Reduction In Spike Amplitude Research Articles

Dynamic of shock–bubble interactions and nonlinear evolution of ablative hydrodynamic instabilities initialed by capsule interior isolated defects

It is believed that isolated defects within the capsule (e.g., void, high-density inclusion) can be one of the essential factors for implosion performance degradation by seeding hydrodynamic instabilities in implosions. Nonetheless, a systematic study on how the isolated defects evolve and why they are not stabilized by ablation given the length scale comparable with the typical cutoff wavelength is still lacking. This paper addresses the above concerns by looking into a simplified model where a planar shell (without convergent geometry) is driven by laser direct-drive, with a single defect (low/high density) of micrometer or sub-micrometer scale residing at different locations inside. The underlying dynamics of two key physical processes are analyzed, i.e., the shock–bubble interactions as well as the subsequent nonlinear evolution of ablative hydrodynamic instabilities initiated by the direct interaction of the deformed defect and ablation front, revealing that compressibility and baroclinic effects drive vorticity production during the interactions between the shock wave and the isolated defect. In the “light-bubble” case, the vortex pair generated in the first process is further strengthened by the laser ablation. Hence, a directed flow is formed in companion with the persistent flow entering the bubble of the surrounding ablator. The bubble exhibits a remarkable growth both laterally and deeply, seriously threatening the shell's integrity. The positive feedback mechanism of the vortex pair is absent in the “heavy-bubble” counterpart, and the ablation stabilization manifested itself in the reduction of spike amplitude. A systematic study of localized perturbation growth as a function of defect placement, size, and preheating intensity is presented.

Protonophoric and Photodynamic Effects of Fluorescein Decyl(triphenyl)phosphonium Ester on the Electrical Activity of Pond Snail Neurons.

Uncouplers of oxidative phosphorylation in mitochondria, which have been essential in elucidating the basic principles of cell bioenergetics, have recently attracted a considerable interest as compounds with therapeutic, e.g., neuroprotective, properties. Here, we report the effect of mitofluorescein (mitoFluo), a new protonophoric uncoupler representing a conjugate of fluorescein with decyl(triphenyl)phosphonium, on the electrical activity of neurons from Lymnaea stagnalis. Incubation with mitoFluo in the dark led to a decrease in the absolute value of the resting membrane potential of the neurons and alterations in their spike activity, such as spike broadening, spike amplitude reduction, and increase in the spike frequency. Prolonged incubation at high (tens micromoles) mitoFluo concentrations resulted in complete suppression of neuronal electrical activity. The effect of mitoFluo on the neurons was qualitatively similar to that of the classical mitochondrial uncoupler carbonyl cyanide m-chlorophenylhydrazone (CCCP) but manifested itself after much longer incubation and at higher concentrations. The distinctive feature of mitoFluo is its light-induced effect on the electrical activity of neurons. Changes in the parameters of the neuronal activity upon illumination in the presence of mitoFluo were similar to the light-induced effects of the well-known photosensitizer Rose Bengal, although less pronounced. It was suggested that the effects of mitoFluo on the electrical activity of neurons, both as a mitochondrial uncoupler and a photosensitizer, are mediated by the changes in the cytoplasmic calcium concentration.

Characterization of human iPS cell-derived cardiomyocyte sheets as a model to detect drug-induced conduction disturbance.

In order to characterize human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) sheets as a model for detecting drug-induced conduction disturbance, we examined their electrophysiological and electropharmacological properties by using the multi-electrode array system with a programmed electrical stimulation protocol. At pre-drug control, the conduction speed, effective refractory period and field potential duration were 0.14 ± 0.01 m/sec, 453 ± 10 msec and 361 ± 9 msec, respectively at a cycle length of 1,000 msec (n = 18). Shortening the pacing cycle length from 1,000 to 600 msec decreased the conduction speed and field potential duration, but prolonged the effective refractory period. Disopyramide, lidocaine and flecainide decreased the conduction speed but prolonged the effective refractory period and field potential duration, whereas the reverse was true for verapamil. Thus, conduction properties of the cell sheet may largely depend on the extent of Na+ channel availability as is the case in the human ventricle. Importantly, there was no relationship between the conduction delay and 1st spike amplitude reduction after the treatment of Na+ channel blockers. These findings may provide crucial guide on future application of this new technology for early phase safety pharmacological screening of new chemical entities.

