Action Potential Failure Research Articles

Myelin dystrophy impairs signal transmission and working memory in a multiscale model of the aging prefrontal cortex.

Normal aging leads to myelin alterations in the rhesus monkey dorsolateral prefrontal cortex (dlPFC), which are positively correlated with degree of cognitive impairment. It is hypothesized that remyelination with shorter and thinner myelin sheaths partially compensates for myelin degradation, but computational modeling has not yet explored these two phenomena together systematically. Here, we used a two-pronged modeling approach to determine how age-related myelin changes affect a core cognitive function: spatial working memory. First, we built a multicompartment pyramidal neuron model fit to monkey dlPFC empirical data, with an axon including myelinated segments having paranodes, juxtaparanodes, internodes, and tight junctions. This model was used to quantify conduction velocity (CV) changes and action potential (AP) failures after demyelination and subsequent remyelination. Next, we incorporated the single neuron results into a spiking neural network model of working memory. While complete remyelination nearly recovered axonal transmission and network function to unperturbed levels, our models predict that biologically plausible levels of myelin dystrophy, if uncompensated by other factors, can account for substantial working memory impairment with aging. The present computational study unites empirical data from ultrastructure up to behavior during normal aging, and has broader implications for many demyelinating conditions, such as multiple sclerosis or schizophrenia.

Alzheimer’s-linked axonal changes accompany elevated antidromic action potential failure rate in aged mice

Alzheimer’s disease (AD) affects both grey and white matter (WM), but considerably more is known about the former. Interestingly, WM disruption has been consistently observed and thoroughly described using imaging modalities, particularly MRI which has shown WM functional disconnections between the hippocampus and other brain regions during AD pathogenesis when early neurodegeneration and synapse loss are also evident. Nonetheless, high-resolution structural and functional analyses of WM during AD pathogenesis remain scarce. Given the importance of the myelinated axons in the WM for conveying information across brain regions, such studies will provide valuable information on the cellular drivers and consequences of WM disruption that contribute to the characteristic cognitive decline of AD. Here, we employed a multi-scale approach to investigate hippocampal WM disruption during AD pathogenesis and determine whether hippocampal WM changes accompany the well-documented grey matter losses. Our data indicate that ultrastructural myelin disruption is elevated in the alveus in human AD cases and increases with age in 5xFAD mice. Unreliable action potential propagation and changes to sodium channel expression at the node of Ranvier co-emerged with this deterioration. These findings provide important insight to the neurobiological substrates and functional consequences of decreased WM integrity and are consistent with the notion that hippocampal disconnection contributes to cognitive changes in AD.

The influence of hyperpolarization-activated cation current on conduction delay and failure of action potentials along axon related to abnormal functions

The influence of hyperpolarization-activated cation current on conduction delay and failure of action potentials along axon related to abnormal functions

Targeted blockade of aberrant sodium current in a stem cell-derived neuron model of SCN3A encephalopathy.

Missense variants in SCN3A encoding the voltage-gated sodium (Na+) channel α subunit Nav1.3 are associated with SCN3A-related neurodevelopmental disorder (SCN3A-NDD), a spectrum of disease that includes epilepsy and malformation of cortical development. How genetic variation in SCN3A leads to pathology remains unclear, as prior electrophysiological work on disease-associated variants has been performed exclusively in heterologous cell systems. To further investigate the mechanisms of SCN3A-NDD pathogenesis, we used CRISPR/Cas9 gene editing to modify a control human induced pluripotent stem cell (iPSC) line to express the recurrent de novo missense variant SCN3A c.2624T>C (p.Ile875Thr). With the established Ngn2 rapid induction protocol, we generated glutamatergic forebrain-like neurons (iNeurons), which we showed to express SCN3A mRNA and Nav1.3-mediated Na+ currents. We performed detailed whole-cell patch clamp recordings to determine the effect of the SCN3A-p.Ile875Thr variant on endogenous Na+ currents in, and intrinsic excitability of, human neurons. Compared to control iNeurons, variant-expressing iNeurons exhibit markedly increased slowly-inactivating/persistent Na+ current, abnormal firing patterns with paroxysmal bursting and plateau-like potentials with action potential failure, and a hyperpolarized voltage threshold for action potential generation. We then validated these findings using a separate iPSC line generated from a patient harbouring the SCN3A-p.Ile875Thr variant compared to a corresponding CRISPR-corrected isogenic control line. Finally, we found that application of the Nav1.3-selective blocker ICA-121431 normalizes action potential threshold and aberrant firing patterns in SCN3A-p.Ile1875Thr iNeurons; in contrast, consistent with action as a Na+ channel blocker, ICA-121431 decreases excitability of control iNeurons. Our findings demonstrate that iNeurons can model the effects of genetic variation in SCN3A yet reveal a complex relationship between gain-of-function at the level of the ion channel versus impact on neuronal excitability. Given the transient expression of SCN3A in the developing human nervous system, selective blockade or suppression of Nav1.3-containing Na+ channels could represent a therapeutic approach towards SCN3A-NDD.

