Membrane Potential Of Neurons Research Articles

A nonparametric test of group distributional differences for hierarchically clustered functional data.

Biological sex and gender are critical variables in biomedical research, but are complicated by the presence of sex-specific natural hormone cycles, such as the estrous cycle in female rodents, typically divided into phases. A common feature of these cycles are fluctuating hormone levels that induce sex differences in many behaviors controlled by the electrophysiology of neurons, such as neuronal membrane potential in response to electrical stimulus, typically summarized using a priori defined metrics. In this paper, we propose a method to test for differences in the electrophysiological properties across estrous cycle phase without first defining a metric of interest. We do this by modeling membrane potential data in the frequency domain as realizations of a bivariate process, also depending on the electrical stimulus, by adopting existing methods for longitudinal functional data. We are then able to extract the main features of the bivariate signals through a set of basis function coefficients. We use these coefficients for testing, adapting methods for multivariate data to account for an induced hierarchical structure that is a product of the experimental design. We illustrate the performance of the proposed approach in simulations and then apply the method to experimentaldata.

Mitochondria-Targeted Antioxidants, an Innovative Class of Antioxidant Compounds for Neurodegenerative Diseases: Perspectives and Limitations

Neurodegenerative diseases comprise a wide spectrum of pathologies characterized by progressive loss of neuronal functions and structures. Despite having different genetic backgrounds and etiology, in recent years, many studies have highlighted a point of convergence in the mechanisms leading to neurodegeneration: mitochondrial dysfunction and oxidative stress have been observed in different pathologies, and their detrimental effects on neurons contribute to the exacerbation of the pathological phenotype at various degrees. In this context, increasing relevance has been acquired by antioxidant therapies, with the purpose of restoring mitochondrial functions in order to revert the neuronal damage. However, conventional antioxidants were not able to specifically accumulate in diseased mitochondria, often eliciting harmful effects on the whole body. In the last decades, novel, precise, mitochondria-targeted antioxidant (MTA) compounds have been developed and studied, both in vitro and in vivo, to address the need to counter the oxidative stress in mitochondria and restore the energy supply and membrane potentials in neurons. In this review, we focus on the activity and therapeutic perspectives of MitoQ, SkQ1, MitoVitE and MitoTEMPO, the most studied compounds belonging to the class of MTA conjugated to lipophilic cations, in order to reach the mitochondrial compartment.

Elementary mechanisms underlying activation of leak sodium channels.

The sodium-leak channel (NALCN) are weakly voltage-dependent ion channels responsible for background Na+ permeability that controls resting membrane potential in neurons and other excitable cells. Although homologous to voltage-gated Na+ and Ca2+ channels, NALCN is distinct in associating with auxiliary subunits FAM155A, UNC-79, and UNC-80 which augment its function. Precise regulation of this channel's activity is physiologically crucial, as gain of function mutations in humans lead to severe congenital neurodevelopmental disorders in humans, including infantile hypotonia with psychomotor retardation and characteristic facies 1 (IHPRF1) and congenital contractures of limbs and face, hypotonia and developmental delay (CLIFAHDD). Here we performed cell-attached low noise single-channel recordings to dissect elementary properties of NALCN gating. Expression of NALCN with its canonical subunits revealed a largely non-selective channel with ∼27 pS conductance and a reversal potential of ∼5.7 mV. Scrutiny of single channel recordings showed distinct gating modes and low open probabilities. As extracellular Ca2+ block of NALCN is fundamental to its physiological function, we further probed underlying single channel mechanisms. In all, these results provide a framework to establish regulatory mechanisms in physiology and to contextualize altered channel function in pathophysiology.

The sodium leak complex and friends: Identifying protein partners of the NALCN channelosome.

The resting membrane potential (RMP) of neurons and other excitable cells is a fundamental property which underpins all electrical signalling in the body. The predominant depolarising influence on the RMP in neurons is mediated by the Na+ leak channel (NALCN), which requires at least three accessory proteins (UNC79, UNC80, and FAM155A) to form a functional channelosome. Knocking out either NALCN or UNC79 in mice leads to neonatal death, and genetic variation NALCN or UNC80 in human patients leads to severe disease phenotypes including pronounced neurological and developmental defects.

