Inhibition Of Action Potentials Research Articles

Vericiguat suppresses ventricular tachyarrhythmias inducibility in a rabbit myocardial infarction model.

The VICTORIA trial demonstrated a significant decrease in cardiovascular events through vericiguat therapy. This study aimed to assess the potential mechanisms responsible for the reduction of cardiovascular events with vericiguat therapy in a rabbit model of myocardial infarction (MI). A chronic MI rabbit model was created through coronary artery ligation. Following 4 weeks, the hearts were harvested and Langendorff perfused. Subsequently, electrophysiological examinations and dual voltage-calcium optical mapping studies were conducted at baseline and after administration of vericiguat at a dose of 5 μmol/L. Acute vericiguat therapy demonstrated a significant reduction in premature ventricular beat burden and effectively suppressed ventricular arrhythmic inducibility. The electrophysiological influences of vericiguat therapy included an increased ventricular effective refractory period, prolonged action potential duration, and accelerated intracellular calcium (Cai) homeostasis, leading to the suppression of action potential and Cai alternans. The pacing-induced ventricular arrhythmias exhibited a reentrant pattern, attributed to fixed or functional conduction block in the peri-infarct zone. Vericiguat therapy effectively mitigated the formation of cardiac alternans as well as the development of reentrant impulses, providing additional anti-arrhythmic benefits. In the MI rabbit model, vericiguat therapy demonstrates anti-ventricular arrhythmia effects. The vericiguat therapy reduces ventricular ectopic beats, inhibiting the initiation of ventricular arrhythmias. Furthermore, the therapy successfully suppresses cardiac alternans, preventing conduction block and, consequently, the formation of reentry circuits.

Modeling ultrasound modulation of neural function in a single cell

BackgroundLow intensity ultrasound stimulation has been shown to non-invasively modulate neural function in the central nervous system (CNS) and peripheral nervous system (PNS) with high precision. Ultrasound sonication is capable of either excitation or inhibition, depending on the ultrasound parameters used. On the other hand, the mode of interaction of ultrasonic waves with the neural tissue for effective neuromodulation remains ambiguous. New methodHere within we propose a numerical model that incorporates the mechanical effects of ultrasound stimulation on the Hodgkin-Huxley (HH) neuron by incorporating the relation between increased external pressure and the membrane induced tension, with a stress on the flexoelectric effect on the neural membrane. The external pressure causes an increase in the total tension of the membrane thus affecting the probability of the ion channels being open after the conformational changes that those channels undergo. ResultsThe interplay between varying the acoustic intensities and frequencies depicts different action potential suppression rates, whereby a combination of low intensity and low frequency ultrasound sonication proved to be the most effective in modulating neural function.Comparison with Existing Methods: Our method solely depends on the HH model of a single neuron and the linear flexoelectric effect of the dielectric neural membrane, when under an ultrasound-induced mechanical strain, while varying the ion-channels conductances based on different sonication frequencies and intensities. We study the effect of ultrasound parameters on the firing rate, latency, and action potential amplitude of a HH neuron for a better understanding of the neuromodulation modality of ultrasound stimulation (in the continuous and pulsed modes). ConclusionsThis simulation work confirms the published experimental data that low intensity and low frequency ultrasound sonication has a higher success rate of modulating neural firing.

Kv1 activator mechanism of action in action potential inhibition.

Delayed-rectifier, voltage-gated potassium channels (Kv), such as the Kv1 family, are found in nociceptive dorsal root ganglion (DRG) neurons and represent a potential target for novel analgesics. Activating Kv1 channels in nociceptive neurons may work to decrease neuronal excitability and diminish the sensation of pain. Here, we explored the mechanism by which a Kv1 activator decreases action potential firing in DRG neurons. The small molecules compound A (cmpd-A) and B (cmpd-B) induced a hyperpolarizing shift in the conductance-voltage relationship of a heterologously-expressed Kv1 channel while cmpd-A additionally slowed the deactivation rate in a voltage-independent manner. Cmpd-A, but not cmpd-B, caused a frequency-dependent inhibition of AP firing in rat DRG neurons. We examined the effects of both compounds on Kv1 biophysics and neuronal membrane properties to explain the mechanism of action underlying cmpd-A AP inhibition.