Facilitation of sensory transmission to motoneurons during cortical or sensory-evoked primary afferent depolarization (PAD) in humans.

Sensory and corticospinal tract (CST) pathways activate spinal GABAergic interneurons that have axoaxonic connections onto proprioceptive (Ia) afferents that cause long-lasting depolarizations (termed primary afferent depolarization, PAD). In rodents, sensory-evoked PAD is produced by GABAA receptors at nodes of Ranvier in Ia afferents, rather than at presynaptic terminals, and facilitates spike propagation to motoneurons by preventing branch-point failures, rather than causing presynaptic inhibition. We examined in 40 human participants whether putative activation of Ia-PAD by sensory or CST pathways can also facilitate Ia afferent activation of motoneurons via the H-reflex. H-reflexes in several leg muscles were facilitated by prior conditioning from low-threshold proprioceptive, cutaneous or CST pathways, with a similar long-lasting time course (∼200ms) to phasic PAD measured in rodent Ia afferents. Long trains of cutaneous or proprioceptive afferent conditioning produced longer-lasting facilitation of the H-reflex for up to 2min, consistent with tonic PAD in rodent Ia afferents mediated by nodal α5-GABAA receptors for similar stimulation trains. Facilitation of H-reflexes by this conditioning was likely not mediated by direct facilitation of the motoneurons because isolated stimulation of sensory or CST pathways did not alone facilitate the tonic firing rate of motor units. Furthermore, cutaneous conditioning increased the firing probability of single motor units (motoneurons) during the H-reflex without increasing their firing rate at this time, indicating that the underlying excitatory postsynaptic potential was more probable, but not larger. These results are consistent with sensory and CST pathways activating nodal GABAA receptors that reduce intermittent failure of action potentials propagating into Ia afferent branches. KEY POINTS: Controlled execution of posture and movement requires continually adjusted feedback from peripheral sensory pathways, especially those that carry proprioceptive information about body position, movement and effort. It was previously thought that the flow of proprioceptive feedback from Ia afferents was only reduced by GABAergic neurons in the spinal cord that sent axoaxonic projections to the terminal endings of sensory axons (termed GABAaxo neurons). Based on new findings in rodents, we provide complementary evidence in humans to suggest that sensory and corticospinal pathways known to activate GABAaxo neurons that project to dorsal parts of the Ia afferent also increase the flow of proprioceptive feedback to motoneurons in the spinal cord. These findings support a new role for spinal GABAaxo neurons in facilitating afferent feedback to the spinal cord during voluntary or reflexive movements.

Microgeometrical dendritic factors predict electrical decoupling between somatic and dendritic compartments in magnocellular neurosecretory neurons.