Multi-objective optimization method for coil current waveform of transcranial magnetic stimulation

Transcranial magnetic stimulation (TMS) has been proved to be effective in the treatment of many kinds of mental diseases. However, the clicking noise produced by the pulse current with large amplitude and short duration in the TMS coil may damage the hearing of patients. The heat produced by the high-frequency pulse current in the coil also reduces the efficiency of TMS equipment. A multi-objective waveform optimization method to improve heat and noise problems at the same time is presented. By analyzing the current waveforms of TMS, the relationship between the current and the vibration energy/Joule heating is established. Taking the Joule heating and the vibration energy as the optimization objectives, exceeding the same amount of neuronal membrane potential as the limiting condition, the Pareto fronts of different current models are obtained by applying the multi-objective particle swarm optimization algorithm (MOPSO). Therefore, the corresponding current waveforms are inversely deduced. A ringing suppression cTMS (RS-cTMS) proof-of-principle experimental platform is constructed. The feasibility of the proposed method is validated through experiments. The results show that the optimized current waveforms can greatly reduce the vibration and heating of the coil compared with the conventional full-sine, recified sine and half-sine waveforms, thus reducing the pulse noise and prolonging the using time of the equipment. The optimized diversified waveforms also provide a reference for the diversity of TMS.

Abstract TP92: Early Hyperacute Ion Dysregulation Following A Temporary Large Vessel Occlusion Stroke

Introduction: Ion dysregulation is a hallmark of energy failure after onset of ischemic stroke. To better understand the nature of the ion concentration changes in the early hyperacute phase after stroke onset we have quantitatively imaged the trace element distribution in the stroke lesion territory after a 30-minute temporary large vessel occlusion stroke. Methods: A temporary large vessel occlusion stroke was generated with the middle cerebral artery occlusion (MCAO) mouse model (insertion of an occluding filament via the ECA) with reperfusion after 30 minutes (occluding filament withdrawn). C57BL/6 mice (5 per time point) were euthanized at 5-, 30-, 60-, 90-, and 120-minutes post reperfusion. Shams included all surgical procedures, however the occluding filament was withdrawn immediately after insertion. Heads were immediately frozen post mortem and sectioned for trace element mapping. Quantitative X-ray fluorescence microscopy was performed at the Stanford Synchrotron Radiation Lightsource. Results: Loss of potassium is observed throughout the affected tissue at all post-reperfusion time points, with most of the initial loss occurring in the 30-minutes prior to reperfusion. Loss of essential zinc began to be observed 1-hour post reperfusion. No significant elevations in chlorine or calcium were observed during the early hyperacute phase. At subsequent post reperfusion time points the lesion (as defined by diminished potassium) grew steadily for 90-minutes. After 90-minutes post reperfusion some lesions demonstrated a distinct pattern consistent with a central infarct core surrounded by an ischemic penumbra. Conclusions: At all early hyperacute time points the stroke lesion demonstrated on-going potassium dysregulation, despite reperfusion. The loss of potassium was a bulk phenomenon in the tissue. Potassium is essential for maintenance of neuronal membrane potential and therefore function. Restoration of normal blood flow is insufficient to protect the brain from the enduring reduction in vital potassium levels or expansion of the region of ion dysregulation. The lack of available potassium within the affected tissue may hinder recovering neuronal cells from restoring action potentials, even after tissue perfusion is restored.

Seeing beyond the spikes: reconstructing the complete spatiotemporal membrane potential distribution from paired intra- and extracellular recordings.