Suppression of transmembrane sodium currents on the freshly isolated hippocampal neuron cell with continuous infrared light

Physiotherapeutic effects of infrared lasers have been proved in clinic. These infrared-based regulations of the bioelectrical activities can roughly be classified into enhancement and suppression of action potential (AP), which are described by sodium (Na) and potassium (K) transmembrane current equations, named as Hodgkin and Huxley (HH)-model. The enhancement effect is able to evoke or strengthen the AP when infrared light is applied. Its corresponding mechanism is commonly ascribed to the changes of the cell membrane capacitance, which is transiently increased in response to the infrared radiation. The distinctive feature of the suppression effect is to inhibit or reduce the AP by the designed protocols of infrared radiation. However, its mechanism presents more complexity than that in enhancement cases. HH-model describes how the Na current determines the initial phase of AP. So, the enhancement and suppression of AP can be also ascribed to the regulations of the corresponding Na currents. Here, a continuous infrared light at the wavelength of 980[Formula: see text]nm (CIS-980) was employed to stimulate a freshly isolated hippocampal neuron in vitro and a suppression effect on the Na currents of the neuron cell was observed. Both Na and K currents, which are named as whole cell currents, were simultaneously recorded with the cell membrane capacitance current by using a patch clamp combined with infrared irradiation. The results demonstrated that the CIS-980 was able to reversibly increase the capacitance currents, completely suppressed Na currents, but little changed K currents, which forms the steady outward whole cell currents and plays a major role on the AP repolarization. A confirmation experiment was designed and carried out by synchronizing tens of milliseconds of infrared stimulation on the same kinds of hippocampal neuron cells. After the blocked K channel, a reduction of Na current amplitude was still recorded. This proved that infrared suppression of Na current was irrelevant to K channel. A membrane capacitance mediation process was preliminarily proposed to explain the Na channel suppression process.

Pentylamine inhibits humidity detection in insect vectors of human and plant borne pathogens

Insects house humidity-sensing neurons in the antenna, which is presumed to be important for a variety of behaviors and survival since water is a crucial component of the environment. Here we use the simple olfactory system of the Asian Citrus Psyllid (ACP), a citrus pest that transmits a deadly bacterium, to identify volatile amines that significantly inhibited humidity-induced activation of antennal neurons. The inhibition of action potentials is observed by single sensillum recordings and mixing these odorants with humid air abolished the humidity avoidance behavior of ACP. The inhibition is conserved in the humidity-sensing coeloconic neurons of dipteran Drosophila melanogaster that are known to detect humidity, but it is not seen in other coeloconic neurons that are not sensitive to humidity. Dipteran mosquitoes Aedes aegypti and Anopheles gambiae oviposit in water, and the addition of the humidity-inhibiting odorants in a two-choice oviposition assay significantly reduces oviposition. Our results demonstrate that a naturally occurring volatile compound can effectively “mask” detection of an important environmental cue and modify behavior of important vectors of plant and human disease pathogens. Odorants targeting the conserved humidity sensing system of insects, therefore, offer a novel strategy for modifying their behavior.

The ethanol inhibition of basolateral amygdala neuron spiking is mediated by a γ-aminobutyric acid type A-mediated tonic current.