Glutamatergic Excitation of Cortical Neurons Depending on the Point of Origin on the Membrane and Cholinergic Regulation in Hypothermia

Experiments on guinea pig sensorimotor cortex slices with cooling of the incubation medium from 34°C to 21–22°C showed that hypothermia had no effect on evoked spike responses to application of glutamate to cell bodies, while application of glutamate to dendritic loci induced spike responses in the body with a short latent period with a hypothermic increase in the level of spontaneous activity and a longer latent period with a hypothermic decrease. Low-frequency neurons mainly showed increases in spontaneous activity on cooling, while high-frequency neurons (activity greater than 4 spikes/sec) responded with decreases in spike activity. The level of spontaneous sensorimotor cortex neuron activity started to change when the temperature dropped below 30°C. At this temperature, responses to iontophoretic delivery of acetylcholine to nerve cells decreased and there was a reduction in spike amplitude, which became greater with increasing cooling. These data provide evidence that hypothermic changes in the level of spontaneous activity evoked by altered influences on cell bodies of glutamatergic excitation of the dendrites, along with impairment to ion homeostasis, leading to decreases in spike amplitude are associated with temperature-dependent limiting of the rate of the M-cholinergic process over the temperature range 27–29°C. Neurons with different functional properties had different sensitivities to hypothermia.

GM1 ganglioside contributes to retain the neuronal conduction and neuronal excitability in visceral and baroreceptor afferents

GM1 ganglioside has a great impact on the function of nodes of Ranvier on myelinated fiber, suggesting its potential role to maintain the electrical and neuronal excitability of neurons. Here we first demonstrate that visceral afferent conduction velocity of myelinated and unmyelinated fibers are reduced significantly by tetrodotoxin (TTX) or cholera toxin-B subunits (CTX-B), and only the effects mediated by CTX-B are prevented by GM1 pre-treatment. At soma of myelinated A and unmyelinated C-type nodose ganglion neurons (NGNs), the action potential spike frequency reduced by CTX-B is also prevented by GM1. Additionally, the current density of both TTX-sensitive (TTX-S) and TTX-resistant (TTX-R) Na(+) channels were significantly decreased by CTX-B without changing the voltage-dependent property. These data confirm that endogenous GM1 may play a dominant role in maintaining the electrical and neuronal excitability via modulation of sodium (Na(+)) channel around nodes and soma as well, especially TTX-S Na(+) channel, which is also confirmed by the reduction of spike amplitude and depolarization. Similar data are also extended to fluorescently identified and electrophysiologically characterized aortic baroreceptor neurons. These findings suggest that GM1 plays an important role in the neural modulation of electric and neuronal excitability in visceral afferent system.

In vivo electrical activity of brainstem neurons in fetal rats during asphyxia

To see changes in the activity and the sensitivity to glutamate of fetal brain neurons during asphyxia, the electrical activity of brainstem neurons was recorded extracellularly in fetal rats which were still connected with the dams by the intact umbilical cord. In urethan-anesthetized pregnant rats, fetal asphyxia (2–10 min) was induced by occluding the umbilical cord with a surgical clip, while reperfusion of the umbilical blood flow was performed by local application of a relaxant of blood vessels to the occlusion site. The spontaneous discharge of fetal brainstem neurons was suppressed for a long period of time by umbilical cord occlusion. The suppression of the firing occurred 48–150 (78±7) s after the start of umbilical cord occlusion, and lasted even after fetal cortical PO 2 recovered to control level after reperfusion. The changes occurred with a marked reduction in spike amplitude. A similar suppression was observed for the spikes induced by iontophoretic application of glutamate, although fetal brainstem neurons were extremely sensitive to glutamate before asphyxia. The suppression of the spontaneous spikes became more notable and longer when asphyxia was repeated. These findings suggest that the long-lasting suppression of fetal neurons during asphyxia may contribute to a reduction of cellular energy requirements in the fetal brain, thereby playing a role in the resistance of fetal neurons to brain damage caused by asphyxia. Furthermore, the reduced sensitivity of fetal neurons to glutamate during asphyxia may also contribute to prevent brain damage due to excitotoxity of glutamate.