Although electrophysiologists have been recording intracellular neural activity routinely ever since the ground-breaking work of Hodgkin and Huxley, and extracellular multichannel electrodes have also been used frequently and extensively, a practical experimental method to track changes in membrane potential along a complete single neuron is still lacking. Instead of obtaining multiple intracellular measurements on the same neuron, we propose an alternative method by combining single-channel somatic patch-clamp and multichannel extracellular potential recordings. In this work, we show that it is possible to reconstruct the complete spatiotemporal distribution of the membrane potential of a single neuron with the spatial resolution of an extracellular probe during action potential generation. Moreover, the reconstruction of the membrane potential allows us to distinguish between the two major but previously hidden components of the current source density (CSD) distribution: the resistive and the capacitive currents. This distinction provides a clue to the clear interpretation of the CSD analysis, because the resistive component corresponds to transmembrane ionic currents (all the synaptic, voltage-sensitive and passive currents), whereas capacitive currents are considered to be the main contributors of counter-currents. We validate our model-based reconstruction approach on simulations and demonstrate its application to experimental data obtained in vitro via paired extracellular and intracellular recordings from a single pyramidal cell of the rat hippocampus. In perspective, the estimation of the spatial distribution of resistive membrane currents makes it possible to distiguish between active and passive sinks and sources of the CSD map and the localization of the synaptic input currents, which make the neuron fire. KEY POINTS: A new computational method is introduced to calculate the unbiased current source density distribution on a single neuron with known morphology. The relationship between extracellular and intracellular electric potential is determined via mathematical formalism, and a new reconstruction method is applied to reveal the full spatiotemporal distribution of the membrane potential and the resistive and capacitive current components. The new reconstruction method was validated on simulations. Simultaneous and colocalized whole-cell patch-clamp and multichannel silicon probe recordings were performed from the same pyramidal neuron in the rat hippocampal CA1 region, in vitro. The method was applied in experimental measurements and returned precise and distinctive characteristics of various intracellular phenomena, such as action potential generation, signal back-propagation and the initial dendritic depolarization preceding the somatic action potential.

Visual Cortical Neurons Depolarize after Hippocampal Ripples

Objective: When memory is consolidated, the hippocampus emits brief high-frequency oscillations called ripples, which often occur simultaneously with slow waves in the neocortex. Long-term visual memory consolidation requires neuronal coordination between the hippocampus and the primary visual cortex (V1). However, little is known about the dynamics of the membrane potentials of neocortical neurons during hippocampal ripples. The aim of this study is to reveal the subthreshold activity in individual V1 neurons during hippocampal ripples. Methods: We patch-clamped V1 layer 2/3 pyramidal cells and monitored their membrane potentials while also recording local field potentials from the hippocampal CA1 region in anesthetized mice. Results: Approximately 20% of V1 neurons were transiently depolarized 18–45 ms after the onset of ripples that occurred in neocortical UP states. The depolarization magnitudes were not correlated with the durations, frequencies, or powers of ripples. Conclusions: Hippocampal ripples are associated with the subthreshold dynamics of V1 neurons, despite the lack of direct synaptic connections between the hippocampus and the V1.

Scaling Limit of a Generalized Contact Process

We derive macroscopic equations for a generalized contact process that is inspired by a neuronal integrate and fire model on the lattice $$\mathbb {Z}^d$$ . The states at each lattice site can take values in $$0,\ldots ,k$$ . These can be interpreted as neuronal membrane potential, with the state k corresponding to a firing threshold. In the terminology of the contact processes, which we shall use in this paper, the state k corresponds to the individual being infectious (all other states are noninfectious). In order to reach the firing threshold, or to become infectious, the site must progress sequentially from 0 to k. The rate at which it climbs is determined by other neurons at state k, coupled to it through a Kac-type potential, of range $$\gamma ^{-1}$$ . The hydrodynamic equations are obtained in the limit $$\gamma \rightarrow 0$$ . Extensions of the microscopic model to include excitatory and inhibitory neuron types, as well as other biophysical mechanisms, are also considered.

Ion gradient-driven bifurcations of a multi-scale neuronal model

Metabolic limitations within the brain frequently arise in the context of aging and disease. As the largest consumers of energy within the brain, ion pumps that maintain the neuronal membrane potential are the most affected when energy supply becomes limited. To characterize the effects of such limitations, we analyze the ion gradients present in a conductance-based (Morris–Lecar) neural mass model. We show the existence and locations of Neimark–Sacker and period-doubling bifurcations in the sodium, calcium, and potassium reversal potentials and demonstrate that these bifurcations form physiologically relevant bounds of ion gradient variability. Within these bounds, we show how depolarization of the gradients causes decreased neural activity. We also show that the depolarization of ion gradients decreases inter-regional coherence, causing a shift in the critical point at which the coupling occurs and thereby inducing loss of synchrony between regions. In this way, we show that the Larter-Breakspear model captures ion gradient variability present at the microscale level and propagates these changes to the macroscale effects such as those observed in human neuroimaging studies.