The basolateral nucleus of the amygdala (BLA) plays an important role in the development of fear and anxiety-related behaviors. The BLA receives inputs from all sensory stimuli. After processing those stimuli, BLA neurons signal neurons within the central amygdala and other brain regions, including the ventral and dorsal striatum and frontal cortex. Studies suggest that the BLA is involved in drug dependence and in the reinforcing actions of ethanol. For example, acute exposure to ethanol reduces anxiety, while withdrawal from chronic ethanol exposure alters BLA synaptic transmission, which increases anxiety, a common underlying cause of relapse. Exposure to and withdrawal from chronic alcohol also disrupts many brain areas that connect with the BLA. Despite these important findings, the acute actions of alcohol on the intrinsic excitability of BLA neurons have not been fully characterized. Brain slices containing the BLA were prepared from adult C57BL/6J male mice. Whole-cell and sharp electrode electrophysiological recordings were performed to characterize the effects of acute ethanol on BLA neuronal and astrocyte function, respectively. Ethanol inhibited action potential (AP) firing of BLA neurons but had no effect on BLA astrocyte resting membrane potential. The ethanol-induced inhibition of firing was concentration-dependent (11 to 66 mM) and accompanied by a reduction in the input resistance and an increase in the rheobase of BLA neurons. The inhibitory effect of ethanol was suppressed by picrotoxin, which blocks both γ-aminobutyric acid type A (GABAA ) and glycine receptors, but not by the selective glycine receptor antagonist strychnine, which suggests an involvement of GABAA receptors. Ethanol did not affect spontaneous inhibitory postsynaptic currents suggesting that the inhibition of BLA neuronal excitability by ethanol was not due to an increase in GABAA -mediated synaptic transmission. However, acute ethanol enhanced the amplitude of the holding current of BLA neurons, an effect that was prevented by picrotoxin, which by itself reduced the holding current. These results suggest that BLA neurons express a GABA-mediated tonic current that is enhanced by acute ethanol, which leads to reduced excitability of BLA neurons.

Mechanistic insights into ultrasonic neurostimulation of disconnected neurons using single short pulses

Ultrasonic neurostimulation is a potentially potent noninvasive therapy, whose mechanism has yet to be elucidated. We designed a system capable of applying ultrasound with minimal reflections to neuronal cultures. Synaptic transmission was pharmacologically controlled, eliminating network effects, enabling examination of single-cell processes. Short single pulses of low-intensity ultrasound were applied, and time-locked responses were examined using calcium imaging.Low-pressure (0.35 MPa) ultrasound directly stimulated ∼20% of pharmacologically disconnected neurons, regardless of membrane poration. Stimulation was resistant to the blockade of several purinergic receptor and mechanosensitive ion channel types. Stimulation was blocked, however, by suppression of action potentials. Surprisingly, even extremely short (4 μs) pulses were effective, stimulating ∼8% of the neurons. Lower-pressure pulses (0.35 MPa) were less effective than higher-pressure ones (0.65 MPa). Attrition effects dominated, with no indication of compromised viability.Our results detract from theories implicating cavitation, heating, non-transient membrane pores >1.5 nm, pre-synaptic release, or gradual effects. They implicate a post-synaptic mechanism upstream of the action potential, and narrow down the list of possible targets involved.

Nerve growth factor-mediated Na+ channel plasticity of bladder afferent neurons in mice with spinal cord injury

AimTo investigate the effect of nerve growth factor (NGF) neutralization on Na+ channel plasticity of bladder afferent neurons in mice with spinal cord injury (SCI). Main methodsFemale C57/BL6 mice were randomly divided into spinal intact (SI) group, SCI group and SCI + NGF-Ab group. SCI was induced by spinal cord transection at the Th8/9 level. In SCI + NGF-Ab group, anti-NGF antibodies (10 μg·kg-1 per hour) were continuously administered for 2 weeks using osmotic pumps. Bladder afferent neurons were labelled with Fluoro‑gold (FG) injected into the bladder wall. L6-S1 dorsal root ganglion (DRG) neurons were dissociated and whole-cell patch clamp recordings were performed on FG-labelled neurons. Expression of Nav1.7 and Nav1.8 was examined by immunofluorescent staining. Key findingsWhole-cell patch clamp recordings showed that TTX only partially inhibited action potentials (AP) and Na+ currents of bladder afferent neurons in SI mice, but it almost completely inhibited them in SCI mice. Total and TTX-sensitive Na+ currents were increased and TTX-resistant currents were decreased in bladder afferent neurons from SCI mice vs. SI mice. These changes in SCI mice were significantly reversed by NGF-antibody treatment. Immunostaining results showed the increased and decreased levels of Nav1.7 and Nav1.8, respectively, in FG-labelled bladder afferent neurons in SCI mice vs. SI mice, which was significantly reversed in SCI + NGF-Ab mice. SignificanceNGF mediates the Na+ channel plasticity with a shift from TTX-resistant Nav1.8 to TTX-sensitive Nav1.7 in bladder afferent neurons, which could be a possible underlying mechanism of bladder afferent hyperexcitability and detrusor overactivity after SCI.