It is generally assumed that dendritic release of neuropeptides from magnocellular neurosecretory neurons (MNNs), a critical process involved in homeostatic functions, is an activity-dependent process that requires backpropagating action potentials (APs). Still, growing evidence indicates that dendritic release can occur in the absence of APs, and axonal APs have been shown to fail to evoke dendritic release. These inconsistencies strongly suggest that APs in MNNs may fail to backpropagating into dendrites. Here we tested whether simple factors of electrical signal attenuation could lead to effective decoupling between cell's body and dendritic release site within typical geometrical characteristics of MNN. We developed a family of linear mathematical models of MNNs and evaluated whether the somato-dendritic transfer of electrical signals is influenced by the geometrical characteristics. We determined the prerequisites for critically strong dendritic attenuation of the somatic input which are sufficient to explain the failure of APs initiated in the soma to backpropagating into dendritic compartments. Being measured in 100 μm from soma voltage attenuations down to 0.1 and 0.01 of the input value were chosen as the markers of electrical decoupling of dendritic sites from the soma, considering 0.1 insufficient for triggering dendritic spikes and 0.01 indistinguishable from background noise. The tested micro-geometrical factors were the dendritic stem diameter, varicosities, and size of peri-dendritic space limited by glial sheath wrapping. Varicosities increased the attenuation along homogeneous proximal dendrites by providing an increased current leak at the junction with the proximal dendritic section. The glial sheath wrapping a dendrite section promoted greater attenuation by increasing longitudinal resistance of the interstitial peri-dendritic space thus playing the insulating role. These decoupling effects were strengthened in the case of the dendritic stems with thinner diameters of and/or increased conductivity of the membrane. These micro-geometrical factors are biophysically realistic and predict electrical decoupling between somatic and dendritic compartments in MNNs.

NaV1.1 is essential for proprioceptive signaling and motor behaviors.

The voltage-gated sodium channel (NaV), NaV1.1, is well-studied in the central nervous system; conversely, its contribution to peripheral sensory neuron function is more enigmatic. Here, we identify a new role for NaV1.1 in mammalian proprioception. RNAscope analysis and in vitro patch-clamp recordings in genetically identified mouse proprioceptors show ubiquitous channel expression and significant contributions to intrinsic excitability. Notably, genetic deletion of NaV1.1 in sensory neurons caused profound and visible motor coordination deficits in conditional knockout mice of both sexes, similar to conditional Piezo2-knockout animals, suggesting that this channel is a major contributor to sensory proprioceptive transmission. Ex vivo muscle afferent recordings from conditional knockout mice found that loss of NaV1.1 leads to inconsistent and unreliable proprioceptor firing characterized by action potential failures during static muscle stretch; conversely, afferent responses to dynamic vibrations were unaffected. This suggests that while a combination of Piezo2 and other NaV isoforms is sufficient to elicit activity in response to transient stimuli, NaV1.1 is required for transmission of receptor potentials generated during sustained muscle stretch. Impressively, recordings from afferents of heterozygous conditional knockout animals were similarly impaired, and heterozygous conditional knockout mice also exhibited motor behavioral deficits. Thus, NaV1.1 haploinsufficiency in sensory neurons impairs both proprioceptor function and motor behaviors. Importantly, human patients harboring NaV1.1 loss-of-function mutations often present with motor delays and ataxia; therefore, our data suggest that sensory neuron dysfunction contributes to the clinical manifestations of neurological disorders in which NaV1.1 function is compromised. Collectively, we present the first evidence that NaV1.1 is essential for mammalian proprioceptive signaling and behaviors.

The peak force-resting membrane potential relationships of mouse fast- and slow-twitch muscle.

We endeavored to understand the factors determining the peak force-resting membrane potential (EM) relationships of isolated slow-twitch soleus and fast-twitch extensor digitorum longus (EDL) muscles from mice (25°C), especially in relation to fatigue. Interrelationships between intracellular K+ activity ([Formula: see text]), extracellular K+ concentration ([K+]o), resting EM, action potentials, and force were studied. The large resting EM variation was mainly due to the variability of [Formula: see text]. Action potential overshoot-resting EM relationships determined at 4 and 8-10 mM [K+]o after short (<5 min) and prolonged (>50 min) depolarization periods revealed a constant overshoot from -90 to -70 mV providing a safety margin. Overshoot decline with depolarization beyond -70 mV was less after short than prolonged depolarization. Inexcitable fibers occurred only with prolonged depolarization. The overshoot decline during action potential trains (2 s) exceeded that during short depolarizations. Concomitant lower extracellular [Na+] and raised [K+]o depressed the overshoot in an additive manner and peak force in a synergistic manner. Raised [K+]o-induced force loss was exacerbated with transverse wire versus parallel plate stimulation in soleus, implicating action potential propagation failure in the surface membrane. Increasing stimulus pulse parameters restored tetanic force at 9-10 mM [K+]o in soleus but not EDL, indicative of action potential failure within trains. The peak tetanic force-resting EM relationships (determined with resting EM from deeper rather than surface fibers) were dynamic and showed pronounced force depression over -69 to -60 mV in both muscle types, implicating that such depolarization contributes to fatigue. The K+-Na+ interaction shifted this relationship toward less depolarized potentials, suggesting that the combined ionic effect is physiologically important during fatigue.