Inhibitory control of somatodendritic interactions underlying action potentials in neocortical pyramidal neurons in vivo: An intracellular and computational study

The effect of synaptic inputs on somatodendritic interactions during action potentials was investigated, in the cat, using in vivo intracellular recording and computational models of neocortical pyramidal cells. An array of 10 microelectrodes, each ending at a different cortical depth, was used to preferentially evoke synaptic inputs to different somatodendritic regions. Relative to action potentials evoked by current injection, spikes elicited by cortical microstimuli were reduced in amplitude and duration, with stimuli delivered at proximal (somatic) and distal (dendritic) levels evoking the largest and smallest decrements, respectively. When the inhibitory postsynaptic potential reversal was shifted to around −50 mV by recording with KCl pipettes, synaptically-evoked spikes were significantly less reduced than with potassium acetate or cesium acetate pipettes, suggesting that spike decrements are not only due to a shunt, but also to voltage-dependent effects. Computational models of neocortical pyramidal cells were built based on available data on the distribution of active currents and synaptic inputs in the soma and dendrites. The distribution of synapses activated by extracellular stimulation was estimated by matching the model to experimental recordings of postsynaptic potentials evoked at different depths. The model successfully reproduced the progressive spike amplitude reduction as a function of stimulation depth, as well as the effects of chloride and cesium. The model revealed that somatic spikes contain an important contribution from proximal dendritic sodium currents up to ≈100 μm and ≈300 μm from the soma under control and cesium conditions, respectively. Proximal inhibitory postsynaptic potentials can prevent this dendritic participation thus reducing the spike amplitude at the soma. The model suggests that the somatic spike amplitude and shape can be used as a “window” to infer the electrical participation of proximal dendrites. Thus, our results suggest that inhibitory postsynaptic potentials can control the participation of proximal dendrites in somatic sodium spikes.

IPSPs modulate spike backpropagation and associated [Ca2+]i changes in the dendrites of hippocampal CA1 pyramidal neurons.

1. We studied the effects of synaptic inhibition on backpropagating Na+ spikes in the apical dendrites of CA1 pyramidal neurons in transverse slices from the rat hippocampus. Action potentials were evoked synaptically by stimulation in the stratum radiatum or antidromically by stimulation in the alveus. 2. Inhibitory postsynaptic potentials, evoked by stimulation in the stratum lacunosum moleculare, reduced the amplitude of single spikes in the distal dendrites but did not change the amplitudes in the somatic or proximal regions. Inhibition also reduced the spike-associated [Ca2+]i changes in the distal dendrites but had little effect on the changes in the proximal part of the cell. Both of these results are consistent with inhibition converting actively backpropagating spikes into passively spreading potentials at some point in the arbor. 3. In most cells, the spike amplitude reduction in the distal dendrites was blocked by bicuculline methiodide (10 microM) and inhibition was most effective when evoked in a time window < 10 ms preceding the action potential. This suggests that the amplitude reduction was due to a conductance shunt activated by gamma-aminobuturic acid-A (GABAA) receptors. Synaptically evoked GABAB responses were detected but usually did not block spike propagation. 4. Direct hyperpolarization in the distal dendrites was also effective in blocking antidromically evoked spike backpropagation but probably does not contribute when the action potentials are evoked synaptically. 5. This effect of inhibition is different from its usual function in synaptic integration because spike generation and propagation down the axon are not significantly affected. This kind of inhibition might be important in regulating transient [Ca2+]i changes in the dendrites including individual dendritic branches.

Ethanol inhibits muscarinic receptor-stimulated phosphoinositide metabolism and calcium mobilization in rat primary cortical cultures

In recent years, it has been hypothesized that muscarinic receptor-stimulated phosphoinositide (PI) metabolism may represent a relevant target for the developmental neurotoxicity of ethanol. Age-, brain region-, and receptor-specific inhibitory effects of ethanol on this system have been found, both in vitro and after in vivo administration. As a direct consequence of this action, alterations of calcium homeostasis would be expected, through alterations of inositol trisphosphate formation, which mediates intracellular calcium mobilization. In the present study, the effects of ethanol (50-500 mM) on carbachol-stimulated PI metabolism and free intracellular calcium levels were investigated in rat primary cortical cultures, by measuring release of inositol phosphates and utilizing the two calcium probes fluo-3 and indo-1 on an ACAS (Adherent Cell Analysis and Sorting) Laser Cytometer. Ethanol exerted a concentration-dependent inhibition of carbachol-stimulated PI metabolism. In addition, ethanol's inhibitory effect paralleled the temporal development of the muscarinic receptor signal transduction system, with the strongest inhibition (25-50%) occurring when maximal stimulation by carbachol occurs (days 5-7). Ethanol also exerted a concentration-dependent decrease in free intracellular calcium levels following carbachol stimulation. Both initial calcium spike amplitude, seen in all responsive cells, as well as the total number of cells responding to carbachol, were decreased by ethanol. The inhibitory effects of ethanol seemed dependent upon preincubation time, in that a longer preincubation (30 min) with the lowest dose (50 mM), showed almost the same decrease in responding cell number and reduction in spike amplitude in responding cells, as a shorter incubation (10 min) with the highest ethanol dose (500 mM). The specificity of the response to carbachol was demonstrated by blocking the response with 10 microM atropine. Moreover, experiments with carbachol in calcium-free buffer with 1 mM EGTA indicated that the initial calcium spike was due to intracellular calcium mobilization from intracellular stores. Since calcium is believed to play important roles in cell proliferation and differentiation, these results support the hypothesis that this intracellular signal-transduction pathway may be a target for ethanol, contributing to its developmental neurotoxicity.