Spontaneously Recycling Synaptic Vesicles Constitute Readily Releasable Vesicles in Intact Neuromuscular Synapses.

Emerging evidence shows that spontaneous synaptic transmission plays crucial roles on neuronal functions through presynaptic molecular mechanisms distinct from that of action potential (AP)-evoked transmission. However, whether the synaptic vesicle (SV) population undergoing the two forms of transmission is segregated remains controversial due in part to the conflicting results observed in cultured neurons. Here we address this issue in intact neuromuscular synapses using transgenic zebrafish larvae expressing two different indicators targeted in the SVs: a pH-sensitive fluorescent protein, pHluorin, and a tag protein, HaloTag. By establishing a quantitative measure of recycled SV fractions, we found that ∼85% of SVs were mobilized by high-frequency AP firings. In contrast, spontaneously recycling SVs were mobilized only from <8% of SVs with a time constant of 45 min at 25°C, although prolonged AP inhibition mobilized an additional population with a delayed onset. The mobilization of the early-onset population was less temperature-sensitive and resistant to tetanus toxin, whereas that of the late-onset population was more sensitive to temperature and was inhibited by tetanus toxin, indicating that prolonged AP inhibition activated a distinct molecular machinery for spontaneous SV fusion. Therefore, the early-onset population limited to <8% was likely the only source of spontaneous release that occurred physiologically. We further showed that this limited population was independent from those reluctant to fuse during AP firing and was used in both the hypertonic stimulation and the immediate phase of AP-evoked releases, thereby matching the characteristics of the readily releasable pool.SIGNIFICANCE STATEMENT Synaptic vesicles (SVs) are divided into functionally distinct pools depending on how they respond to action potential (AP) firing. The origin of SVs used for spontaneous fusion remains enigmatic despite intensive studies in cultured preparations. We addressed this question in intact neuromuscular synapses and provided two findings. First, prolonged AP inhibition activated a distinct population of fusion, which needs to be distinguished from genuine spontaneous fusion arising from a highly limited fraction. Second, the limited fraction observed early in the AP inhibition period exhibited the characteristics of readily releasable pool in the subsequent round of stimulation. Our study revealed that the origin of spontaneous SV fusion is restricted to the readily releasable pool among the SV pools involved in AP-evoked fusion.

Enhancing GABA inhibition is the next generation of medications for essential tremor.

γ-Aminobutyric acid (GABA) is the most prevalent inhibitory CNS neurotransmitter. Activating GABA-A receptors hyperpolarizes cells via Cl- influx, which inhibits action potentials. Although the exact pathophysiologies of tremor are incompletely understood, proposed neuroanatomy extensively implicates GABA pathways. Pathological studies and imaging studies also show GABA abnormalities in patients with ET. Most importantly, medications that activate GABA-A receptors, such as primidone, often improve tremor. Ongoing clinical trials and physiology research should further refine potential future GABAergic targets and treatments, which are currently the most promising targets for pharmacological intervention.

Central opioid receptors mediate morphine-induced itch and chronic itch via disinhibition.