Somatostatin-Positive Interneurons Contribute to Seizures in SCN8A Epileptic Encephalopathy.

SCN8A epileptic encephalopathy is a devastating epilepsy syndrome caused by mutant SCN8A, which encodes the voltage-gated sodium channel NaV1.6. To date, it is unclear if and how inhibitory interneurons, which express NaV1.6, influence disease pathology. Using both sexes of a transgenic mouse model of SCN8A epileptic encephalopathy, we found that selective expression of the R1872W SCN8A mutation in somatostatin (SST) interneurons was sufficient to convey susceptibility to audiogenic seizures. Patch-clamp electrophysiology experiments revealed that SST interneurons from mutant mice were hyperexcitable but hypersensitive to action potential failure via depolarization block under normal and seizure-like conditions. Remarkably, GqDREADD-mediated activation of WT SST interneurons resulted in prolonged electrographic seizures and was accompanied by SST hyperexcitability and depolarization block. Aberrantly large persistent sodium currents, a hallmark of SCN8A mutations, were observed and were found to contribute directly to aberrant SST physiology in computational modeling and pharmacological experiments. These novel findings demonstrate a critical and previously unidentified contribution of SST interneurons to seizure generation not only in SCN8A epileptic encephalopathy, but epilepsy in general.SIGNIFICANCE STATEMENTSCN8A epileptic encephalopathy is a devastating neurological disorder that results from de novo mutations in the sodium channel isoform Nav1.6. Inhibitory neurons express NaV1.6, yet their contribution to seizure generation in SCN8A epileptic encephalopathy has not been determined. We show that mice expressing a human-derived SCN8A variant (R1872W) selectively in somatostatin (SST) interneurons have audiogenic seizures. Physiological recordings from SST interneurons show that SCN8A mutations lead to an elevated persistent sodium current which drives initial hyperexcitability, followed by premature action potential failure because of depolarization block. Furthermore, chemogenetic activation of WT SST interneurons leads to audiogenic seizure activity. These findings provide new insight into the importance of SST inhibitory interneurons in seizure initiation, not only in SCN8A epileptic encephalopathy, but for epilepsy broadly.

Essential Role of Somatic Kv2 Channels in High-Frequency Firing in Cartwheel Cells of the Dorsal Cochlear Nucleus.

Among all voltage-gated potassium (Kv) channels, Kv2 channels are the most widely expressed in the mammalian brain. However, studying Kv2 in neurons has been challenging because of a lack of high-selective blockers. Recently, a peptide toxin, guangxitoxin-1E (GxTX), has been identified as a specific inhibitor of Kv2, thus facilitating the study of Kv2 in neurons. The mammalian dorsal cochlear nucleus (DCN) integrates auditory and somatosensory information. In the DCN, cartwheel inhibitory interneurons receive excitatory synaptic inputs from parallel fibers conveying somatosensory information. The activation of parallel fibers drives action potentials in the cartwheel cells up to 130 Hz in vivo, and the excitation of cartwheel cells leads to the strong inhibition of principal cells. Therefore, cartwheel cells play crucial roles in monaural sound localization and cancelling detection of self-generated sounds. However, how Kv2 controls the high-frequency firing in cartwheel cells is unknown. In this study, we performed immunofluorescence labeling with anti-Kv2.1 and anti-Kv2.2 antibodies using fixed mouse brainstem slice preparations. The results revealed that Kv2.1 and Kv2.2 were largely present on the cartwheel cell body membrane but not on the axon initial segment (AIS) nor the proximal dendrite. Whole-cell patch-clamp recordings using mouse brainstem slice preparation and GxTX demonstrated that blockade of Kv2 induced failure of parallel fiber-induced action potentials when parallel fibers were stimulated at high frequencies (30–100 Hz). Thus, somatic Kv2 in cartwheel cells regulates the action potentials in a frequency-dependent manner and may play important roles in the DCN function.

