impact of biophysical parameters on abrupt transitions between asynchronous and synchronous states of electrical activity in the brain.

Interpretation of Action Potential Generation Mechanism in Cardiomyocytes by Potassium Channel “Origami Windmill” Model

The study of the action potential of cardiomyocytes is as important as the study of nerve fiber cells. The theoretical basis of the action potential of cardiomyocytes is the ionic theory formed by nerve fiber cells. Its core point of view: the decline phase of the action potential of cells is dominated by K+ outflow. Applying the principle of the K+ channel “origami windmill” model, the mechanism of action potential generation of nerve fiber cells has been reasonably explained, and a point contrary to the ion theory has been drawn: the phase of the action potential decline is dominated by K+ influx. Similarly, applying the principle of the K+ channel “origami windmill” model can also give a reasonable explanation for the mechanism of action potential generation of cardiomyocytes. The difference between cardiomyocyte action potential and nerve fiber cell: In addition to K+, Cl-, Na+, the process of generating cardiomyocyte action potential also involves the participation of Ca2+. Ca2+ inflow in the rising phase will shorten the depolarization time; Ca2+ inflow in the falling phase will prolong the repolarization time. K+, Ca2+ space substitution proportion: rotate into 2 K+, squeeze out 3 Ca2+, and 4 extra negative charges in the cell, the proportion is 2: 3: 4; Conversely, squeeze out 2 K+, rotate into 3 Ca2+, 4 extra positive charges the cells, the proportion is 3: 2: 4. Na+, Ca2+ space substitution proportion: rotate into 1 Na+, squeeze out 1 Ca2+, and 1 extra negative charges in the cell, the proportion is 1: 1:1; Conversely, rotate into 1 Ca2+, squeeze out 1 Na+, there is 1 more positive charge in the cell, and the proportion is 1: 1: 1. Application of “origami windmill” model principle, can reasonably explain the cardiomyocytes action potential generation mechanism, further proveding “origami windmill” the model theory, “the theory of dove-like particles”“the theory of braincell activation” of science, also proved that the viewpoint of “action potential descending phase, dominated by K+ internal current” is correct. The scientific and rational interpretation of the action potential of cardiomyocytes has far-reaching impact and great significance to the basic theoretical research and clinical practice of the heart from now on.

Interpretation of Action Potential Generation Mechanism in Cardiomyocytes by Potassium Channel "Origami Windmill" Model

Interpretation of Action Potential Generation Mechanism in Cardiomyocytes by Potassium Channel "Origami Windmill" Model

Spontaneous random potential spike induction across a nonliving separator intervening two aqueous solutions and the implication of its physiological meaning

Membrane theory attributes the cause of action potential generation to the ion transport across the plasma membrane. It even states that the action potential generation is a unique phenomenon in the living cell. There have been some reports that the action potential-like potential spike is induced even in the nonliving system. Ling’s adsorption theory (LA theory) is a typical opposing concept to the membrane theory. The LA theory attributes the action potential generation mechanism to the ion adsorption-desorption process. The authors examined the LA theory and found that the membrane theory has a limitation. By contrast, the LA theory is in line with the experimental results. Therefore, it might be necessary to take into consideration the ion adsorption-desorption effect at least as a part of the action potential generation mechanism.

A compartmentalized mathematical model of mouse atrial myocytes.

Various experimental mouse models are extensively used to research human diseases, including atrial fibrillation, the most common cardiac rhythm disorder. Despite this, there are no comprehensive mathematical models that describe the complex behavior of the action potential and [Ca2+]i transients in mouse atrial myocytes. Here, we develop a novel compartmentalized mathematical model of mouse atrial myocytes that combines the action potential, [Ca2+]i dynamics, and β-adrenergic signaling cascade for a subpopulation of right atrial myocytes with developed transverse-axial tubule system. The model consists of three compartments related to β-adrenergic signaling (caveolae, extracaveolae, and cytosol) and employs local control of Ca2+ release. It also simulates ionic mechanisms of action potential generation and describes atrial-specific Ca2+ handling as well as frequency dependences of the action potential and [Ca2+]i transients. The model showed that the T-type Ca2+ current significantly affects the later stage of the action potential, with little effect on [Ca2+]i transients. The block of the small-conductance Ca2+-activated K+ current leads to a prolongation of the action potential at high intracellular Ca2+. Simulation results obtained from the atrial model cells were compared with those from ventricular myocytes. The developed model represents a useful tool to study complex electrical properties in the mouse atria and could be applied to enhance the understanding of atrial physiology and arrhythmogenesis.NEW & NOTEWORTHY A new compartmentalized mathematical model of mouse right atrial myocytes was developed. The model simulated action potential and Ca2+ dynamics at baseline and after stimulation of the β-adrenergic signaling system. Simulations showed that the T-type Ca2+ current markedly prolonged the later stage of atrial action potential repolarization, with a minor effect on [Ca2+]i transients. The small-conductance Ca2+-activated K+ current block resulted in prolongation of the action potential only at the relatively high intracellular Ca2+.