Opioids such as morphine are mainstay treatments for clinical pain conditions. Itch is a common side effect of opioids, particularly as a result of epidural or intrathecal administration. Recent progress has advanced our understanding of itch circuits in the spinal cord. However, the mechanisms underlying opioid-induced itch are not fully understood, although an interaction between µ-opioid receptor (MOR) and gastrin-releasing peptide receptor (GRPR) in spinal GRPR-expressing neurons has been implicated. In this study we investigated the cellular mechanisms of intrathecal opioid-induced itch by conditional deletion of MOR-encoding Oprm1 in distinct populations of interneurons and sensory neurons. We found that intrathecal injection of the MOR agonists morphine or DAMGO elicited dose-dependent scratching as well as licking and biting, but this pruritus was totally abolished in mice with a specific Oprm1 deletion in Vgat+ neurons [Oprm1-Vgat (Slc32a1)]. Loss of MOR in somatostatin+ interneurons and TRPV1+ sensory neurons did not affect morphine-induced itch but impaired morphine-induced antinociception. In situ hybridization revealed Oprm1 expression in 30% of inhibitory and 20% of excitatory interneurons in the spinal dorsal horn. Whole-cell recordings from spinal cord slices showed that DAMGO induced outward currents in 9 of 19 Vgat+ interneurons examined. Morphine also inhibited action potentials in Vgat+ interneurons. Furthermore, morphine suppressed evoked inhibitory postsynaptic currents in postsynaptic Vgat- excitatory neurons, suggesting a mechanism of disinhibition by MOR agonists. Notably, morphine-elicited itch was suppressed by intrathecal administration of NPY and abolished by spinal ablation of GRPR+ neurons with intrathecal injection of bombesin-saporin, whereas intrathecal GRP-induced itch response remained intact in mice lacking Oprm1-Vgat. Intrathecal bombesin-saporin treatment reduced the number of GRPR+ neurons by 97% in the lumber spinal cord and 91% in the cervical spinal cord, without changing the number of Oprm1+ neurons. Additionally, chronic itch from DNFB-induced allergic contact dermatitis was decreased by Oprm1-Vgat deletion. Finally, naloxone, but not peripherally restricted naloxone methiodide, inhibited chronic itch in the DNFB model and the CTCL model, indicating a contribution of central MOR signalling to chronic itch. Our findings demonstrate that intrathecal morphine elicits itch via acting on MOR on spinal inhibitory interneurons, leading to disinhibition of the spinal itch circuit. Our data also provide mechanistic insights into the current treatment of chronic itch with opioid receptor antagonist such as naloxone.

In situ labeling of non-accommodating interneurons based on metabolic rates

Maintaining high frequency firing of narrow action potentials puts a large metabolic load on fast spiking (FS), perisomatic-inhibitory interneurons compared to their slow-spiking, dendrite targeting counterparts. Although the relationship of action potential (AP) firing and metabolism is firmly established, there is no single method to differentiate interneurons in situ based on their firing properties.In this study, we explore a novel strategy to easily identify the metabolically active FS cells among different classes of interneurons.We found that the oxidation of the fluorescent free radical marker 2,7-dichlorodihydrofluorescein (H2DCF) preferentially occurs in interneurons both in slice cultures and acute brain slices. Despite their morphological heterogeneity, almost all DCF-positive (DCF+) neurons belonged to the cluster of non-accommodating FS interneurons. Furthermore, all FS interneurons expressing parvalbumin (PV) both in slice cultures and in acute slices from tdTomato-PVCre transgenic mice were also DCF+. However, only half of the recorded DCF + cells were also PV+, indicating that H2DCF-oxidation occurs in different interneuron classes characterized by non-accomodating AP-firing. Comprehensively enhancing spontaneous neuronal activity led to mitochondrial oxidation of DCF in pyramidal cells as well as interneurons, suggesting that the apparent selectivity towards interneurons represents differences in the underlying metabolic load.While radical-scavenging, inhibition of APs or NO-synthesis, and iron chelation had no effect on the staining pattern, exposure to the complex-I inhibitor, rotenone, prevented interneuronal DCF accumulation. We conclude that H2DCF oxidation is independent of free radicals but correlates with the intensive oxidative energy metabolism and high mitochondrial mass in interneurons sharing the non-accommodating FS phenotype.