Effects of extracellular potassium on calcium handling and force generation in a model of excitation-contraction coupling in skeletal muscle

It is well-established that extracellular potassium (Ko+) accumulation reduces muscle fiber excitability, however the effects of Ko+ on the excitation–contraction coupling (ECC) pathway are less understood. In vivo and in vitro studies following fatiguing stimulation protocols are limited in their ability to capture the effects of Ko+ on force production in combination with other simultaneously changing factors. To address this, a computational model of ECC for slow and fast twitch muscle is presented to explore the relative contributions of excitability-induced and metabolic-induced changes in force generation in response to increasing K+o. The model incorporates mechanisms previously unexplored in modelling studies, including the effects of extracellular calcium on excitability, calcium-dependent inhibition of calcium release, ATP-dependent ionic pumping, and the contribution of ATP hydrolysis to intracellular phosphate accumulation rate. The model was able to capture the frequency-dependent biphasic Force-K+o response observed experimentally. Force potentiation for moderately elevated K+o was driven by increased action potential duration, myoplasmic calcium potentiation, and phosphate accumulation rate, while attenuation of force at higher K+o was due to action potential failure resulting in reduced calcium release. These results suggest that altered calcium release and phosphate accumulation work together with elevated Ko+ to affect force during sustained contractions.

MUSCLE FUNCTION & HOMEOSTASIS / MOLECULAR THERAPEUTIC APPROACHES: P.73 Depletion of ATP limits membrane excitability of skeletal muscle by increasing both ClC1-open probability and membrane conductance

Activation of skeletal muscle contractions require that action potentials can be excited and propagated along the muscle fibers. It is known that muscle fiber excitability is regulated during repeated firing of action potentials by cellular signalling systems that control the function of ion channels that determine the resting membrane conductance (Gm). In fast-twitch muscle, prolonged firing of action potentials triggers a marked increase in Gm, reducing muscle fiber excitability and causing action potential failure.

Depletion of ATP Limits Membrane Excitability of Skeletal Muscle by Increasing Both ClC1-Open Probability and Membrane Conductance

Activation of skeletal muscle contractions require that action potentials can be excited and propagated along the muscle fibers. Recent studies have revealed that muscle fiber excitability is regulated during repeated firing of action potentials by cellular signaling systems that control the function of ion channel that determine the resting membrane conductance (Gm). In fast-twitch muscle, prolonged firing of action potentials triggers a marked increase in Gm, reducing muscle fiber excitability and causing action potential failure. Both ClC-1 and KATP ion channels contribute to this Gm rise, but the exact molecular regulation underlying their activation remains unclear. Studies in expression systems have revealed that ClC-1 is able to bind adenosine nucleotides, and that low adenosine nucleotide levels result in ClC-1 activation. In three series of experiments, this study aimed to explore whether ClC-1 is also regulated by adenosine nucleotides in native skeletal muscle fibers, and whether the adenosine nucleotide sensitivity of ClC-1 could explain the rise in Gm muscle fibers during prolonged action potential firing. First, whole cell patch clamping of mouse muscle fibers demonstrated that ClC-1 activation shifted in the hyperpolarized direction when clamping pipette solution contained 0 mM ATP compared with 5 mM ATP. Second, three-electrode Gm measurement during muscle fiber stimulation showed that glycolysis inhibition, with 2-deoxy-glucose or iodoacetate, resulted in an accelerated and rapid >400% Gm rise during short periods of repeated action potential firing in both fast-twitch and slow-twitch rat, and in human muscle fibers. Moreover, ClC-1 inhibition with 9-anthracenecarboxylic acid resulted in either an absence or blunted Gm rise during action potential firing in human muscle fibers. Third, Gm measurement during repeated action potential firing in muscle fibers from a murine McArdle disease model suggest that the rise in Gm was accelerated in a subset of fibers. Together, these results are compatible with ClC-1 function being regulated by the level of adenosine nucleotides in native tissue, and that the channel operates as a sensor of skeletal muscle metabolic state, limiting muscle excitability when energy status is low.