Depression of synaptic connections between identified motor neurons in the locust.

1. The fast extensor tibiae motor neuron makes direct excitatory central connections with the posterior group of flexor tibiae motor neurons in the locust metathoracic ganglion. The flexor group has a slow, a fast, and an intermediate motor neuron. The motor neurons are involved in the motor program for kicking and jumping, the defensive and escape behaviors of the locust. An antidromic action potential in fast extensor tibiae motor neuron (FETi) results in a monosynaptic, glutamatergic excitatory postsynaptic potential (EPSP) in each of the flexor motor neurons. 2. A train of 10 antidromic spikes in FETi at frequencies of 1-20 Hz resulted in depression of the amplitude of the EPSP in each of the flexor motor neurons. The depression was not significantly different in the different flexor motor neurons. The depression was greater with higher frequency stimulation and was reduced in low calcium saline. 3. After stimulation at 20 Hz, the EPSP amplitude was depressed by approximately 80%. This did not change when the number of stimuli was increased to 20, when stimulation was done in high calcium saline, or when the frequency of stimulation was increased to 50 or 100 Hz. The recovery from depression was greater after 20-Hz stimulation than at lower frequencies, although the recovery was reduced when the number of stimuli was increased, and also in high calcium saline. 4. In normal saline the depression of the EPSP amplitude was associated with a reduction of the presynaptic spike amplitude at frequencies of > or = 5 Hz. In tetraethylammonium (TEA) saline the width of a TEA-broadened spike was also reduced. The reduction in spike amplitude and spike width correlated with the depression of the EPSP. 5. Certain of these results are consistent with a depletion model of synaptic depression, whereas others are not consistent with this model. The depression may be partly due to an initial depletion of transmitter stores, and partly to modulation of the presynaptic action potential that reduces calcium entry, and therefore transmitter release. The significance of the depression on the motor program for kicking and jumping is discussed.

The influence of an unmyelinated terminal on repetitive firing of a mammalian receptor afferent fiber.

The distal end of a myelinated receptor afferent fiber consists of an unmyelinated terminal membrane which is assumed to be the site of sensory transduction, whereas the action potential encoding appears at a distal node of Ranvier. In the present paper a model of a mammalian myelinated nerve fiber was augmented by an unmyelinated terminal segment into which stimulating current was injected thus modelling the situation at a myelinated receptor afferent fiber. It was found that the introduction of the unmyelinated terminal reduces the repetitive firing rate shown by the model. However, also the amplitude of the spikes at the site of action potential generation diminishes through the large electrical load which the unmyelinated terminal imposes onto the active parts of the nerve fiber model. This "loss" of spike amplitude can abolish the ability of the model to show repetitive activity, if the unmyelinated terminal increases in size. On the other hand, the incorporation of sodium channels into the terminal membrane compensates the spike amplitude reduction introduced by the electrical load of that membrane. This allows repetitive firing at a lower frequency than would be possible for a model with an equivalent sodium-channel-free terminal. The results show that the unmyelinated terminal present at the distal end of myelinated receptor afferent fibers has not only the ability to provide sensory transduction but evokes also a reduction in the discharge rate of the encoding membrane.