Approved LXR agonists exert unspecific effects on pancreatic \u03b2-cell function

Novel agonists of the nuclear liver-X-receptor (LXR) are designed to treat metabolic disorders or cancer. The rationale to develop these new drugs is based on promising results with established LXR agonist like T0901317 and GW3965. LXRα and LXRβ are expressed in β-cells, and expression is increased by T0901317. The aim of the present study was to evaluate whether effects of these drugs on β-cell function are specific and reliably linked to LXR activation. T0901317 and GW3965, widely used as specific LXR agonists, show rapid, non-genomic effects on stimulus-secretion coupling of mouse pancreatic β-cells at low µM concentrations. T0901317 lowered the cytosolic Ca2+ concentration, reduced or completely inhibited action potentials, and decreased insulin secretion. GW3965 exerted similar effects on insulin secretion. T0901317 affected the production of reactive oxygen species and ATP. The involvement of the classical nuclear LXRs in T0901317- and GW3965-mediated effects in β-cells could be ruled out using LXRα, LXRβ and double knockout mice. Our results strongly suggest that LXR agonists, that are considered to be specific for this receptor, interfere with mitochondrial metabolism and metabolism-independent processes in β-cells. Thus, it is indispensable to test novel LXR agonists accompanying to ongoing clinical trials for acute and chronic effects on cell function in cellular systems and/or animal models lacking classical LXRs.

Anaesthesia with diethyl ether impairs jasmonate signalling in the carnivorous plant Venus flytrap (Dionaea muscipula).

General anaesthetics are compounds that induce loss of responsiveness to environmental stimuli in animals and humans. The primary site of action of general anaesthetics is the nervous system, where anaesthetics inhibit neuronal transmission. Although plants do not have neurons, they generate electrical signals in response to biotic and abiotic stresses. Here, we investigated the effect of the general volatile anaesthetic diethyl ether on the ability to sense potential prey or herbivore attacks in the carnivorous plant Venus flytrap (Dionaea muscipula). We monitored trap movement, electrical signalling, phytohormone accumulation and gene expression in response to the mechanical stimulation of trigger hairs and wounding under diethyl ether treatment. Diethyl ether completely inhibited the generation of action potentials and trap closing reactions, which were easily and rapidly restored when the anaesthetic was removed. Diethyl ether also inhibited the later response: jasmonic acid (JA) accumulation and expression of JA-responsive genes (cysteine protease dionain and type I chitinase). However, external application of JA bypassed the inhibited action potentials and restored gene expression under diethyl ether anaesthesia, indicating that downstream reactions from JA are not inhibited. The Venus flytrap cannot sense prey or a herbivore attack under diethyl ether treatment caused by inhibited action potentials, and the JA signalling pathway as a consequence.

Adenosine A3 receptor activation inhibits pronociceptive N-type Ca2+ currents and cell excitability in dorsal root ganglion neurons.

Recently, studies have focused on the antihyperalgesic activity of the A3 adenosine receptor (A3AR) in several chronic pain models, but the cellular and molecular basis of this effect is still unknown. Here, we investigated the expression and functional effects of A3AR on the excitability of small- to medium-sized, capsaicin-sensitive, dorsal root ganglion (DRG) neurons isolated from 3- to 4-week-old rats. Real-time quantitative polymerase chain reaction experiments and immunofluorescence analysis revealed A3AR expression in DRG neurons. Patch-clamp experiments demonstrated that 2 distinct A3AR agonists, Cl-IB-MECA and the highly selective MRS5980, inhibited Ca-activated K (KCa) currents evoked by a voltage-ramp protocol. This effect was dependent on a reduction in Ca influx via N-type voltage-dependent Ca channels, as Cl-IB-MECA-induced inhibition was sensitive to the N-type blocker PD173212 but not to the L-type blocker, lacidipine. The endogenous agonist adenosine also reduced N-type Ca currents, and its effect was inhibited by 56% in the presence of A3AR antagonist MRS1523, demonstrating that the majority of adenosine's effect is mediated by this receptor subtype. Current-clamp recordings demonstrated that neuronal firing of rat DRG neurons was also significantly reduced by A3AR activation in a MRS1523-sensitive but PD173212-insensitive manner. Intracellular Ca measurements confirmed the inhibitory role of A3AR on DRG neuronal firing. We conclude that pain-relieving effects observed on A3AR activation could be mediated through N-type Ca channel block and action potential inhibition as independent mechanisms in isolated rat DRG neurons. These findings support A3AR-based therapy as a viable approach to alleviate pain in different pathologies.