A dual-mode neurostimulation approach to enhance athletic performance outcome in experienced taekwondo practitioners

Transcranial Direct Current Stimulation (tDCS) is a growing empirical approach to improve athletic performance. Some recent studies have investigated the effects of transcutaneous spinal direct current stimulation (tsDCS) on the motor performance such as reaction time. TDCS and tsDCS can lead to alteration of the spontaneous neural activity, and the membrane potentials of motor neurons in cerebral cortex and spinal interneurons, respectively. Given the paucity of experimental studies on the non-invasive brain stimulation in the field of sports neuroscience, especially martial sports, the present study aimed at investigating the effects of neurostimulation in potentiating the motor and cognitive functions in experienced taekwondo practitioners. The study sample included 15 experienced male taekwondo players who received real or sham direct current stimulation on the primary motor cortex (M1) and the lumbar spinal segment (T12-L2) over two sessions, 72 h apart. Next, the performance of the participants was evaluated through a simulation of taekwondo exercise directly after the sham and real sessions. Moreover, a cognitive platform (CBS: Cambridge Brain Science) was used to investigate the participants’ cognitive profile in each instance. Unlike sham stimulation, real tDCS was associated with improved selective attention and reaction time in both in the simulated task performance and cognitive examination. The concurrent cortical and trans-spinal tDCS was found to improve selective attention (31% performance improvement) (P < 0.0001) [EFFECT SIZE; 1.84]. and reduce reaction time (4.7% performance improvement) (P < 0.0001) [EFFECT SIZE; 0.02]. Meanwhile, the intervention failed to leave a significant change in cognitive functions evaluated through CBS (P > 0.05). As informed by our results, the present dual-mode neurostimulation could improve motor functions potentially through the effect of tsDCS over the spinal interneurons and tDCS over the primary motor cortex. Likewise, our findings suggested an improved performance in simulated taekwondo task after real- but not sham-stimulation. This study paves the way for designing neurostimulation protocols to improve the performance of professional athletes, namely martial art practitioners, including their accuracy and velocity of reactions. Such positive effects of neuostimulation in athletic performance as demonstrated in this research and similar reports are expected to enhance the athletes’ success in professional competitions.

О патогенезе эпилептических приступов (обзор)

The review shows the statistics about the epilepsy morbidity in different countries, including Russia and its individual regions. We discuss various mechanisms of development of epileptic hyperexcitability of brain neurons. We summarize the knowledge about the role of ion imbalance, transmitters, neurochemical disorders in the epileptic activity development, both acquired and hereditary, including the significance of molecular genetic alterations, namely mutations and epigenetic mechanisms that together cause pathological changes in the membrane potential of brain neurons. The article highlights the causes and mechanisms of development of membrane channelopathy and transmembrane ion transport disorders, which underlie changes in the electrophysiological properties of neurons. The article provides information from Russian and foreign literature about the significance of immunological and cytokine shifts in the pathogenesis of epileptic hyperexcitability of neurons in different parts of the brain.

Metastability in a Stochastic System of Spiking Neurons with Leakage

We consider a finite system of interacting point processes with memory of variable length modeling a finite but large network of spiking neurons with two different leakage mechanisms. Associated to each neuron there are two point processes, describing its successive spiking and leakage times. For each neuron, the rate of the spiking point process is an exponential function of its membrane potential, with the restriction that the rate takes the value 0 when the membrane potential is 0. At each spiking time, the membrane potential of the neuron resets to 0, and simultaneously, the membrane potentials of the other neurons increase by one unit. The leakage can be modeled in two different ways. In the first way, at each occurrence time of the leakage point process associated to a neuron, the membrane potential of that neuron is reset to 0, with no effect on the other neurons. In the second way, if the membrane potential of the neuron is strictly positive, at each occurrence time of the leakage point process associated to that neuron, its membrane potential decreases by one unit, with no effect on the other neurons. In both cases, the leakage point process of the neurons has constant rate. For both models, we prove that the system has a metastable behavior as the population size diverges. This means that the time at which the system gets trapped by the list of null membrane potentials suitably re-scaled converges to a mean one exponential random time.