Antiarrhythmic and Cardiovascular Actions of the New Antibiotic Agent Pirlimycin Adenylate

Pirlimycin adenylate (U-63,440) is a clindamycin analog possessing antiarrhythmic activity. In the anesthetized dog, the sustained ventricular tachycardia produced by ouabain intoxication is converted to a normal sinus rhythm with an average dose of 26.0 +/- 5.1 mg/kg of pirlimycin adenylate (range 13.4-40.7 mg/kg i.v.). The drug failed, however, to decrease arrhythmia frequency in a modified 2-day Harris dog preparation even with doses of up to 100 mg/kg. The efficacy of pirlimycin adenylate against ouabain-induced arrhythmias cannot be ascribed to a local anesthetic action, since concentrations of up to 5 X 10(-3) M produced only a small (26 +/- 5%) reduction in the spike amplitude of desheathed isolated frog sciatic nerves. In contrast, lidocaine (5 X 10(-3) M) produced a 91% reduction in single spike amplitude. Neither did pirlimycin adenylate (up to 10(-3) M) produce any negative inotropic effect in isolated cat papillary muscles, while both lidocaine and quinidine were cardiodepressant at 10(-3) M. It is concluded that pirlimycin adenylate may be an interesting prototype antiarrhythmic agent and further chemical modification of the drug molecule might increase the spectrum of antiarrhythmic activity without altering the drug's toxicity.

Effects of iontophoretically applied (+)- and (−)-naloxone on rat hypothalamic and septal neurons

The purpose of this study was to investigate the possible independent actions of both (+)- and (-)-naloxone on individual neurons in the preoptic/anterior hypothalamus (POAH) and septal area (SA) of the rat brain. Morphine and (-)-naloxone were applied to 31 neurons in the SA (n= 11) and the POAH (n= 20). Morphine depressed the spontaneous activity in 19 of 31 neurons. (-)-Naloxone at currents less than 10 nA did not influence these neurons. However, (-)-naloxone applied in excess of 10 nA reduced spontaneous activity in 28 of 29 neurons. This effect of (-)-naloxone was stereospecific; (+)-naloxone did not alter the spontaneous rate in 12 of 14 cells when alternately applied with (-)-naloxone at the same current intensity. Application of (+)- and (-)-naloxone at supramaximal currents produced a diminution of spike amplitude and an increase in the duration of the action potential. The results of this study indicate that naloxone reduces spontaneous activity via two mechanisms. One involves a direct stereospecific action, and a second produces a non-specific reduction in spike amplitude and a prolongation of spike duration.

Effect of cortisol microiontophoresis on discharge time structure of dorsal hippocampal neurons in rabbits

The effect of microiontophoretic application of cortisol to single neurons of the dorsal hippocampus on the character of distribution of interspike intervals in their discharges was studied in chronic experiments on rabbits. Cortisol modified the time structure of regular and rhythmic discharges of hippocampal neurons. Regularization of discharges in the form of bursting activity appeared as the result of cortisol in cells with irregular spontaneous activity. Activity of more than half of the neurons, in which bursting discharges corresponded in frequency to the theta-rhythm, was intensified as a result of microapplication of cortisol. In neurons discharging complex spikes, in which under normal conditions a phenomenon of reduction of spike amplitude was observed within each burst, no definite rule as regards changes in the time structure of the discharges could be observed after administration of the hormone. It is suggested that cortisol plays a modulating role in mechanisms of generation of spike activity by hippocampal neurons.

CNS site of β-adrenergic blocker-induced hypotension in the cat: A microiontophoretic study of bulbar cardiovascular neurones

For the purpose of localizing the central site and mechanism of β-adrenergic blocker-induced hypotension, propranolol and sotalol were applied by the technique of microiontophoresis to neurones of the bulbar cardiovascular centre in midcollicular decerebratc cats. The excitatory and inhibitory cardiovascular neurones were identified by their response to an increase in the arterial blood pressure induced by intravenous injections of small doses of norepinephrine (NE). Both β-adrenergic blockers exhibited an inhibitory effect on the spontaneous firing rate of excitatory cardiovascular neurones but had no effect on the firing rate of inhibitory cardiovascular neurones. At the same or greater doses, they had no effect on the firing rate of noncardiovascular neurones recorded from the same area. However, at high doses, only propranolol produced a reduction of spike amplitude on each of the 3 types of neurones, indicative of a nonspecific local anaesthetic action which was unrelated to propranolol-induced cardiovascular neurone slowing. In 3 control experiments, sodium nitrite, a direct acting vasodilator agent, was found to have no effect on the activity of the cardiovascular neurones. While these results cannot exclude the possibility of a peripheral influence in β-adrenergic blocker induced-hypotension, it is concluded that the major hypotensive effect is the result of their action on β-adrenergic receptors of bulbar cardiovascular neurones.