16-Channel biphasic current-mode programmable charge balanced neural stimulation

BackgroundNeural stimulation is an important method used to activate or inhibit action potentials of the neuronal anatomical targets found in the brain, central nerve and peripheral nerve. The neural stimulator system produces biphasic pulses that deliver balanced charge into tissue from single or multichannel electrodes. The timing and amplitude of these biphasic pulses are precisely controlled by the neural stimulator software or imbedded algorithms. Amplitude mismatch between the anodic current and cathodic current of the biphasic pulse will cause permanently damage for the neural tissues. The main goal of our circuit and layout design is to implement a 16-channel biphasic current mode programmable neural stimulator with calibration to minimize the current mismatch caused by inherent complementary metal oxide semiconductor (CMOS) manufacturing processes.MethodsThis paper presents a 16-channel constant current mode neural stimulator chip. Each channel consists of a 7-bit controllable current DAC used as sink and source current driver. To reduce the LSB quantization error and the current mismatch, an automatic calibration circuit and flow diagram is presented in this paper. There are two modes of operation of the stimulator chip—namely, stimulation mode and calibration mode. The chip also includes a digital interface used to control the stimulator parameters and calibration levels specific for each individual channel.ResultsThis stimulator Application Specific Integrated Circuit (ASIC) is designed and fabricated in a 0.18 μm High-Voltage CMOS technology that allows for ±20 V power supply. The full-scale stimulation current was designed to be at 1 mA per channel. The output current was shown to be constant throughout the timing cycles over a wide range of electrode load impedances. The calibration circuit was also designed to reduce the effect of CMOS process variation of the P-channel metal oxide semiconductor (PMOS) and N-channel metal oxide semiconductor (NMOS) devices that will result in charge delivery to have less than 0.13% error.ConclusionsA 16-channel integrated biphasic neural stimulator chip with calibration is presented in this paper. The stimulator circuit design was simulated and the chip layout was completed. The chip layout was verified using design rules check (DRC) and layout versus schematic (LVS) design check using computer aided design (CAD) software. The test results we presented show constant current stimulation with charge balance error within 0.13% least-significant-bit (LSB). This LSB error was consistent throughout a variety stimulation patterns and electrode load impedances.

Ryanodine and IP3 receptor-mediated calcium signaling play a pivotal role in neurological infrared laser modulation.

Pulsed infrared (IR) laser energy has been shown to modulate neurological activity through both stimulation and inhibition of action potentials. While the mechanism(s) behind this phenomenon is (are) not completely understood, certain hypotheses suggest that the rise in temperature from IR exposure could activate temperature- or pressure-sensitive ion channels or create pores in the cellular outer membrane, allowing an influx of typically plasma-membrane-impermeant ions. Studies using fluorescent intensity-based calcium ion ([Formula: see text]) sensitive dyes show changes in [Formula: see text] levels after various IR stimulation parameters, which suggests that [Formula: see text] may originate from the external solution. However, activation of intracellular signaling pathways has also been demonstrated, indicating a more complex mechanism of increasing intracellular [Formula: see text] concentration. We quantified the [Formula: see text] mobilization in terms of influx from the external solution and efflux from intracellular organelles using Fura-2 and a high-speed ratiometric imaging system that rapidly alternates the dye excitation wavelengths. Using nonexcitable Chinese hamster ovarian ([Formula: see text]) cells and neuroblastoma-glioma (NG108) cells, we demonstrate that intracellular [Formula: see text] receptors play an important role in the IR-induced [Formula: see text], with the [Formula: see text] response augmented by ryanodine receptors in excitable cells.