A Configurable Spiking Convolution Architecture Supporting Multiple Coding Schemes on FPGA

In this brief, an event-driven spiking convolution architecture with multi-kernel and multi-layer capability is designed. The proposed architecture can be configured in multiple-spike (MS) mode or single-spike (SS) mode to adapt to different spiking convolution neural network (SCNN) models with either rate coding scheme or temporal coding scheme. A skipped zero kernel step is designed to reduce access neuron membrane potentials in memories. In addition, the proposed design supports two pooling methods for increasing flexibility. The proposed architecture is implemented in a Xilinx Kintex-7 FPGA development board, and two SCNN models with different coding schemes are applied to verify the efficiency of the architecture. For the first SCNN model with rate coding scheme, the proposed architecture achieves a 99% classification accuracy with 0.46 mJ/classification. For the second SCNN model with temporal coding scheme, the proposed architecture obtains a classification accuracy over 95.4% with 7.4 uJ/classification. Experimental results demonstrate that the proposed design is adaptable and has a low power consumption overhead.

Insights and Future Directions on the Combined Effects of Mind-Body Therapies with Transcranial Direct Current Stimulation: An Evidence-based Review.

Mind-body therapies (MBTs) use mental abilities to modify electrical neural activity across brain networks. Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that modulates neuronal membrane potentials to enhance neuroplasticity. A combination of these treatment strategies may generate synergistic or additive effects, and thus has been more commonly tested in clinical trials, fostering a novel yet promising field of research. We conducted a literature search in four different databases including only randomized clinical trials (RCTs) that tested the combination of MBTs with tDCS. Ten studies (n=461) were included. Combined protocols included meditation/mindfulness (8/10), biofeedback (1/10), and hypnosis (1/10). The RCTs were heterogeneous with regards to population, design, and types of outcomes. Based on the findings of this search, we provide here a content description, methodological and practical insights, and future directions for the field. We hope this review will provide future authors with information to facilitate the development of trials with improved protocols.

Electrophysiological and computational analysis of Cav3.2 channel variants associated with familial trigeminal neuralgia

Trigeminal neuralgia (TN) is a rare form of chronic neuropathic pain characterized by spontaneous or elicited paroxysms of electric shock-like or stabbing pain in a region of the face. While most cases occur in a sporadic manner and are accompanied by intracranial vascular compression of the trigeminal nerve root, alteration of ion channels has emerged as a potential exacerbating factor. Recently, whole exome sequencing analysis of familial TN patients identified 19 rare variants in the gene CACNA1H encoding for Cav3.2T-type calcium channels. An initial analysis of 4 of these variants pointed to a pathogenic role. In this study, we assessed the electrophysiological properties of 13 additional TN-associated Cav3.2 variants expressed in tsA-201 cells. Our data indicate that 6 out of the 13 variants analyzed display alteration of their gating properties as evidenced by a hyperpolarizing shift of their voltage dependence of activation and/or inactivation resulting in an enhanced window current supported by Cav3.2 channels. An additional variant enhanced the recovery from inactivation. Simulation of neuronal electrical membrane potential using a computational model of reticular thalamic neuron suggests that TN-associated Cav3.2 variants could enhance neuronal excitability. Altogether, the present study adds to the notion that ion channel polymorphisms could contribute to the etiology of some cases of TN and further support a role for Cav3.2 channels.

Closed-form modeling of neuronal spike train statistics using multivariate Hawkes cumulants.

We derive exact analytical expressions for the cumulants of any orders of neuronal membrane potentials driven by spike trains in a multivariate Hawkes process model with excitation and inhibition. Such expressions can be used for the prediction and sensitivity analysis of the statistical behavior of the model over time and to estimate the probability densities of neuronal membrane potentials using Gram-Charlier expansions. Our results are shown to provide a better alternative to Monte Carlo estimates via stochastic simulations and computer codes based on combinatorial recursions are included.