Preparation of dissociated mouse primary neuronal cultures from long-term cryopreserved brain tissue

BackgroundDissociated primary neuronal cultures are widely used as a model system to investigate the cellular and molecular properties of diverse neuronal populations and mechanisms of action potential generation and synaptic transmission. Typically, rodent primary neuronal cultures are obtained from freshly-dissociated embryonic or postnatal brain tissue, which often requires intense animal husbandry. This can strain resources when working with genetically modified mice. New methodHere we describe an experimental protocol for frozen storage of mouse hippocampi, which allows fully functional dissociated primary neuronal cultures to be prepared from cryopreserved tissue. ResultsWe show that thawed hippocampal neurons have functional properties similar to those of freshly dissociated neurons, including neuronal morphology, excitability, action potential waveform and synaptic neurotransmitter release, even after cryopreservation for several years. Comparison to the existing methodsIn contrast to the existing methods, the protocol described here allows for efficient long-term storage of samples, allowing researchers to perform functional experiments on neuronal cultures from brain tissue collected in other laboratories. ConclusionsWe anticipate that this method will facilitate collaborations among laboratories based at distant locations and will thus optimise the use of genetically modified mouse models, in line with the 3Rs (Replacement, Reduction and Refinement) recommended for scientific use of animals in research.

Interpretation of Action Potential Generation Mechanism in Cells by Potassium Channel "Origami Windmill" Model

Interpretation of Action Potential Generation Mechanism in Cells by Potassium Channel "Origami Windmill" Model

Quantitative Decomposition of Dynamics of Mathematical Cell Models: Method and Application to Ventricular Myocyte Models.

Mathematical cell models are effective tools to understand cellular physiological functions precisely. For detailed analysis of model dynamics in order to investigate how much each component affects cellular behaviour, mathematical approaches are essential. This article presents a numerical analysis technique, which is applicable to any complicated cell model formulated as a system of ordinary differential equations, to quantitatively evaluate contributions of respective model components to the model dynamics in the intact situation. The present technique employs a novel mathematical index for decomposed dynamics with respect to each differential variable, along with a concept named instantaneous equilibrium point, which represents the trend of a model variable at some instant. This article also illustrates applications of the method to comprehensive myocardial cell models for analysing insights into the mechanisms of action potential generation and calcium transient. The analysis results exhibit quantitative contributions of individual channel gating mechanisms and ion exchanger activities to membrane repolarization and of calcium fluxes and buffers to raising and descending of the cytosolic calcium level. These analyses quantitatively explicate principle of the model, which leads to a better understanding of cellular dynamics.

Electrophysiological characterization of Grueneberg ganglion olfactory neurons: spontaneous firing, sodium conductance, and hyperpolarization-activated currents

Mammals rely on their acute olfactory sense for their survival. The most anterior olfactory subsystem in the nose, the Grueneberg ganglion (GG), plays a role in detecting alarm pheromone, cold, and urinary compounds. GG neurons respond homogeneously to these stimuli with increases in intracellular [Ca(2+)] or transcription of immediate-early genes. In this electrophysiological study, we used patch-clamp techniques to characterize the membrane properties of GG neurons. Our results offer evidence of functional heterogeneity in the GG. GG neurons fire spontaneously and independently in several stable patterns, including phasic and repetitive single-spike modes of discharge. Whole cell recordings demonstrated two distinct voltage-gated fast-inactivating Na(+) currents with different steady-state voltage dependencies and different sensitivities to tetrodotoxin. Hodgkin-Huxley simulations showed that these Na(+) currents confer dual mechanisms of action potential generation and contribute to different firing patterns. Additionally, GG neurons exhibited hyperpolarization-activated inward currents that modulated spontaneous firing in vitro. Thus, in GG neurons, the heterogeneity of firing patterns is linked to the unusual repertoire of ionic currents. The membrane properties described here will aid the interpretation of chemosensory function in the GG.

Dynamics of action potential initiation in the GABAergic thalamic reticular nucleus in vivo.