Kv3.1 and Kv3.3 subunits differentially contribute to Kv3 channels and action potential repolarization in principal neurons of the auditory brainstem.

Kv3.1 and Kv3.3 subunits are highly expressed in the auditory brainstem, with little or no mRNA for Kv3.2 or Kv3.4. Changes in Kv3 currents and action potential (AP) firing were analysed from wild-type, Kv3.1 and Kv3.3 knockout (KO) mice. Both Kv3.1 and Kv3.3 immunostaining was present and western blots confirmed loss of subunit protein in the respective KO. Medial nucleus of the trapezoid body (MNTB) AP repolarization utilized Kv3.1 and/or Kv3.3; while in the lateral superior olive (LSO) Kv3.3 was essential. Voltage-gated calcium currents were unchanged between the genotypes. But APs evoked higher [Ca2+ ]i in LSO than MNTB neurons; and were highest in the Kv3.3KO, consistent with longer AP durations. High frequency stimulation increased AP failure rates and AP latency in LSO neurons from the Kv3.3KO, underlining the physiological consequences for binaural integration. LSO neurons require Kv3.3 for functional Kv3 channels, while MNTB neurons can utilize either Kv3.1 or Kv3.3 subunits. Kv3 voltage-gated potassium channels mediate action potential (AP) repolarization. The relative importance of Kv3.1 and Kv3.3 subunits for assembly of functional channels in neurons of the auditory brainstem was examined from the physiological perspective that speed and precision of AP firing are crucial for sound source localization. High levels of Kv3.1 and Kv3.3 mRNA and protein were measured, with no evidence of compensation by Kv3.2 or Kv3.4 in the respective knockout (KO) mouse. Using the KOs, composition of Kv3 channels was constrained to either Kv3.1 or Kv3.3 subunits in principal neurons of the medial nucleus of the trapezoid body (MNTB) and lateral superior olive (LSO); while TEA (1mm) was employed to block Kv3-mediated outward potassium currents in voltage- and current clamp experiments. MNTB neuron APs (half-width 0.31±0.08ms, n=25) were fast, reliable, and showed no distinction between channels assembled from Kv3.1 or Kv3.3 subunits (in the respective KO). LSO AP half-widths were also fast, but absolutely required Kv3.3 subunits for fast repolarization (half-widths: 0.25±0.08ms, n=19 wild-type, 0.60±0.17ms, n=21 Kv3.3KO, p=0.0001). The longer AP duration increased LSO calcium influx and AP failure rates, and increased AP latency and jitter during high frequency repetitive firing. Both Kv3.1 and Kv3.3 subunits contribute to Kv3 channels in the MNTB (and compensate for each other in each KO); in contrast, LSO neurons require Kv3.3 subunits for fast repolarization and to sustain AP firing during high frequency stimulation. In conclusion, Kv3 channels exhibit both redundancy and Kv3.3 dominance between the brainstem nuclei involved in sound localization.

Modeling the Effect of Temperature on Membrane Response of Light Stimulation in Optogenetically-Targeted Neurons.