Efficient Hardware Acceleration of Sparsely Active Convolutional Spiking Neural Networks

Spiking neural networks (SNNs) compute in an event-based manner to achieve a more efficient computation than standard neural networks. In SNNs, neuronal outputs are not encoded as real-valued activations but as sequences of binary spikes. The motivation of using SNNs over conventional neural networks is rooted in the special computational aspects of spike-based processing, especially the high degree of sparsity of spikes. Well-established implementations of convolutional neural networks (CNNs) feature large spatial arrays of processing elements (PEs) that remain highly underutilized in the face of activation sparsity. We propose a novel architecture optimized for the processing of convolutional SNNs (CSNNs) featuring a high degree of sparsity. The proposed architecture consists of an array of PEs of the size of the kernel of a convolution and an intelligent spike queue that provides a high PE utilization. A constant flow of spikes is ensured by compressing the feature maps into queues that can then be processed spike-by-spike. This compression is performed at run-time, leading to a self-timed schedule. This allows the processing time to scale with the number of spikes. Also, a novel memory organization scheme is introduced to efficiently store and retrieve the membrane potentials of the individual neurons using multiple small parallel on-chip RAMs. Each RAM is hardwired to its PE, reducing switching circuitry. We implemented the proposed architecture on an FPGA and achieved a significant speedup compared to previously proposed SNN implementations (~10 times) while needing less hardware resources and maintaining a higher energy efficiency (~15 times).

Size-Based Effects of Anthropogenic Ultrafine Particles on Lysosomal TRPML1 Channel and Autophagy in Motoneuron-like Cells.

An emerging body of evidence indicates an association between anthropogenic particulate matter (PM) and neurodegeneration. Although the historical focus of PM toxicity has been on the cardiopulmonary system, ultrafine PM particles can also exert detrimental effects in the brain. However, only a few studies are available on the harmful interaction between PM and CNS and on the putative pathomechanisms. Ultrafine PM particles with a diameter &lt; 0.1 μm (PM0.1) and nanoparticles &lt; 20 nm (NP20) were sampled in a lab-scale combustion system. Their effect on cell tracking in the space was studied by time-lapse and high-content microscopy in NSC-34 motor neurons while pHrodo™ Green conjugates were used to detect PM endocytosis. Western blotting analysis was used to quantify protein expression of lysosomal channels (i.e., TRPML1 and TPC2) and autophagy markers. Current-clamp electrophysiology and Fura2-video imaging techniques were used to measure membrane potential, intracellular Ca2+ homeostasis and TRPML1 activity in NSC-34 cells exposed to PM0.1 and NP20. NP20, but not PM0.1, reduced NSC-34 motor neuron movement in the space. Furthermore, NP20 was able to shift membrane potential of motor neurons toward more depolarizing values. PM0.1 and NP20 were able to enter into the cells by endocytosis and exerted mitochondrial toxicity with the consequent stimulation of ROS production. This latter event was sufficient to determine the hyperactivation of the lysosomal channel TRPML1. Consequently, both LC3-II and p62 protein expression increased after 48 h of exposure together with AMPK activation, suggesting an engulfment of autophagy. The antioxidant molecule Trolox restored TRPML1 function and autophagy. Restoring TRPML1 function by an antioxidant agent may be considered a protective mechanism able to reestablish autophagy flux in motor neurons exposed to nanoparticles.

Scale free avalanches in excitatory-inhibitory populations of spiking neurons with conductance based synaptic currents

We investigate spontaneous critical dynamics of excitatory and inhibitory (EI) sparsely connected populations of spiking leaky integrate-and-fire neurons with conductance-based synapses. We use a bottom-up approach to derive a single neuron gain function and a linear Poisson neuron approximation which we use to study mean-field dynamics of the EI population and its bifurcations. In the low firing rate regime, the quiescent state loses stability due to saddle-node or Hopf bifurcations. In particular, at the Bogdanov-Takens (BT) bifurcation point which is the intersection of the Hopf bifurcation and the saddle-node bifurcation lines of the 2D dynamical system, the network shows avalanche dynamics with power-law avalanche size and duration distributions. This matches the characteristics of low firing spontaneous activity in the cortex. By linearizing gain functions and excitatory and inhibitory nullclines, we can approximate the location of the BT bifurcation point. This point in the control parameter phase space corresponds to the internal balance of excitation and inhibition and a slight excess of external excitatory input to the excitatory population. Due to the tight balance of average excitation and inhibition currents, the firing of the individual cells is fluctuation-driven. Around the BT point, the spiking of neurons is a Poisson process and the population average membrane potential of neurons is approximately at the middle of the operating interval [V_{Rest}, V_{th}]. Moreover, the EI network is close to both oscillatory and active-inactive phase transition regimes.