Understanding the neural mechanisms of action potential generation is critical to establish the way neural circuits generate and coordinate activity. Accordingly, we investigated the dynamics of action potential initiation in the GABAergic thalamic reticular nucleus (TRN) using in vivo intracellular recordings in cats in order to preserve anatomically-intact axo-dendritic distributions and naturally-occurring spatiotemporal patterns of synaptic activity in this structure that regulates the thalamic relay to neocortex. We found a wide operational range of voltage thresholds for action potentials, mostly due to intrinsic voltage-gated conductances and not synaptic activity driven by network oscillations. Varying levels of synchronous synaptic inputs produced fast rates of membrane potential depolarization preceding the action potential onset that were associated with lower thresholds and increased excitability, consistent with TRN neurons performing as coincidence detectors. On the other hand the presence of action potentials preceding any given spike was associated with more depolarized thresholds. The phase-plane trajectory of the action potential showed somato-dendritic propagation, but no obvious axon initial segment component, prominent in other neuronal classes and allegedly responsible for the high onset speed. Overall, our results suggest that TRN neurons could flexibly integrate synaptic inputs to discharge action potentials over wide voltage ranges, and perform as coincidence detectors and temporal integrators, supported by a dynamic action potential threshold.

A scriptable DSP-based system for dynamic conductance injection

A variety of software and hardware systems have been developed to inject controlled electrical conductances into excitable cells, to investigate the physiological mechanisms of action potential generation. These systems face several challenges: the need to model complex conductances, including voltage-gated ion channels, synaptic conductances controlled by electrical models of entire cells or even networks of cells, to do so rapidly and stably, with precisely controlled update intervals of 20 μs or less, and to present an easy and flexible interface to the user, allowing new experiments to be designed and executed easily. In this paper I describe a new software system (SM-2) which is designed to meet these requirements, and which runs on the current generation of digital-signal-processing (DSP) analog input–output I/O boards, hosted in Windows PCs. Its key innovation is its configurability by simple user-written text scripts, or “scriptability”, which gives it a high flexibility of purpose, and allows non-programmers the capacity to rapidly design and use new Hodgkin–Huxley-type active conductances, conductances with arbitrary current–voltage relationships, Markov process conductance mechanisms with user-specified rate matrices, and hybrid networks of virtual cells. At the same time, the hardware platform allows this to be achieved with a fast and accurately timed input–computation–output cycle.

Kinetic and functional analysis of transient, persistent and resurgent sodium currents in rat cerebellar granule cells in situ: an electrophysiological and modelling study

Cerebellar neurones show complex and differentiated mechanisms of action potential generation that have been proposed to depend on peculiar properties of their voltage-dependent Na+ currents. In this study we analysed voltage-dependent Na(+) currents of rat cerebellar granule cells (GCs) by performing whole-cell, patch-clamp experiments in acute rat cerebellar slices. A transient Na+ current (I(NaT)) was always present and had the properties of a typical fast-activating/inactivating Na+ current. In addition to I(NaT), robust persistent (I(NaP)) and resurgent (I(NaR)) Na+ currents were observed. I(NaP) peaked at approximately -40 mV, showed half-maximal activation at approximately -55 mV, and its maximal amplitude was about 1.5% of that of I(NaT). I(NaR) was elicited by repolarizing pulses applied following step depolarizations able to activate/inactivate I(NaT), and showed voltage- and time-dependent activation and voltage-dependent decay kinetics. The conductance underlying I(NaR) showed a bell-shaped voltage dependence, with peak at -35 mV. A significant correlation was found between GC I(NaR) and I(NaT) peak amplitudes; however, GCs expressing I(NaT) of similar size showed marked variability in terms of I(NaR) amplitude, and in a fraction of cells I(NaR) was undetectable. I(NaT), I(NaP) and I(NaR) could be accounted for by a 13-state kinetic scheme comprising closed, open, inactivated and blocked states. Current-clamp experiments carried out to identify possible functional correlates of I(NaP) and/or I(NaR) revealed that in GCs single action potentials were followed by depolarizing afterpotentials (DAPs). In a majority of cells, DAPs showed properties consistent with I(NaR) playing a role in their generation. Computer modelling showed that I(NaR) promotes DAP generation and enhances high-frequency firing, whereas I(NaP) boosts near-threshold firing activity. Our findings suggest that special properties of voltage-dependent Na+ currents provides GCs with mechanisms suitable for shaping activity patterns, with potentially important consequences for cerebellar information transfer and computation.

Analog LSI neuron model inspired by biological excitable membrane

AbstractAn analog hardware neuron model having biological neuron characteristics is proposed and its basic characteristics are reported. The proposed circuit model is constructed from a membrane capacitance part, negative resistance circuit part, and reactance circuit part, and realizes the membrane excitability observed in biological neurons by voltage‐controlled negative resistance characteristics. This model exhibits an action potential generation mechanism similar to that of biological neurons. HSPICE simulation reveals that this model can reproduce both the well‐known responses to excitatory inputs and the postinhibitory rebound (PIR) firing which is a neuronal activity occurring by the release from an inhibitory input discharge, and that the characteristics of the input pulse amplitude‐latency and entrained response to the periodic input are similar to those of biological neurons. In addition, this model is developed by considering compatibility with integrated circuit processes, and design results of LSI implementation of the model are also presented in this article. PIR firing cannot be reproduced by the simple neuronal model used in conventional neurochips, but it plays an important role in information processing in the brain. The functionality of neurochips is expected to be improved by simulating biological neurons by such a biologically inspired hardware neuron model. © 2005 Wiley Periodicals, Inc. Syst Comp Jpn, 36(6): 84–91, 2005; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/scj.10676

Influence of low and high frequency inputs on spike timing in visual cortical neurons.