Optogenetics is revolutionizing Neuroscience, but an often neglected effect of light stimulation of the brain is the generation of heat. In extreme cases, light-generated heat kills neurons, but mild temperature changes alter neuronal function. To date, most in vivo experiments rely on light stimulation of neural tissue using fiber-coupled lasers of various wavelengths. Brain tissue is irradiated with high light power that can be deleterious to neuronal function. Furthermore, absorbed light generates heat that can lead to permanent tissue damage and affect neuronal excitability. Thus, light alone can generate effects in neuronal function that are unrelated to the genuine “optogenetic effect.” In this work, we perform a theoretical analysis to investigate the effects of heat transfer in rodent brain tissue for standard optogenetic protocols. More precisely, we first use the Kubelka-Munk model for light propagation in brain tissue to observe the absorption phenomenon. Then, we model the optothermal effect considering the common laser wavelengths (473 and 593 nm) used in optogenetic experiments approaching the time/space numerical solution of Pennes' bio-heat equation with the Finite Element Method. Finally, we then modeled channelrhodopsin-2 in a single and spontaneous-firing neuron to explore the effect of heat in light stimulated neurons. We found that, at commonly used light intensities, laser radiation considerably increases the temperature in the surrounding tissue. This effect alters action potential size and shape and causes an increase in spontaneous firing frequency in a neuron model. However, the shortening of activation time constants generated by heat in the single firing neuron model produces action potential failures in response to light stimulation. We also found changes in the power spectrum density and a reduction in the time required for synchronization in an interneuron network model of gamma oscillations. Our findings indicate that light stimulation with intensities used in optogenetic experiments may affect neuronal function not only by direct excitation of light sensitive ion channels and/or pumps but also by generating heat. This approach serves as a guide to design optogenetic experiments that minimize the role of tissue heating in the experimental outcome.

Memristor reduces conduction failure of action potentials along axon with Hopf bifurcation

Memristor has been identified to modulate electronic activities of the nervous system, and conduction failure of action potentials along axon has been identified to play important roles in information transition related to pathological pain. In the present paper, the influences of the memristor on the conduction failure induced by the external stimulation with high frequency are investigated. After introducing electromagnetic induction mediated by memristor into Hodgkin-Hexley (HH) model, the Hopf bifurcation advances with increasing depolarization current, and the membrane potential of the resting state near the bifurcation increases. Such two changes mainly lead to the decrease of conduction failure rate of action potentials along axon which is described with a network model composed of HH neurons. Moreover, the reduction of conduction failure rate induced by memristor is well interpreted with the nonlinear dynamics near the bifurcation point, for example, the dynamics of the current threshold to evoke the second action potential from the after-potential following the first one. The results present that memristor can promote the conduction ability of action potentials along axon, which presents a novel function of memristor and contributes to the information transmission related to pathological pain in the nervous system.

Influence of Hopf Bifurcation Dynamics on Conduction Failure of Action Potentials Along Nerve C-Fiber

Contrary to faithful conduction of every action potential or spike along the axon, some spikes induced by the external stimulation with a high frequency at one end of the unmyelinated nerve fiber (C-fiber) disappear during the conduction process to the other end, which leads to conduction failure. Many physiological functions such as information coding or pathological pain are involved. In the present paper, the dynamic mechanism of the conduction failure is well interpreted by two characteristics of the focus near Hopf bifurcation of the Hodgkin–Huxley (HH) model. One is that the current threshold to evoke a spike from the after-potential corresponding to the focus exhibits damping oscillations, and the other is that the damping oscillations exhibit an internal period. A chain network model composed of HH neurons and stimulated by the external periodic stimulation is used to stimulate C-fiber. In the two-dimensional parameter space of the stimulation period and coupling strength, the conduction failure appears for the coupling strength lower than that of the faithful conduction, which is due to some maximal values of the coupling current for low coupling strength not being strong enough to evoke spikes, and the coupling strength threshold between the faithful conduction and conduction failure exhibiting damping oscillations with respect to the stimulation period, due to the damping oscillations of the current threshold. The damping oscillations of the coupling strength exhibit close correlations to those of the current threshold. The coupling strength for the conduction failure exhibits maximal values as the stimulation period is approximated to 1-, 2-, 3- or 4-times of the internal period and the maximal values decrease with increasing stimulation period. In addition, the correspondence between the simulation results and the previous experimental observations is discussed. The results present deep insights into the dynamics of the conduction failure with Hopf bifurcation and are helpful to investigate the influence of other modulation factors on the conduction failure.

Spike-Related Electrophysiological Identification of Cultured Hippocampal Excitatory and Inhibitory Neurons.