13 The effects of bio sugar influence on toad sciatic nerve-trunk action potential

Objectives MSD is a type of bio sugar made by an MS bio sugar research institute in South Korea. The bio sugar has a glycan structure with a functional group on the monosaccharide. Our objective was to observe the effects of different concentrations of MSD on toad sciatic nerve-trunk action potential, and whether MSD can improve the inhibitory effect on toad sciatic nerve-trunk action potential of hypertonic glucose solution. Methods Toad sciatic nerve trunks were randomly divided into three groups, namely a control group, an MSD group and a hypertonic glucose group. Following soaking with different concentrations of MSD, toad sciatic nerve-trunk action potential amplitudes and conduction velocities were determined using a BL-420 biological function experimental system. Results Compared with the control group, 1% MS inhibited toad sciatic nerve-trunk action potential amplitude and conduction velocity but the effects disappeared after 10 min, while 0.5% MSD decreased action potential amplitude and increased conduction velocity. Soaking in 10% hypertonic glucose with 0.5% MSD after processing permanently inhibited toad sciatic nerve-trunk action potential. MSD can inhibit toad sciatic nerve-trunk action potential amplitude and conduction velocity. Conclusions The activity of 0.5% MSD is better than that of 1% MSD. MSD can improve the inhibitory effects of 10% hypertonic glucose solution on toad sciatic nerve-trunk action potential. Acknowledgments This research was financially supported by the National Natural Science Foundation of China (Grant No. 31260207).

Dopamine Regulation of Lateral Inhibition between Striatal Neurons Gates the Stimulant Actions of Cocaine

Striatal medium spiny neurons (MSNs) form inhibitory synapses on neighboring striatal neurons through axon collaterals. The functional relevance of this lateral inhibition and its regulation by dopamine remains elusive. We show that synchronized stimulation of collateral transmission from multiple indirect-pathway MSNs (iMSNs) potently inhibits action potentials in direct-pathway MSNs (dMSNs) in the nucleus accumbens. Dopamine D2 receptors (D2Rs) suppress lateral inhibition from iMSNs to disinhibit dMSNs, which are known to facilitate locomotion. Surprisingly, D2R inhibition of synaptic transmission was larger at axon collaterals from iMSNs than their projections to the ventral pallidum. Targeted deletion of D2Rs from iMSNs impaired cocaine's ability to suppress lateral inhibition and increase locomotion. These impairments were rescued by chemogenetic activation of Gi-signaling in iMSNs. These findings shed light on the functional significance of lateral inhibition between MSNs and offer a novel synaptic mechanism by which dopamine gates locomotion and cocaine exerts its canonical stimulant response. VIDEO ABSTRACT.

Rate-dependent activation failure in isolated cardiac cells and tissue due to Na+ channel block.

While it is well established that class-I antiarrhythmics block cardiac sodium channels, the mechanism of action of therapeutic levels of these drugs is not well understood. Using a combination of mathematical modeling and in vitro experiments, we studied the failure of activation of action potentials in single ventricular cells and in tissue caused by Na(+) channel block. Our computations of block and unblock of sodium channels by a theoretical class-Ib antiarrhythmic agent predict differences in the concentrations required to cause activation failure in single cells as opposed to multicellular preparations. We tested and confirmed these in silico predictions with in vitro experiments on isolated guinea-pig ventricular cells and papillary muscles stimulated at various rates (2-6.67 Hz) and exposed to various concentrations (5 × 10(-6) to 500 × 10(-6) mol/l) of lidocaine. The most salient result was that whereas large doses (5 × 10(-4) mol/l or higher) of lidocaine were required to inhibit action potentials temporarily in single cells, much lower doses (5 × 10(-6) mol/l), i.e., therapeutic levels, were sufficient to have the same effect in papillary muscles: a hundredfold difference. Our experimental results and mathematical analysis indicate that the syncytial nature of cardiac tissue explains the effects of clinically relevant doses of Na(+) channel blockers.