Cortical neurons in vivo respond to sensory stimuli with the generation of action potentials that can show a high degree of variability in both their number and timing with repeated presentations as wells as, on occasion, a high degree of synchronization with other cortical neurons, including in the gamma frequency range of 30-70 Hz. Here we examined whether or not this variability may arise from the intrinsic mechanisms of action potential generation in cortical regular spiking, fast spiking and intrinsic burst-generating neurons maintained in vitro. For this purpose, we performed intracellular recordings in slices of ferret visual cortex and activated these cells with the intracellular injection of various current waveforms. Some of these waveforms were derived from barrages of postsynaptic potentials evoked by visual stimulation recorded in vivo; others were artificially created and contained various amounts of gamma range fluctuations; finally, others consisted of swept-sinewave current (ZAP current) functions. Using such stimuli, we found that, as expected given the resistive and capacitive properties of cortical neurons, low frequencies have a larger effect on the membrane potential of cortical neurons than do higher frequencies. However, increasing the amount of gamma range fluctuations in a stimulus leads to more precise timing of action potentials. This suggests that different frequencies play different roles, low frequencies being efficient for depolarizing cells with high frequencies increasing the precision of action potential timing. In parallel to increases in temporal precision, the addition of higher frequency components increases the range of interspike intervals present in the action potential discharge. These results suggest that higher frequency components such as gamma range fluctuations may facilitate the generation of action potentials with a high temporal precision while at the same time exhibiting a high degree of variability in interspike intervals on single trials. This temporal precision may facilitate the use of temporal codes or the generation of precise synchronization for the transmission and analysis of information within cortical networks.

Antidromic action potentials in spinal motoneurons of the chick embryo

Antidromic action potentials of hind-limb motoneurons were studied in a preparation of the isolated perfused spinal cord of a chick embryo by a microelectrode recording technique. Most cells suffered appreciable damage when the microelectrode was introduced into them, but their functional characteristics recovered to some extent. From the 11th through the 18th day of embryonic development the amplitude and rise time of action potentials and the presence of components in them reflecting activation of the initial segment of the axon and the soma-dendritic membrane, and also values of resting potential of motoneurons after recovery revealed no age-dependent changes and were similar to the corresponding characteristics of motoneurons in adult birds and mammals. Meanwhile the conduction velocity along motor axons increased from 0.3–0.5 m/sec on the 10th day to 2–4 m/sec on the 18th day of embryonic development. Contrary to the view that mechanisms of action potential generation arise late in the course of ontogenetic development of warm-blooded animals, in the postnatal period, the results indicate that in fact they are formed quite early, in agreement with the concept of phylogenetic antiquity of this mechanism and also with data obtained on various preparations of the developing CNSin vitro.

Manifestation of a monosynaptic excitatory connection in the structure of the cross-correlation histogram

Manifestation of a monosynaptic excitatory connection in the structure of the cross-correlation histogram was studied on a mathematical model of interneuronal interaction. Specific features of the shape and position of the primary peak on the cross-correlation histogram distinguishing monosynaptic excitation of one neuron by another from monosynaptic excitation of these units by a third neuron are described. The height of the primary peak is shown to change with a change in certain parameters of the model describing mechanisms of action potential generation and synaptic transmission of excitation. The structure of the autocorrelation histogram is shown to be reflected to some extent in the structure of the cross-correlation histogram on either side of the primary peak and to take part in the formation of secondary peaks and troughs.

Ionic selectivity of excitable neurone membrane: Are there any separate potential-dependent channels for Na +,Ca 2+, Mg 2+?

1. 1. The dependence of the action potential overshoot and inward currents on ionic concentration has been studied on both intact and completely isolated neurones of Limnaea stagnalis. 2. 2. The dependence of action potential on ion concentration in the medium is similar to that of intact ones. 3. 3. The overshoot dependence on the log of Ca 2+ Mg 2+ and Na + concentration in the medium is linear. This and the character of inward current dependence on ion concentration allow us to suppose the existence of separate channels for Ca, Na and Mg ions along which they move under the action of their own electrochemical potentials. Conductance of these channels depends slightly on ionic concentration in the medium. 4. 4. If the medium contains both Ca and Sr ions the overshoot dependence on the log of their concentration is of a non-linear character. This indicates that both these kinds of ions pass through the same channel. 5. 5. A physiological role of different ion mechanisms of action potential generation is discussed.