Cultured hippocampal neurons represent the most widely used experimental substrate for in vitro electrophysiological studies. Nevertheless, in most cases, the nature of neuron under study is not identified as excitatory or inhibitory, or even worse, recorded neurons are considered as excitatory because of the paucity of GABAergic interneurons. Thus, the definition of reliable criteria able to guarantee an unequivocal identification of excitatory and inhibitory cultured hippocampal neurons is an unmet need. To reach this goal, we compared the electrophysiological properties and the localization and size of the axon initial segment (AIS) of cultured hippocampal neurons, taking advantage from GAD67-GFP knock-in mice, which expressing green fluorescent protein (GFP) in gamma-aminobutyric acid (GABA)-containing cells, allowed to unambiguously determine the precise nature of the neuron under study. Our results demonstrate that the passive electrophysiological properties, the localization and size of the AIS, and the shape and frequency of the action potential (AP) are not reliable to unequivocally identify neurons as excitatory or inhibitory. The only parameter, related to the shape of the single AP, showing minimal overlap between the sample-point distributions of the two neuronal subpopulations, was the AP half-width. However, the estimation of the AP failure ratio evoked by a short train of high-current steps applied at increasing frequency (40-140Hz) resulted to be indisputably the safer and faster way to identify the excitatory or inhibitory nature of an unknown neuron. Our findings provide a precise framework for further electrophysiological investigations of in vitro hippocampal neurons.

Perfidious synaptic transmission in the guinea-pig auditory brainstem.

The presence of ‘giant’ synapses in the auditory brainstem is thought to be a specialization designed to encode temporal information to support perception of pitch, frequency, and sound-source localisation. These ‘giant’ synapses have been found in the ventral cochlear nucleus, the medial nucleus of the trapezoid body and the ventral nucleus of the lateral lemniscus. An interpretation of these synapses as simple relays has, however, been challenged by the observation in the gerbil that the action potential frequently fails in the ventral cochlear nucleus. Given the prominence of these synapses it is important to establish whether this phenomenon is unique to the gerbil or can be observed in other species. Here we examine the responses of units, thought to be the output of neurons in receipt of ‘giant’ synaptic endings, in the ventral cochlear nucleus and the medial nucleus of the trapezoid body in the guinea pig. We found that failure of the action-potential component, recorded from cells in the ventral cochlear nucleus, occurred in ~60% of spike waveforms when recording spontaneous activity. In the medial nucleus of the trapezoid body, we did not find evidence for action-potential failure. In the ventral cochlear nucleus action-potential failures transform the receptive field between input and output of bushy cells. Additionally, the action-potential failures result in “non-primary-like” temporal-adaptation patterns. This is important for computational models of the auditory system, which commonly assume the responses of ventral cochlear nucleus bushy cells are very similar to their “primary like” auditory-nerve-fibre inputs.

More of an SRO – FINRA unveils its priorities for 2018

PurposeTo explain FINRA’s priorities for 2018, as reflected in its Annual Regulatory and Examination Priorities Letter.Design/methodology/approachEvaluates the overall tone of FINRA’s letter as self-reflective, describes most of FINRA’s priorities for 2018 as unchanged from previous years, and highlights new areas of focus for FINRA.FindingsFINRA plans a number of organizational improvements over the next year which could facilitate positive dialogue between firms and FINRA examiners, helping to reduce the burden on broker-dealers and possibly avoid low-level enforcement action. FINRA expressed a desire to better leverage its model as a self-regulatory organization to achieve its mission. Most of FINRA’s priorities for 2018 are old standbys, including fraud, high-risk firms and brokers, cybersecurity and AML programs, product suitability vetting, and best execution surveillance. FINRA’s new areas of focus for 2018 include business continuity plans, technology governance, cryptoassets, options violations, new report cards, and new rules.Practical implicationsDespite FINRA leadership’s commitment to self-analysis and enhanced communication, FINRA continues to be highly committed to examining and addressing through enforcement action potential failures to comply with its rules. Firms facing FINRA or SEC examinations should brush up on FINRA’s old standby priorities and fine-tune their practices to ensure compliance with industry trends.Originality/valuePractical guidance from experienced securities and financial services lawyers that summarizes FINRA’s stated approach for 2018.